U.S. patent application number 17/700804 was filed with the patent office on 2022-07-21 for treatment of aging-associated disease with modulators of leukotriene a4 hydrolase.
The applicant listed for this patent is Alkahest, Inc.. Invention is credited to Meghan Kerrisk Campbell, Eva Czirr, Balazs Szoke.
Application Number | 20220226304 17/700804 |
Document ID | / |
Family ID | 1000006226651 |
Filed Date | 2022-07-21 |
United States Patent
Application |
20220226304 |
Kind Code |
A1 |
Campbell; Meghan Kerrisk ;
et al. |
July 21, 2022 |
Treatment of Aging-Associated Disease with Modulators of
Leukotriene A4 Hydrolase
Abstract
Methods and compositions for treating and/or preventing
aging-related conditions are described. The compositions used in
the methods include inhibitors or antagonists of leukotriene A4
hydrolase ("LTA4H") with efficacy in treating and/or preventing
aging-related conditions such as neurocognitive disorders.
Inventors: |
Campbell; Meghan Kerrisk;
(San Francisco, CA) ; Czirr; Eva; (Foster City,
CA) ; Szoke; Balazs; (San Carlos, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Alkahest, Inc. |
San Carlos |
CA |
US |
|
|
Family ID: |
1000006226651 |
Appl. No.: |
17/700804 |
Filed: |
March 22, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16412275 |
May 14, 2019 |
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17700804 |
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62694921 |
Jul 6, 2018 |
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62671882 |
May 15, 2018 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/085 20130101;
A61K 31/197 20130101; C07K 16/40 20130101; C07K 2317/76 20130101;
A61P 25/28 20180101; A61K 31/353 20130101; A61K 31/47 20130101 |
International
Class: |
A61K 31/47 20060101
A61K031/47; A61K 31/197 20060101 A61K031/197; A61K 31/085 20060101
A61K031/085; C07K 16/40 20060101 C07K016/40; A61P 25/28 20060101
A61P025/28; A61K 31/353 20060101 A61K031/353 |
Claims
1. A method of improving cognitive function in a subject diagnosed
with a dementia disorder, the method comprising administering a
therapeutically effective amount of an LTA4H modulatory agent.
2. The method of claim 1 wherein the dementia disorder is selected
from the group consisting of vascular dementia and dementia with
Lewy bodies.
3. The method of claim 1 wherein the LTA4H modulatory agent is a
small organic molecule antagonist to LTA4H.
4. The method of claim 1 wherein the LTA4H modulatory agent is an
antibody to LTA4H.
5. The method of claim 3 wherein the antagonist to LTA4H
antagonizes the epoxide hydrolase activity of LTA4H.
6. The method of claim 3 wherein the antagonist to LTA4H
antagonizes both the epoxide hydrolase activity and the
aminopeptidase activity of LTA4H.
7. The method of claim 1 wherein the subject is a mammal.
8. The method of claim 7 wherein the mammal is a human.
9. A kit for use in improving cognitive function in a subject
diagnosed with an age-related cognitive disease, the kit comprising
an LTA4H modulatory agent.
10. The kit of claim 9 wherein the LTA4H modulatory agent is a
small organic molecule antagonist to LTA4H.
11. The kit of claim 9 wherein the LTA4H modulatory agent is an
antibody to LTA4H.
12. The kit of claim 11 wherein the antagonist to LTA4H antagonizes
the epoxide hydrolase activity of LTA4H.
13. The kit of claim 12 wherein the antagonist to LTA4H antagonizes
both the epoxide hydrolase activity and the aminopeptidase activity
of LTA4H.
14. The method of claim 1 wherein the dementia disorder is vascular
dementia.
15. The method of claim 1 wherein the dementia disorder is dementia
with Lewy bodies.
Description
I. CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] Pursuant to 35 U.S.C. .sctn. 119 (e), this application
claims priority to the filing dates of: U.S. Provisional Patent
Application No. 62/671,882, filed May 15, 2018 and U.S. Provisional
Patent Application No. 62/694,921, filed Jul. 6, 2018; the
disclosures of which applications are herein incorporated by
reference.
II. INTRODUCTION
[0002] This invention pertains to the prevention and treatment of
aging-associated disease. The invention relates to the use of
modulators of leukotriene A4 hydrolase ("LTA4H"), to treat and/or
prevent conditions associated with aging, such as cognitive
disorders, motor disorders, and neuroinflammation.
BACKGROUND
[0003] The following is offered as background information only and
is not admitted as prior art to the present invention.
[0004] Aging is an important risk factor for multiple human
diseases including cognitive impairment, cancer, arthritis, vision
loss, osteoporosis, diabetes, cardiovascular disease, and stroke.
In addition to normal synapse loss during natural aging, synapse
loss is an early pathological event common to many
neurodegenerative conditions and is the best correlate to the
neuronal and cognitive impairment associated with these conditions.
As such, aging remains the single most dominant risk factor for
dementia-related neurodegenerative diseases such as Alzheimer's
disease (AD) (Bishop N. A. et al., Neural mechanisms of ageing and
cognitive decline. Nature 464(7288), 529-535 (2010); Heeden T. et
al., Insights into the ageing mind: a view from cognitive
neuroscience. Nat. Rev. Neurosci. 5(2), 87-96 (2004); Mattson, M.
P., et al., Ageing and neuronal vulnerability. Nat. Rev. Neurosci.
7(4), 278-294 (2006)). Similarly, a decline in motor skills
correlates with aging. (Hoogendam Y Y, et al., Older Age Relates to
Worsening of Fine Motor Skills: A Population-Based Study of
Middle-Aged and Elderly Persons, Front. Aging Neurosci. 6 (2014)).
Additionally, neuroinflammation has been associated with aging in
both healthy brains and in diseased brains such as in AD. (Lynch M
A, Age-related neuroinflammatory changes negatively impact on
neuronal function. Front. Aging Neurosci. 1(6), 1-8 (2010)). Aging
affects all tissues and functions of the body including the central
nervous system, and neurodegeneration and a decline in functions
such as cognition or motor skills, can severely impact quality of
life. Treatment for cognitive decline, motor impairment,
neuroinflammation, and neurodegenerative disorders has had limited
success in preventing and reversing impairment. It is therefore
important to identify new treatments for maintaining cognitive and
motor integrity by protecting against, countering, or reversing the
effects of aging.
[0005] Leukotriene A.sub.4 hydrolase ("LTA.sub.4H" or "LTA4H") is a
soluble, monomeric enzyme that converts lipid metabolite
leukotriene A.sub.4 ("LTA.sub.4" or "LTA4") to leukotriene B.sub.4
("LTB.sub.4" or "LTB4"). The LTA.sub.4H enzyme through its ability
to produce the LTB4 lipid metabolite has been characterized as
pro-inflammatory. Additionally, LTB4 lipid metabolite is associated
with neutrophil recruitment. Thus, the LTA4H enzyme has been
implicated in such diseases as atherosclerosis, atherosclerotic
coronary artery disease, rheumatoid arthritis, cystic fibrosis,
chronic obstructive pulmonary disease, sepsis, adult respiratory
distress syndrome, inflammatory bowel disease, and asthma.
(Snelgrove R J, Leukotriene A4 Hydrolase: An Anti-Inflammatory Role
for A Proinflammatory Enzyme, Thorax 66:550-51 (2011); Shim Y M, et
al., Leukotriene A4 Hydrolase--An Evolving Therapeutic Target,
Inflammatory Diseases--Immunopathology, Clinical and
Pharmacological Bases (Dr. Mahin Khatami (Ed.)), 253-278,
(2012)).
[0006] The LTA4H enzyme has recently been characterized as having
an additional catalytic activity. LTA4H not only exhibits the
epoxide hydrolase activity converting LTA4 to LTB4, but an
additional aminopeptidase activity (or "peptidase" activity),
cleaving Pro-Gly-Pro peptides (P-G-P) to Pro+Gly-Pro. This
aminopeptidase activity is thought to contribute an
anti-inflammatory role for LTA4H by reducing accumulation of P-G-P.
(Snelgrove, et al. A critical role for LTA4H in limiting chronic
pulmonary neutrophilic inflammation, Science 330(6000):90-4
(2010)). This discovery may provide insights into the clinical
failures of LTA4H inhibitors within inflammatory diseases.
Modulators of the LTA4H enzyme have been described, including small
molecule inhibitors. These include small molecules that: bind both
the epoxide hydrolase pocket and the aminopeptidase active site,
such as SC-57461A; and selectively bind the epoxide hydrolase
binding pocket of LTA4H, such as pinostilbene hydrate (Low C M et
al., The development of novel LTA4H modulators to selectively
target LTB4 generation. Sci. Rep. 7, 44449 (2017)).
[0007] The second class of Leukotrienes ("LTs") are the cysteinyl
leukotrienes (Cys-LT), LTC4, LTD4, and LTE4, which are ligands for
the cysteinyl leukotriene receptors type 1 and 2 (CysLT1R,
CysLT2R), GPR17, and others. (Ghosh, A., et al., Cysteinyl
Leukotrienes and Their Receptors: Emerging Therapeutic Targets in
Central Nervous System Disorders. CNS Neurosci Ther, 22(12): p.
943-51 (2016)). LTs in general have been associated with
inflammation and studied for their role in diseases such as asthma.
(Y. Michael Shim, M. P., Leukotriene A4 Hydrolase--An Evolving
Therapeutic Target in Inflammatory Diseases--Immunopathology,
Clinical and Pharmacological Bases, M. Khatami, Editor. InTech. p.
253-78 (2012)). More recently, Cys-LTs have been shown to influence
central nervous system diseases including traumatic brain injury,
Alzheimer's disease (AD), Parkinson's disease, multiple sclerosis,
epilepsy, Huntington's disease, and depression. (Ghosh A, supra).
For example, LTD4 and CysLT1R are increased in transgenic mouse
models of AD and administration of CysLT1R antagonists, Pranlukast
and Montelukast, alleviate some of the pathological symptoms in
these mice. (Tang, S. S., et al., Protective effect of pranlukast
on Abeta(1)(-)(4)(2)-induced cognitive deficits associated with
downregulation of cysteinyl leukotriene receptor 1. Int J
Neuropsychopharmacol, 17(4): p. 581-92 (2014); Tang, S. S., et al.,
Leukotriene D4 induces cognitive impairment through enhancement of
CysLT(1) R-mediated amyloid-beta generation in mice.
Neuropharmacology, 65: p. 182-92 (2013); Wang, X. Y., et al.,
Leukotriene D4 induces amyloid-beta generation via
CysLT(I)R-mediated NF-kappaB pathways in primary neurons. Neurochem
Int, 62(3): p. 340-47 (2013); and Herbst-Robinson, K J., et al.,
Inflammatory Eicosanoids Increase Amyloid Precursor Protein
Expression via Activation of Multiple Neuronal Receptors. Sci Rep,
5: p. 18286 (2015)), Additionally, administration of Montelukast in
aged mice reduces brain inflammation, increases neurogenesis, and
improves cognition. (Marschallinger, J., et al., Structural and
functional rejuvenation of the aged brain by an approved
anti-asthmatic drug. Nat Commun, 6: p. 8466 (2015)). While the
Cys-LTs have been shown to influence the CNS, the production of
LTB4 by LTA4H has not be implicated in cognition or diseases of the
CNS.
III. SUMMARY
[0008] The present invention recognizes that as people age, the
amounts of certain plasma proteins also increase. The present
invention recognizes that such proteins can be referred to as
"pro-aging factors," and modulation of their activity or
concentration in the blood circulation can protect or even reverse
certain aging-related symptoms and/or disease. The present
invention is also based on work demonstrating that the LTA4H enzyme
and its product LTB4 occur at higher concentrations in older
subjects than in younger subjects. The present invention shows that
the introduction of exogenous LTA4H enzyme in vivo results in a
reduction of cognitive ability, neuronal cell survival, and
proliferation of neural stem/progenitor cells in young animals. The
present also demonstrates, among other things, that modulation of
the LTA4H enzyme through pharmacological intervention in vivo leads
to an improvement in cognition and reduction in inflammatory
markers in aged animals. The present invention also recognizes that
modulation of the LTA4H enzyme through pharmacological intervention
may cause a reduction in the progression or reverse certain
aging-associated symptoms or disease.
[0009] The present invention is based on targeting the LTA4H enzyme
for treating and/or preventing age-related disorders, such as
cognitive impairment conditions, age-related dementia, impairment
of motor function, neuroinflammation, and neurodegenerative
disease. The present invention recognizes, among other things, the
need for new therapies and new mechanisms of action for the
treatment and/or prevention of cognitive impairment, age-related
dementia, motor impairment, neuroinflammation, and
neurodegenerative disease. The present compositions of the
invention relate to a solution for the failures and shortcomings of
current therapies through utilization of inhibitors of the LTA4H
enzyme in the treatment and/or prevention of cognitive impairment,
age-related dementia, motor impairment, neuroinflammation, and
neurodegenerative disease.
[0010] An embodiment of the invention includes treating a subject
diagnosed with a cognitive impairment by administering to the
subject an effective amount of one or more LTA4H modulatory agents.
Another embodiment of the invention includes administering the
effective amount of one or more LTA4H modulatory agents and
subsequently monitoring the subject for improved cognitive
function. Another embodiment of the invention includes treating a
subject diagnosed with a cognitive impairment by administering to
the subject an effective amount of one or more LTA4H modulatory
agents wherein the one or more LTA4H modulatory agents are
administered in a manner resulting in improved cognitive function,
improved neurogenesis, or reduced neuroinflammation.
[0011] An embodiment of the invention includes treating a subject
diagnosed with a neurodegenerative motor disorder such as, by way
of example and not limitation, Parkinson's Disease, by
administering to the subject an effective amount of one or more
LTA4H modulatory agents. Another embodiment of the invention
includes administering the effective amount of one or more LTA4H
modulatory agents and subsequently monitoring the subject for
improved motor function. Another embodiment of the invention
includes treating a subject diagnosed with a neurodegenerative
motor disorder by administering to the subject an effective amount
of one or more LTA4H modulatory agents wherein the one or more
LTA4H modulatory agents are administered in a manner resulting in
improved motor function, neurogenesis, or reduced
neuroinflammation.
[0012] An embodiment of the invention includes treating a subject
diagnosed with neuroinflammation or a neuroinflammation-associated
disorder by administering to the subject an effective amount of one
or more LTA4H modulatory agents. Another embodiment of the
invention includes administering the effective amount of one or
more LTA4H modulatory agents and subsequently monitoring the
subject for reduced neuroinflammation. Another embodiment of the
invention includes treating a subject diagnosed with
neuroinflammation or a neuroinflammation-associated disorder by
administering to the subject an effective amount of one or more
LTA4H modulatory agents wherein the one or more LTA4H modulatory
agents are administered in a manner resulting in reduced
neuroinflammation.
[0013] Another embodiment of the invention includes utilizing an
inhibitor of the LTA4H enzyme as the one or more LTA4H modulatory
agent(s). Further embodiments contemplate using one or more LTA4H
modulatory agent(s) that selectively inhibits the epoxide hydrolase
activity of LTA4H, and not the aminopeptidase activity of LTA4H. A
further embodiment contemplates using one or more LTA4H modulatory
agent(s) that inhibits both the epoxide hydrolase activity of LTA4H
and the aminopeptidase activity of LTA4H. A further embodiment of
the invention contemplates the LTA4H modulatory agent(s) having the
ability to selectively bind to one or more sites on the LTA4H
enzyme, such as by way of example and not limitation, the epoxide
hydrolase active site and/or the aminopeptidase active site.
[0014] An embodiment of the invention includes treating a subject
diagnosed with a cognitive impairment, impaired motor function, or
neuroinflammation or a decline in neurogenesis by administering to
the subject an effective amount of one or more LTA4H modulatory
agent(s), with the subject following an exercise regimen after the
administration. Another embodiment of the invention includes
following an exercise regimen that is prescribed to the subject.
Another embodiment of the invention includes the subject exercising
at a higher intensity and/or greater frequency than the subject
exercised preceding the administration. Another embodiment of the
invention includes the subject exercising at a similar intensity
and/or frequency as the subject exercised preceding the
administration.
IV. INCORPORATION BY REFERENCE
[0015] All publications and patent applications mentioned in this
specification are herein incorporated by reference to the same
extent as if each individual publication or patent application was
specifically and individually indicated to be incorporated by
reference.
V. BRIEF DESCRIPTION OF THE DRAWINGS
[0016] FIG. 1A depicts the concentration of LTA4H in young
(18-year-old) and old (65-year-old) human plasma.
[0017] FIG. 1B depicts the concentration of LTB4 in young
(18-year-old) and old (65-year-old) human plasma.
[0018] FIG. 2A depicts the concentration of LTB4 in young (3 month,
3M) and old (22.5 month, 22.5M) mouse plasma.
[0019] FIG. 2B depicts the concentration of LTB4 in young (3 month,
3M) and old (22.5 month, 22.5M) mouse plasma either unstimulated or
stimulated with calcimycin to increase LTB4 production.
[0020] FIG. 3 depicts treatment paradigm 1 of LTA4H recombinant
protein or phosphate buffered saline (PBS) administration in 8-week
old (young) wild-type (C57BL/6) mice.
[0021] FIG. 4A reports the total distance travelled in an open
field test in young mice treated with recombinant human LTA4H
protein or phosphate buffered saline (PBS) control.
[0022] FIG. 4B reports the average velocity in an open field test
in young mice treated with recombinant human LTA4H protein or
phosphate buffered saline (PBS) control.
[0023] FIG. 4C reports the percent time spent in the periphery or
center in an open field test in young mice treated with recombinant
human LTA4H protein or phosphate buffered saline (PBS) control.
[0024] FIG. 5A depicts the percent time spent freezing in 30 sec
bins in a contextual fear conditioning task in young mice treated
with recombinant human LTA4H protein or phosphate buffered saline
(PBS) control.
[0025] FIG. 5B depicts the percent time spent freezing during the
whole duration of the contextual fear conditioning task in young
mice treated with recombinant human LTA4H protein or phosphate
buffered saline (PBS) control.
[0026] FIG. 5C depicts the time spent freezing pre and post-cue
tone in a cued fear conditioning task in young mice treated with
recombinant human LTA4H protein or phosphate buffered saline (PBS)
control.
[0027] FIG. 6 reports the number of EdU-labeled cells within
granule cell layer of the hippocampus in young mice treated with
recombinant human LTA4H protein or phosphate buffered saline (PBS)
control.
[0028] FIG. 7 depicts cell nuclei labeled with DAPI (blue) and
dividing Ki67 (green) labeled cells in the dentate gyrus in young
mice treated with recombinant human LTA4H protein or phosphate
buffered saline (PBS) control.
[0029] FIG. 8 reports the number of Ki67-labeled dividing cells in
the blade of the dentate gyrus in the hippocampus in young mice
treated with recombinant human LTA4H protein or phosphate buffered
saline (PBS) control.
[0030] FIG. 9 reports the results of quantitative polymerase chain
reaction (qPCR) quantifying mRNA levels of vesicular glutamate
receptor (vglut1), synapsin 1 (syn1), synaptophysin (syp), early
growth response 1 (egr1), doublecortin (dcx), beta III tubulin
(tuj1), glial acidic fibrillary protein (gfap), SRY-Box 2 (sox2),
and oligodendrocyte transcription factor 2 in young mice treated
with recombinant human LTA4H protein or phosphate buffered saline
(PBS) control.
[0031] FIG. 10 depicts treatment paradigm 2 of LTA4H recombinant
protein administered for 1 week at the start of the study (pulse)
or continuously for 6 weeks, or phosphate buffered saline (PBS) in
8-week old (young) wild-type (C57BL/6) mice.
[0032] FIG. 11A reports the total distance travelled in an open
field test in young mice treated with recombinant human LTA4H
protein or phosphate buffered saline (PBS) control.
[0033] FIG. 11B reports the average velocity in an open field test
in young mice treated with recombinant human LTA4H protein or
phosphate buffered saline (PBS) control.
[0034] FIG. 11C reports the percent time spent in the periphery or
center in an open field test in young mice treated with recombinant
human LTA4H protein or phosphate buffered saline (PBS) control.
[0035] FIG. 12A reports the number entries made into the familiar
arm during training of the Y-maze task of young mice treated with
recombinant human LTA4H protein or phosphate buffered saline
(PBS).
[0036] FIG. 12B reports the percentage of the number of entries
into the novel and familiar arms of the Y-maze during testing in
young mice treated with recombinant human LTA4H protein or
phosphate buffered saline (PBS).
[0037] FIG. 13 reports the number of BrdU and DCX co-labeled cells
within granule cell layer of the hippocampus in young mice treated
with recombinant human LTA4H protein or phosphate buffered saline
(PBS) control.
[0038] FIG. 14 reports the average number of Iba1-labeled microglia
in the hippocampus in young mice treated with recombinant human
LTA4H protein or phosphate buffered saline (PBS) control.
[0039] FIG. 15 depicts treatment paradigm 3 of LTA4H recombinant
protein or phosphate buffered saline (PBS) administration in 8-week
old (young) wild-type (C57BL/6) mice.
[0040] FIG. 16 reports the average number of CD68 puncta in the
hippocampus in young mice treated with recombinant human LTA4H
protein or phosphate buffered saline (PBS) control.
[0041] FIG. 17A displays a schematic of the LTA4H biochemical
signaling pathway.
[0042] FIG. 17B displays a key to accompany the schematic in FIG.
17A.
[0043] FIG. 18A reports the total distance travelled in an open
field test in aged mice treated for one month with vehicle, the
LTA4H hydrolase and peptidase inhibitor SC 57461A, the LTB4
receptor inhibitor CP 105,696, the cysteinyl leukotriene receptor
inhibitor Montelukast, and the LTA4H hydrolase inhibitor
pinostilbene hydrate.
[0044] FIG. 18B reports the average velocity in an open field test
in aged mice treated for one month with vehicle, the LTA4H
hydrolase and peptidase inhibitor SC 57461A, the LTB4 receptor
inhibitor CP 105,696, the cysteinyl leukotriene receptor inhibitor
Montelukast, and the LTA4H hydrolase inhibitor pinostilbene
hydrate.
[0045] FIG. 18C reports the percent time spent in the periphery or
center in an open field test in aged mice treated for one month
with vehicle, the LTA4H hydrolase and peptidase inhibitor SC
57461A, the LTB4 receptor inhibitor CP 105,696, the cysteinyl
leukotriene receptor inhibitor Montelukast, and the LTA4H hydrolase
inhibitor pinostilbene hydrate.
[0046] FIG. 19A reports the latency to find the platform in the
radial arm water maze in aged mice treated for one month with
vehicle, the LTA4H hydrolase and peptidase inhibitor SC 57461A, the
LTB4 receptor inhibitor CP 105,696, the cysteinyl leukotriene
receptor inhibitor Montelukast, and the LTA4H hydrolase inhibitor
pinostilbene hydrate.
[0047] FIG. 19B reports the number of errors made in finding the
platform in the radial arm water maze in aged mice treated for one
month with vehicle, the LTA4H hydrolase and peptidase inhibitor SC
57461A, the LTB4 receptor inhibitor CP 105,696, the cysteinyl
leukotriene receptor inhibitor Montelukast, and the LTA4H hydrolase
inhibitor pinostilbene hydrate.
[0048] FIG. 19C reports the latency to find the platform in the
last two trials of training of the radial arm water maze in aged
mice treated for one month with vehicle, the LTA4H hydrolase and
peptidase inhibitor SC 57461A, the LTB4 receptor inhibitor CP
105,696, the cysteinyl leukotriene receptor inhibitor Montelukast,
and the LTA4H hydrolase inhibitor pinostilbene hydrate.
[0049] FIG. 19D reports the latency to find the platform in the
last two trials of testing of the radial arm water maze in aged
mice treated for one month with vehicle, the LTA4H hydrolase and
peptidase inhibitor SC 57461A, the LTB4 receptor inhibitor CP
105,696, the cysteinyl leukotriene receptor inhibitor Montelukast,
and the LTA4H hydrolase inhibitor pinostilbene hydrate.
[0050] FIG. 19E reports the number of errors made in finding the
platform in the last two trials of training of the radial arm water
maze in aged mice treated for one month with vehicle, the LTA4H
hydrolase and peptidase inhibitor SC 57461A, the LTB4 receptor
inhibitor CP 105,696, the cysteinyl leukotriene receptor inhibitor
Montelukast, and the LTA4H hydrolase inhibitor pinostilbene
hydrate.
[0051] FIG. 19F reports the number of errors made in finding the
platform in the last two trials of testing of the radial arm water
maze in aged mice treated for one month with vehicle, the LTA4H
hydrolase and peptidase inhibitor SC 57461A, the LTB4 receptor
inhibitor CP 105,696, the cysteinyl leukotriene receptor inhibitor
Montelukast, and the LTA4H hydrolase inhibitor pinostilbene
hydrate.
[0052] FIG. 20A reports the percentage of the number of entries
into the novel and familiar arms of the Y-maze during testing in
aged mice treated for one month with vehicle, the LTA4H hydrolase
and peptidase inhibitor SC 57461A, the LTB4 receptor inhibitor CP
105,696, the cysteinyl leukotriene receptor inhibitor Montelukast,
and the LTA4H hydrolase inhibitor pinostilbene hydrate.
[0053] FIG. 20B reports the total distance traveled in the Y-maze
during testing in aged mice treated for one month with vehicle, the
LTA4H hydrolase and peptidase inhibitor SC 57461A, the LTB4
receptor inhibitor CP 105,696, the cysteinyl leukotriene receptor
inhibitor Montelukast, and the LTA4H hydrolase inhibitor
pinostilbene hydrate.
[0054] FIG. 21A reports the average integrated optical density of
aquaporin-4 (AQP4) in the hippocampus of aged mice treated for one
month with vehicle, the LTA4H hydrolase and peptidase inhibitor SC
57461A, the LTB4 receptor inhibitor CP 105,696, the cysteinyl
leukotriene receptor inhibitor Montelukast, and the LTA4H hydrolase
inhibitor pinostilbene hydrate.
[0055] FIG. 21B reports the average fluorescence intensity of
aquaporin-4 (AQP4) in the perivascular space in the hippocampus of
aged mice treated for one month with vehicle, the LTA4H hydrolase
and peptidase inhibitor SC 57461A, the LTB4 receptor inhibitor CP
105,696, the cysteinyl leukotriene receptor inhibitor Montelukast,
and the LTA4H hydrolase inhibitor pinostilbene hydrate.
[0056] FIG. 21C reports the average fluorescence intensity of
aquaporin-4 (AQP4) immediately surround blood vessels (vascular) of
hippocampus of aged mice treated for one month with vehicle, the
LTA4H hydrolase and peptidase inhibitor SC 57461A, the LTB4
receptor inhibitor CP 105,696, the cysteinyl leukotriene receptor
inhibitor Montelukast, and the LTA4H hydrolase inhibitor
pinostilbene hydrate.
[0057] FIG. 22 reports the total plasma concentrations of LTB4
measured by ELISA in aged mice treated for one month with vehicle,
the LTA4H hydrolase and peptidase inhibitor SC 57461A, the LTB4
receptor inhibitor CP 105,696, the cysteinyl leukotriene receptor
inhibitor Montelukast, and the LTA4H hydrolase inhibitor
pinostilbene hydrate.
[0058] FIG. 23A-F reports the results of quantitative polymerase
chain reaction (qPCR) quantifying mRNA levels of ionized
calcium-binding adapter molecule 1 (Iba-1), interleukin 6 (IL-6),
interleukin 1-beta (IL-1.beta.), Eotaxin, nuclear factor
kappa-light-chain-enhancer of activated B cells (NF-.kappa.B), and
tumor necrosis factor alpha (TNF.alpha.) in aged mice treated for
one month with vehicle, the LTA4H hydrolase and peptidase inhibitor
SC 57461A, the LTB4 receptor inhibitor CP 105,696, the cysteinyl
leukotriene receptor inhibitor Montelukast, and the LTA4H hydrolase
inhibitor pinostilbene hydrate.
[0059] FIG. 24A reports the results of quantitative polymerase
chain reaction (qPCR) quantifying mRNA levels of the neuronal genes
tuj1, syn1, dlg4, and bdnf in aged mice treated for one month with
vehicle, the LTA4H hydrolase and peptidase inhibitor SC 57461A, the
LTB4 receptor inhibitor CP 105,696, the cysteinyl leukotriene
receptor inhibitor Montelukast, and the LTA4H hydrolase inhibitor
pinostilbene hydrate.
[0060] FIG. 24B reports the results of quantitative polymerase
chain reaction (qPCR) quantifying mRNA levels of microglia genes,
cluster of differentiation molecule 11b (CD11b), interleukin 18
(IL-18), cluster of differentiation (CD68), interleukin 1.alpha.
(IL-1.alpha.), interleukin 4 (IL-4), insulin-like growth factor 1
(IGF-1), and transforming growth factor .beta. (TGF3.beta.) in aged
mice treated for one month with vehicle, the LTA4H hydrolase and
peptidase inhibitor SC 57461A, the LTB4 receptor inhibitor CP
105,696, the cysteinyl leukotriene receptor inhibitor Montelukast,
and the LTA4H hydrolase inhibitor pinostilbene hydrate.
[0061] FIG. 24C reports the results of quantitative polymerase
chain reaction (qPCR) quantifying mRNA levels astrocytic genes,
aquaporin 4 (aqp4), glial acidic fibrillary protein (gfap), six
transmembrane epithelial antigen of prostate 4 (steap4),
sphingosine-1-phosphate receptor 1 (s1pr3), tissue inhibitor of
metalloproteinases (timp1), H2 class I histocompatibility antigen
(h2d1), guanylate-binding protein 2 (gbp2), N-acetyllactosaminide
alpha-1 3-galactosyltransferase (ggta1), H2T23 protein (h2t23), and
cardiotrophin-like cytokine factor 1 (clcf1) in aged mice treated
for one month with vehicle, the LTA4H hydrolase and peptidase
inhibitor SC 57461A, the LTB4 receptor inhibitor CP 105,696, the
cysteinyl leukotriene receptor inhibitor Montelukast, and the LTA4H
hydrolase inhibitor pinostilbene hydrate.
[0062] FIG. 24D reports the results of quantitative polymerase
chain reaction (qPCR) quantifying mRNA levels of immediate early
genes, cfos, egr1, and creb1 in aged mice treated for one month
with vehicle, the LTA4H hydrolase and peptidase inhibitor SC
57461A, the LTB4 receptor inhibitor CP 105,696, the cysteinyl
leukotriene receptor inhibitor Montelukast, and the LTA4H hydrolase
inhibitor pinostilbene hydrate.
VI. DETAILED DESCRIPTION
A. Introduction
[0063] The present invention relates to the identification and
discovery of methods and compositions for the treatment and/or
prevention of cognitive and motor impairment, including
age-associated dementia, decline in motor skills,
neuroinflammation, and neurodegenerative disease. Described herein
are methods and compositions for the treatment of subjects
suffering from such disorders, which are aspects of the present
invention. The methods and compositions described herein are useful
in: preventing or treating cognitive or motor impairment,
age-associated dementia or motor impairment, neuroinflammation, and
neurodegenerative disease; ameliorating the symptoms of cognitive
or motor impairment, age-associated dementia or motor impairment,
neuroinflammation, and neurodegenerative disease; slowing
progression of aging-associated cognitive or motor impairment,
age-associated dementia or motor impairment, neuroinflammation, and
neurodegenerative disease; and/or reversing the progression of
aging-associated cognitive or motor impairment, age-associated
dementia or motor impairment, neuroinflammation, and
neurodegenerative disease. An implementation of the invention
includes using the LTA4H modulatory agent(s) as treatment. An
embodiment of the invention includes the LTA4H modulatory agent(s).
Another embodiment of the invention includes using an LTA4H
modulating agent which selectively inhibits the epoxide hydrolase
activity of the LTA4H enzyme. Another embodiment of the invention
includes using an LTA4H modulating agent which inhibits both the
epoxide hydrolase activity and the aminopeptidase activity of the
LTA4H enzyme. Another embodiment of the invention includes one or
more LTA4H modulating agent(s) that bind to the epoxide hydrolase
and/or aminopeptidase active site(s).
[0064] Before describing the present invention in detail, it is to
be understood that this invention is not limited to a particular
method or composition described, as such may, of course, vary. It
is also understood that the terminology used herein is for the
purpose of describing particular embodiments only, and is not
intended to be limiting, since the scope of the present invention
will be limited only by the appended claims.
[0065] The publications discussed herein are provided solely for
their disclosure prior to the filing date of the present
application. Nothing herein is to be construed as an admission that
the present invention is not entitled to antedate such publication
by virtue of prior invention. Further, the dates of publication
provided may be different from the actual publication dates which
may need to be independently confirmed.
[0066] Where a range of values is provided, it is understood that
each intervening value, to the tenth of the unit of the lower limit
unless the context clearly dictates otherwise, between the upper
and lower limits of that range is also specifically disclosed. Each
smaller range between any stated value or intervening value in a
stated range and any other stated or intervening value in that
stated range is encompassed within the invention. The upper and
lower limits of these smaller ranges may independently be included
or excluded in the range, and each range where either, neither or
both limits are included in the smaller ranges is also encompassed
within the invention, subject to any specifically excluded limit in
the stated range. Where the stated range includes one or both of
the limits, ranges excluding either or both of those included
limits are also included in the invention.
[0067] It is noted that the claims may be drafted to exclude any
optional element. As such, this statement is intended to serve as
antecedent basis for use of such exclusive terminology as "solely,"
"only" and the like in connection with the recitation of claim
elements or use of a "negative" limitation.
[0068] As will be apparent to those of skill in the art upon
reading this disclosure, each of the individual embodiments
described and illustrated herein have discrete components and
features which may be readily separated from or combined with the
features of any of the other several embodiments without departing
from the scope or the spirit of the present invention. Any recited
method can be carried out in the order of events recited or in any
other order which is logically possible.
[0069] While the apparatus and method has or will be described for
the sake of grammatical fluidity with functional explanations, it
is to be expressly understood that the claims, unless expressly
formulated under 35 U.S.C. .sctn. 112, are not to be construed as
necessarily limited in any way by the construction of "means" or
"steps" limitations, but are to be accorded the full scope of the
meaning and equivalents of the definition provided by the claims
under the judicial doctrine of equivalents, and in the case where
the claims are expressly formulated under 35 U.S.C. .sctn. 112 are
to be accorded full statutory equivalents under 35 U.S.C. .sctn.
112.
B. Definitions
[0070] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one
having ordinary skill in the art to which the invention belongs.
Although any methods and materials similar or equivalent to those
described herein can be used in the practice or testing of the
present invention, some potential and preferred methods and
materials are now described. All publications mentioned herein are
incorporated herein by reference to disclose and describe the
methods and/or materials in connection with which the publications
are cited. It is understood that the present disclosure supersedes
any disclosure of an incorporated publication to the extent there
is a contradiction.
[0071] It must be noted that as used herein and in the appended
claims, the singular forms "a," "an," and "the" include plural
referents unless the context clearly dictates otherwise. Thus, for
example, reference to "a cell" includes a plurality of such cells
and reference to "the peptide" includes reference to one or more
peptides and equivalents thereof, e.g. polypeptides, known to those
having skill in the art, and so forth.
[0072] In describing methods of the present invention, the terms
"host", "subject", "individual" and "patient" are used
interchangeably and refer to any mammal in need of such treatment
according to the disclosed methods. Such mammals include, e.g.,
humans, ovines, bovines, equines, porcines, canines, felines,
non-human primate, mice, and rats. In certain embodiments, the
subject is a non-human mammal. In some embodiments, the subject is
a farm animal. In other embodiments, the subject is a pet. In some
embodiments, the subject is mammalian. In certain instances, the
subject is human. Other subjects can include domestic pets (e.g.,
dogs and cats), livestock (e.g., cows, pigs, goats, horses, and the
like), rodents (e.g., mice, guinea pigs, and rats, e.g., as in
animal models of disease), as well as non-human primates (e.g.,
chimpanzees, and monkeys). As such, subjects of the invention,
include but are not limited to mammals, e.g., humans and other
primates, such as chimpanzees and other apes and monkey species;
and the like, where in certain embodiments the subject are humans.
The term subject is also meant to include a person or organism of
any age, weight or other physical characteristic, where the
subjects may be an adult, a child, an infant or a newborn.
[0073] By a "young" or "young individual" it is meant an individual
that is of chronological age of 40 years old or younger, e.g., 35
years old or younger, including 30 years old or younger, e.g., 25
years old or younger or 22 years old or younger. As such, "young"
and "young individual" may refer to a subject that is between the
ages of 0 and 40, e.g., 0, 1, 5, 10, 15, 20, 25, 30, 35, or 40
years old. In other instances, "young" and "young individual" may
refer to a biological (as opposed to chronological) age such as an
individual who has not exhibited the levels of inflammatory
cytokines in the plasma exhibited in comparatively older
individuals. Conversely, these "young" and "young individual" may
refer to a biological (as opposed to chronological) age such as an
individual who exhibits greater levels of anti-inflammatory
cytokines in the plasma compared to levels in comparatively older
individuals. By way of example, and not limitation, the
inflammatory cytokine is Eotaxin, and the fold difference between a
young subject or young individual and older individuals is at least
1.5-fold. Similarly, the fold difference between older and younger
individuals in other inflammatory cytokines may be used to refer to
a biological age. (See U.S. patent application Ser. No. 13/575,437
which is herein incorporated by reference). Usually, the individual
is healthy, e.g., the individual has no hematological malignancy or
autoimmune disease at the time of harvest.
[0074] By "an individual suffering from or at risk of suffering
from an aging-associated impairment" is meant an individual that is
about more than 50% through its expected lifespan, such as more
than 60%, e.g., more than 70%, such as more than 75%, 80%, 85%,
90%, 95% or even 99% through its expected lifespan. The age of the
individual will depend on the species in question. Thus, this
percentage is based on the predicted life-expectancy of the species
in question. For example, in humans, such an individual is 50 year
old or older, e.g., 60 years old or older, 70 years old or older,
80 years old or older, 90 years old or older, and usually no older
than 100 years old, such as 90 years old, i.e., between the ages of
about 50 and 100, e.g., 50 . . . 55 . . . 60 . . . 65 . . . 70 . .
. 75 . . . 80 . . . 85 . . . 90 . . . 95 . . . 100 years old or
older, or any age between 50-1000, that suffers from an
aging-associated condition as further described below, e.g.,
cognitive or motor impairment associated with the natural aging
process; an individual that is about 50 years old or older, e.g.,
60 years old or older, 70 years old or older, 80 years old or
older, 90 years old or older, and usually no older than 100 years
old, i.e., between the ages of about 50 and 100, e.g., 50 . . . 55
. . . 60 . . . 65 . . . 70 . . . 75 . . . 80 . . . 85 . . . 90 . .
. 95 . . . 100 years old, that has not yet begun to show symptoms
of an aging-associated condition e.g., cognitive or motor
impairment; an individual of any age that is suffering from a
cognitive or motor impairment due to an aging-associated disease,
as described further below, and an individual of any age that has
been diagnosed with an aging-associated disease that is typically
accompanied by cognitive or motor impairment, where the individual
has not yet begun to show symptoms of cognitive or motor
impairment. The corresponding ages for non-human subjects are known
and are intended to apply herein.
[0075] As used herein, "treatment" refers to any of (i) the
prevention of the disease or disorder, or (ii) the reduction or
elimination of symptoms of the disease or disorder. Treatment may
be effected prophylactically (prior to the onset of disease) or
therapeutically (following the onset of the disease). The effect
may be prophylactic in terms of completely or partially preventing
a disease or symptom thereof and/or may be therapeutic in terms of
a partial or complete cure for a disease and/or adverse effect
attributable to the disease. Thus, the term "treatment" as used
herein covers any treatment of an aging-related disease or disorder
in a mammal and includes: (a) preventing the disease from occurring
in a subject which may be predisposed to the disease but has not
yet been diagnosed as having it; (b) inhibiting the disease, i.e.,
arresting its development; or (c) relieving the disease, i.e.,
causing regression of the disease. Treatment may result in a
variety of different physical manifestations, e.g., modulation in
gene expression, rejuvenation of tissue or organs, etc. The
therapeutic agent may be administered before, during or after the
onset of disease. The treatment of ongoing disease, where the
treatment stabilizes or reduces the undesirable clinical symptoms
of the patient, is of particular interest. Such treatment may be
performed prior to complete loss of function in the affected
tissues. The subject therapy may be administered during the
symptomatic stage of the disease, and in some cases after the
symptomatic stage of the disease. In another embodiment of the
invention, "treatment" refers to reducing local tissue or blood
levels of neutrophils to a more homeostatic state, i.e. to levels
observed in a healthy individual of the same or similar age.
[0076] In some embodiments, the aging-associated condition that is
treated is an aging-associated impairment in cognitive ability in
an individual. By cognitive ability, or "cognition," it is meant
the mental processes that include attention and concentration,
learning complex tasks and concepts, memory (acquiring, retaining,
and retrieving new information in the short and/or long term),
information processing (dealing with information gathered by the
five senses), visuospatial function (visual perception, depth
perception, using mental imagery, copying drawings, constructing
objects or shapes), producing and understanding language, verbal
fluency (word-finding), solving problems, making decisions, and
executive functions (planning and prioritizing). By "cognitive
decline", it is meant a progressive decrease in one or more of
these abilities, e.g., a decline in memory, language, thinking,
judgment, etc. By "an impairment in cognitive ability" and
"cognitive impairment", it is meant a reduction in cognitive
ability relative to a healthy individual, e.g., an age-matched
healthy individual, or relative to the ability of the individual at
an earlier point in time, e.g., 2 weeks, 1 month, 2 months, 3
months, 6 months, 1 year, 2 years, 5 years, or 10 years or more
previously. By "aging-associated cognitive impairment," it is meant
an impairment in cognitive ability that is typically associated
with aging, including, for example, cognitive impairment associated
with the natural aging process, e.g., mild cognitive impairment
(M.C.I.); and cognitive impairment associated with an
aging-associated disorder, that is, a disorder that is seen with
increasing frequency with increasing senescence, e.g., a
neurodegenerative condition such as Alzheimer's disease,
Parkinson's disease, frontotemporal dementia, Huntington disease,
amyotrophic lateral sclerosis, multiple sclerosis, glaucoma,
myotonic dystrophy, vascular dementia, and the like.
[0077] In some embodiments, the aging-associated condition that is
treated is an aging-associated impairment in motor ability in an
individual. By motor ability, it is meant the motor processes that
include the ability to perform complex muscle-and-nerve actions
that produce movement such as fine motor skills producing small or
precise movements (e.g. writing, tying shoes) and gross motor
skills for large movements (e.g. walking, running, kicking). By
"motor decline", it is meant a progressive decrease in one or more
of these abilities, e.g., a decline in find movement or gross motor
skills, etc. By "motor impaired" and "motor impairment", it is
meant a reduction in motor ability/skills relative to a healthy
individual, e.g., an age-matched healthy individual, or relative to
the ability of the individual at an earlier point in time, e.g., 2
weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 5
years, or 10 years or more previously. By "aging-associated motor
impairment," it is meant an impairment or decline in motor ability
that is typically associated with aging, including, for example,
motor impairment associated with the natural aging process and
motor impairment or decline associated with an aging-associated
disorder, that is, a disorder that is seen with increasing
frequency with increasing senescence, e.g., a neurodegenerative
condition such as Parkinson's disease, amyotrophic lateral
sclerosis, and the like.
[0078] In some embodiments, the aging-associated condition that is
treated is an aging-associated increase in neuroinflammation in an
individual. By "neuroinflammation" it is meant biochemical and
cellular responses of the nervous system to injury, infection, or
neurodegenerative diseases. Such responses are directed at
decreasing the triggering factors by involving central nervous
system immunity to defend against potential harm. Neurodegeneration
occurs in the central nervous system and exhibits hallmarks of loss
of neuronal structure and function. Neuroinflammatory diseases or
neuroinflammatory-associated conditions or diseases, includes by
way of example and not limitation, neurodegenerative diseases such
as Alzheimer's disease; Parkinson's disease, multiple sclerosis and
the like.
C. Treatment
[0079] Aspects of the methods of the inventions described herein
include treatment of a subject with an LTA4H modulatory agent,
e.g., as described above. An embodiment includes treatment of a
human subject with an LTA4H modulatory agent. One of skill in the
art would recognize that methods of treatment of subjects with
LTA4H modulatory agents are recognized in the art. By way of
example, and not limitation, one embodiment of the methods of the
inventions described herein is comprised of administering an LTA4H
modulatory agent to a subject for treatment and/or prevention of
cognitive impairment and/or age-related dementia. The LTA4H
modulatory agent may be administered through one or more routes
such as IP, IV, PO, and the like. Additionally, the LTA4H
modulatory agent may be administered one or more time per day, such
as once per day, twice per day, thrice per day, four time per day,
etc., and such doses may be administered chronically (e.g. greater
that one month, greater than two months, greater than 3 to five
months, greater than six months, greater than one year, etc.), or
acutely for a shorter time span (e.g. shorter than one month).
[0080] Aspects of the methods described herein include use of LTA4H
modulatory agents. Any convenient LTA4H modulatory agent may find
use in the disclosed methods. In some instances, the LTA4H
modulatory agent is a small molecule. Naturally occurring or
synthetic small molecule compounds of interest include numerous
chemical classes, such as organic molecules, e.g., small organic
compounds having a molecular weight of more than 50 and less than
about 2,500 daltons. The compounds can include functional groups
for structural interaction with proteins, particularly hydrogen
bonding, and typically include at least an amine, carbonyl,
hydroxyl or carboxyl group, preferably at least two of the
functional chemical groups. The candidate agents may include
cyclical carbon or heterocyclic structures and/or aromatic or
polyaromatic structures substituted with one or more of the above
functional groups. In some embodiments, the LTA4H modulatory agent
may be a small organic molecule that selectively binds to the LTA4H
enzyme and reduces (i.e. antagonizes) one or more of its activities
including, for example, its epoxide hydrolase activity and/or its
aminopeptidase activity. In some cases, the LTA4H modulatory agent
may be a small organic molecule that selectively binds to the LTA4H
enzyme and augments (i.e. acts an agonist) one or more of its
activities including, for example, its epoxide hydrolase activity
and/or its aminopeptidase activity. In some embodiments, the LTA4H
modulatory agent is a selective or competitive inhibitor of LTA4H.
The LTA4H modulatory agent can also be a pharmaceutically
acceptable salt thereof of a LTA4H inhibitor.
[0081] In certain embodiments, the small molecule LTA4H modulatory
agent is a peptide or a peptidomimetic compound. In certain
embodiments, the peptide or peptidomimetic compound comprises one
or more of leucine, proline, valine, norvaline, isoleucine,
norleucine, methionine and arginine. In certain embodiments, the
LTA4H modulatory agent is a peptidomimetic derivative comprising a
hydroxamic acid group. In certain embodiments, the LTA4H modulatory
agent is a heterocyclic compound. Non-limiting examples of
heterocyclic compounds include a piperadine derivative, a
piperazine derivative, an oxazole derivative, a thiozole
derivative, an imidazole derivative, a pyridine derivative, a
pyrimidine derivative, a benzoxazole derivative, a benzothiazole
derivative, a benzoimidazole derivative, a thiazolopyridine
derivative, a thiazolopyrazine derivative, a
diazabicyclo[2.2.1]heptane derivative, a benzodioxane derivative,
and an arylpyrazole derivative. In certain embodiments, the LTA4H
modulatory agent is an aryl compound. In some cases, the aryl
compound is a stilbenoid derivative (e.g., a resveratrol
derivative). In some cases, the LTA4H modulatory agent is an aryl
or biaryl substituted heterocycle derivative. In will be understood
that any convenient small molecule LTA4H modulatory agent may find
use in the subject methods.
[0082] In certain embodiments, the LTA4H modulatory compound is a
peptide derivative. In certain embodiments the LTA4H modulatory
agent is described by the formula (I):
##STR00001##
[0083] where:
[0084] R.sup.1 is selected from alkyl, substituted alkyl,
cycloalkanoalkyl, phenyl, substituted phenyl, benzyl, substituted
benzyl; and
[0085] R.sup.2 is selected from hydrogen, alkyl, substituted alkyl,
hydroxylalkyl, mercaptoalkyl, carboxyamidoalkyl, alkoxyalkyl,
alkylmercaptoalkyl, carboxylalkyl, aryl, substituted aryl, aralkyl,
substituted aralkyl, amidinealkyl, substituted amidinealkyl,
[0086] or a pharmaceutically acceptable salt, or solvate
thereof.
[0087] In some embodiments, R.sup.1 is a benzyl group or a
substituted benzyl group and R.sup.2 is an isobutyl group. In
certain embodiments, R.sup.1 a benzyl group, or a substituted
benzyl group and R.sup.2 is
--CH.sub.2CH.sub.2CH.sub.2NHC(.dbd.NH)NH.sub.2. In certain cases,
the compound of formula (I) is a racemate. In certain cases, the
compound of formula (I) is an enantiomer thereof. In certain cases,
the configuration of the compound is (2S,3R, 2'R), (2S,3S, 2'S) or
(2S,3S, 2'R).
[0088] In certain embodiments, the compound of formula (I) is
selected from
(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl-(R)-leucine,
(2S,3S)-3-amino-2-hydroxy-4-phenylbutanoyl-(R)-leucine,
(2S,3R)-3-amino-2-hydroxy-4-p-nitrophenylbutanoyl-(S)-leucine,
(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl-(R)-valine,
(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl-(S)-norvaline,
(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl-(S)-methionine,
(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl-(S)-isoleucine,
(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl-(R)-norleucine,
(2RS,3RS)-3-amino-2-hydroxy-4-p-chlorophenylbutanoyl-(S)-leucine,
(2RS,3RS)-3-amino-2-hydroxy-4-o-chlorophenylbutanoyl-(S)-leucine,
(2RS,3RS)-3-amino-2-hydroxy-4-p-methylphenylbutanoyl-(S)-leucine,
(2S,3R)-3-amino-2-hydroxy-4-p-aminophenylbutanoyl-(S)-leucine,
(2RS, 3RS)-3-amino-2-hydroxy-4-hydroxyphenylbutanoyl-(S)-leucine,
(2S,3R)-3-amion-2-hydroxy-4-p-hyroxyphenylbutanoyl-(S)-leucine.
[0089] In certain embodiments, the compound of formula (I) is
selected from
(2S,3R)-3-amino-2-hydroxyl-4-phenylbutanoyl-(S)-arginine,
(2S,3R)-3-amino-2-hydroxy-4-p-hydroxyphenyl-butanoyl-(S)-arginine,
(2RS,
3RS)-3-amino-2-hydroxy-4-p-methylphenyl-butanoyl-(S)-arginine.
[0090] In certain embodiments, the compound of formula (I) is the
compound know as ubenimex (bestatin), which has the following
structure:
##STR00002##
[0091] Ubenimex analogs and derivatives useful in the methods of
the invention include LTA4H inhibitor compounds described in U.S.
Pat. Nos. 4,185,156; 4,189,604; 4,370,318; and 4,474,764, and G.B.
Pat. Nos. 1,510,477, 1,510,323, each of which is incorporated
herein by reference.
[0092] In certain embodiments, the LTA4H modulatory compound is a
peptiodomietic derivative. In certain cases, the peptiodomietic
derivative comprises a hydroxamic acid group. In certain
embodiments the LTA4H modulatory agent is described by the formula
(II):
##STR00003##
[0093] where:
[0094] R.sup.9 is selected from hydrogen, hydroxy, amino, methyl,
and trifluoromethyl;
[0095] R.sup.10 is R.sub.10a--(X).sub.n--(ALK)--, wherein R.sub.10a
is selected from hydrogen, a C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, cycloalkyl, aryl, or heterocycle
group, any of which may be unsubstituted or substituted by
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, hydroxy, mercapto,
(C.sub.1-C.sub.6)alkylthio, amino, trifluoromethyl, cyano, nitro,
--COOH, --CONH.sub.2, --COOR.sup.A, --NHCOR.sup.A, --CONHR.sup.A,
--NHR.sup.A, --NR.sup.AR.sup.B, or --CONR.sup.AR.sup.B wherein
R.sup.A and R.sup.B are independently a (C.sub.1-C.sub.6)alkyl
group;
[0096] ALK represents a straight or branched divalent
C.sub.1-C.sub.6 alkylene, C.sub.2-C.sub.6 alkenylene,
C.sub.2-C.sub.6 alkynylene radical, and may be interrupted by one
or more non-adjacent --NH--, --O-- or --S-- linkages;
[0097] X represents --NH--, --O-- or --S--, and
[0098] n is 0 or 1;
[0099] R is selected from hydrogen or C.sub.1-C.sub.6 alkyl;
[0100] R.sup.11 is a characterizing group of a natural or
non-natural amino acid in which any functional groups may be
protected; and
[0101] R.sub.4 represents an ester or thioester group, or a
pharmaceutically acceptable salt, hydrate or solvate thereof.
[0102] In certain embodiments, the compound of formula (II) is
selected from,
2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3-phenylpropi-
onic acid cyclopentyl ester,
2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3-phenylpropionic
acid benzyl ester,
2S-{2R-[1S-Hydroxycarbamoyl-2-(thiophen-2-ylsulphanyl)-ethyl]4-methyl-pen-
tanoylamino}-3-phenyl-propionic acid isopropyl ester,
2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-4-methyl-pentanoic
acid cyclopentyl ester, 2S-{2R-[1
S-Hydroxycarbamoyl-2-(thiophen-2-ylsulphanyl)-ethyl]-4-methyl-pentanoylam-
ino}-3-phenyl-propionic acid isopropyl ester,
2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3-phenylpropionic
acid methyl ester,
2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3-phenylpropionic
acid ethyl ester,
2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3-phenylpropionic
acid isopropyl ester, 3R-(2-Phenyl-1
S-methylcarboxy-ethylcarbamoyl)-2S, 5-dimethylhexanohydroxamic
acid,
2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3-phenyl-propionic
acid tert-butyl ester,
2S-(2R-Hydroxycarbamoylmethyl4-methyl-pentanoylamino)-3-phenyl-propionic
acid isopropyl ester,
2S-[2R--(S-Hydroxy-hydroxycarbamoyl-methyl)-4-methyl-pentanoytamine]-3-ph-
enyl-propionic acid isopropyl ester,
2S-[2R-(1S-Hydroxycarbamoyl-ethyl)-4-methyl-pentanoylamino]-3-phenyl-prop-
ionic acid isopropyl ester,
2S-(2R-Hydroxycarbamoylmethyl-octanoylamino)-3-phenyl-propionic
acid isopropyl ester,
2S-[2R--(S-Hydroxy-hydroxycarbamoyl-methyl)-4-methyl-pentanoylamino]-3-ph-
enyl-propionic acid cyclopentyl ester,
2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3S-methyl-pentanoic
acid cyclopentyl ester,
2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3-phenylpropionic
acid 2-methoxy-ethyl ester, 2S-[2R-(1
S-Hydroxycarbamoyl-ethyl)-4-methyl-pentanoylamino]-3-phenyl-propionic
acid 2-methoxy-ethyl ester,
2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hexanoylamino)-3,3-dimethyl-butyric
acid 2-methoxy-ethyl ester,
2S-[2R--(S-Hydroxycarbamoyl-methoxy-methyl)-4-methyl-pentanoylamino]-3-ph-
enyl-propionic acid isopropyl ester, 2S-[2-R-(1
S-Hydroxycarbamoyl-ethyl)-4-methyl-pentanoylamino]-3,3-dimethyl-butyric
acid 2-methoxy-ethyl ester,
2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3,3-dimethyl-butyri-
c acid 2-methoxy-ethyl ester,
2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hexanoylamino)-3-phenylpropionic
acid isopropyl ester,
2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3,3-dimethyl-butyri-
c acid isopropyl ester,
2R-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3-phenylpropionic
acid isopropyl ester,
2S-[2R--(S-Hydroxycarbamoyl-methoxy-methyl)-4-methyl-pentanoylamino]-3,3--
dimethyl-butyric acid isopropyl ester,
2S-{(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoyl)-methyl-amino)-3-phenylp-
ropionic acid isopropyl ester,
3-Cyclohexyl-2S-(3S-hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-propio-
nic acid cyclopentyl ester,
2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3-phenylpropionic
acid 1-methyl-piperidin-4-yl ester,
2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3-phenylpropionic
acid 1-ethyl-propyl ester,
2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3-phenylpropionic
acid 1 S-methyl-butyl ester,
2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3-phenylpropionic
acid cyclohexyl ester, 2S-{2R-[1
S-Hydroxycarbamoyl-2-(thiophen-2-ylsulphanyl)-ethyl]-4-methyl-pentanoylam-
ino}-3,3-dimethyl-butyric acid isopropyl ester,
2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3-phenylpropionic
acid 1 R-methyl-butyl ester,
2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3-phenylpropionic
acid tetrahydro-furan-3(R, S)-yl ester,
2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3,3-dimethyl-butyri-
c acid cyclopentyl ester, 2S-[2R-(1
S-Cyclopentyl-hydroxycarbamoyl-methyl)-4-methyl-pentanoylamino]-3-phenyl--
propionic acid cyclopentyl ester, 2S-[2R-(1
S-Hydroxy-hydroxycarbamoyl-methyl)-pent-4-ynoylamino]-3-phenylpropionic
acid cyclopentyl ester,
2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3-pyridin-3-yl-prop-
ionic acid cyclopentyl ester,
3-tert-Butoxy-2S-(3S-hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-propi-
onic acid cyclopentyl ester,
2S-3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-2-phenylethanoic
acid cyclopentyl ester, 2S-[5-(2-Chlorophenyl)-2R-(1
S-hydroxy-hydroxycarbamoyl-methyl)-pent-4-ynoylamino]-3-phenylpropionic
acid cyclopentyl ester, and
2S-(3S-Hydroxycarbamoyl-2R-isobutyl-6-phenyl-hex-5-enoylamino)-3-phenyl-p-
ropionic acid cyclopentyl ester, and pharmaceutically acceptable
salts, hydrates and esters thereof.
[0103] In certain embodiments, the compound of formula (II) is the
compound known as tosedostat (CHR-2797), which has the following
structure:
##STR00004##
[0104] In certain cases, tosedostat is converted intracellularly
into an active form, known as CHR79888, which has the following
structure:
##STR00005##
[0105] Tosedostat analogs and derivatives useful in the methods of
the invention include compounds described in U.S. Pat. Nos.
6,462,023, 5,861,436; and 6,545,051; and International Patent
Application Nos. WO1999046241A1; and WO2000044373A1.
[0106] In certain embodiments, the LTA4H modulatory agent is a
heterocyclic compound. In some cases, the heterocyclic compound is
a benzoxazole derivative, a benzothiazole derivative, or a
benzoimidazole derivative. In certain embodiments the LTA4H
modulatory agent is described by the formula (III):
##STR00006##
[0107] where:
[0108] X is selected from the group consisting of NR.sup.5a, O, and
S, with R.sup.5a being one of H and CH.sub.3;
[0109] Y is selected from the group consisting of CH.sub.2, and
0;
[0110] R.sup.5 is selected from the group consisting of H,
OCH.sub.3, Cl, F, Br, I, OH, NH.sub.2, CN, CF.sub.3 and
CH.sub.3;
[0111] R.sup.6 is H or F; and
[0112] R.sup.3 and R are each independently selected from the group
consisting of:
[0113] A) H, C1-7alkyl, C3-7alkenyl, wherein the carbon in said
alkenyl that is attached to the nitrogen member has only single
bonds, C3-7alkynyl, wherein the carbon in said alkynyl that is
attached to the nitrogen member has only single bonds,
C3-7cycloalkyl optionally benzofused, C5-7cycloalkenyl,
--C3-7cycloalkylC1-7alkyl, --C1-7alkylC3-7cycloalkyl and phenyl,
wherein each of the substituents A) is independently substituted
with 0, 1, or 2 R.sup.Q, and each of said R.sup.Q is a substituent
at a carbon member that is at least one carbon member removed from
the nitrogen member;
[0114] B) a substituent HetR.sup.a;
[0115] C) --C1-7alkylC(O)R.sup.x, optionally substituted with
CH.sub.2R.sup.Ar or CH.sub.2R.sup.Ar';
[0116] D) --C2-5alkylC(O)R.sup.x, wherein two valence allowed
carbon members in the C2-5alkyl of said --C2-5alkylC(O)R.sup.x are
part of a saturated C3-6carbocycle;
[0117] E) --C2-5alkylOH wherein two valence allowed carbon members
in the C2-5alkyl of said --C2-5alkylOH are part of a saturated
C3-6carbocycle;
[0118] F) --C0-4alkylphenyl, wherein the phenyl in said
--C0-4alkylphenyl is fused at two adjacent carbon members in said
phenyl to R.sup.f, or is benzofused;
[0119] G) --C0-4alkylAr.sup.6, where Ar.sup.6 is a 6-membered
heteroaryl having a carbon member point of attachment and having
one or two --N=heteroatom members, and benzofused;
[0120] H) --C0-4alkylAr.sup.5, where Ar.sup.5 is a 5-membered
heteroaryl, having one heteroatom member selected from the group
consisting of O, S, and >NR.sup.Y, and having 0 or 1
--N=additional heteroatom member, optionally containing two
carbonyl groups, and optionally benzofused;
[0121] I) --C1-4alkylAr.sup.5', where Ar.sup.5' is a 5-membered
heteroaryl containing 3 or 4 nitrogen members, optionally
substituted with R.sup.Y, and having a valence allowed site as a
point of attachment;
[0122] J) --C0-4alkylAr.sup.6-6, where Ar.sup.6-6 is a
C0-4alkyl-attached phenyl fused at valence allowed sites to a
6-membered heteroaryl, wherein said 6-membered heteroaryl has one
or two --N=heteroatom members;
[0123] K) --C0-4alkylAr.sup.6-5, where Ar.sup.6-5 is a
C0-4alkyl-attached phenyl fused at valence allowed sites to a
5-membered heteroaryl, said 5-membered heteroaryl having one
heteroatom member selected from the group consisting of O, S, and
>NR.sup.Y, and said 5-membered heteroaryl having 0 or 1
additional heteroatom member which is --N.dbd.;
[0124] L) one of 2-(4-ethyl-phenoxy)-benzothiazole,
2-(4-ethyl-phenoxy)-benzooxazole, and
2-(4-ethyl-phenoxy)-1H-benzoimidazole; and
[0125] M) SO.sub.2C.sub.1-4alkyl;
[0126] alternatively R.sup.2 and R.sup.3 are taken together with
the nitrogen to which they are attached to form a heterocyclic ring
that contains at least one heteroatom member that is said
attachment nitrogen, said heterocyclic ring being selected from the
group consisting of:
i) a 4-7 membered heterocyclic ring HetR.sup.b, said 4-7 membered
heterocyclic ring HetR.sup.b having one heteroatom member that is
said attachment nitrogen, and being substituted with 0, 1, or 2
substituents at the same or at different substitution members, said
substituents being selected from the group consisting of --R.sup.Y,
--CN, --C(O)R.sup.Y, --C.sub.0-4alkylCO.sub.2R.sup.Y,
--C.sub.0-4alkylC(O)CO.sub.2R.sup.Y, --C.sub.0-4alkylOR.sup.Y,
--C.sub.0-4 alkylC(O)NR.sup.YR.sup.Z,
--C.sub.0-4alkylNR.sup.YC(O)R.sup.Z,
--C(O)NR.sup.ZOR.sup.Y,--C.sub.0-4akylNR.sup.YC(O)CH.sub.2OR.sup.Y,
--C.sub.0-4alkylNR.sup.YC(O)CH.sub.2C(O)R.sup.Y,
--C.sub.0-4alkylNR.sup.YCO.sub.2R.sup.Y,--C.sub.0-4alkylNR.sup.YC(O)NR.su-
p.YR.sup.Z, --C.sub.0-4 alkylNR.sup.YC(S)NR.sup.YR.sup.Z,
--NR.sup.YC(O)CO.sub.2R.sup.Y, --NR.sup.YR.sup.Z,
--C.sub.0-4alkylNR.sup.WSO.sub.2R.sup.Y,
1,3-dihydro-indol-2-one-1-yl, 1,3-dihydro-benzoimidazol-2-one-1-yl,
tetrazol-5-yl, 1-R.sup.Y-1H-tetrazol-5-yl, R.sup.Y-triazolyl,
2-R.sup.Y-2H-tetrazol-5-yl, pyrrolidine-2-thion-1-yl,
piperidine-2-thion-1-yl,
--C.sub.0-4alkylC(O)N(R.sup.Y)SO.sub.2R.sup.Y), --C.sub.0-4
alkylN(R.sup.Y)(SO.sub.2)NR.sup.YR.sup.Y,
--C.sub.0-4alkylN(R.sup.Y)(SO.sub.2)NR.sup.YCO.sub.2R.sup.Y,
halo,
##STR00007##
[0127] ii) a 5-7 membered heterocyclic ring HetR.sup.c, said 5-7
heterocyclic ring HetR.sup.c having one additional heteroatom
member separated from said attachment nitrogen by at least one
carbon members, said additional heteroatom member being selected
from the group consisting of O, S(.dbd.O).sub.0-2, and
>NR.sup.M, said 5-7 membered heterocyclic ring HetR.sup.c having
0 or 1 carbonyl members, and being substituted with 0, 1, or 2
substituents at the same or at different carbon substitution
members, said substituents being selected from the group consisting
of --C(O)R.sup.Y, --CO.sub.2R.sup.Y --C.sub.3-4alkylCO.sub.2R.sup.Y
and R.sup.Z;
[0128] iii) one of imidazolidin-1-yl, 2-imidazolin-1-yl,
pyrazol-1-yl, imidazol-1-yl, 2H-tetrazol-2-yl, 1H-tetrazol-1-yl,
pyrrol-1-yl, 2-pyrrolin-1-yl, and 3-pyrrolin-1-yl, wherein each of
said 2H-tetrazol-2-yl and 1H-tetrazol-1-yl is substituted at the
carbon member with 0 or 1 of --C.sub.0-4alkylR.sup.Z,
--C.sub.0-4alkylSR.sup.Y, --C.sub.0-4 alkylCO.sub.2R.sup.Y, and
substituent HetR.sup.a; and
[0129] iv) one of 1,2,3,4-tetrahydro-quinolin-1-yl,
1,2,3,4-tetrahydro-isoquinolin-2-yl, indol-1-yl, isoindol-2-yl,
indolin-1-yl, benzimidazol-1-yl,
2,8-diaza-spiro[4.5]decan-1-one-8-yl,
4-{[(2-tert-butoxycarbonylamino-cyclobutanecarbonyl)-amino]-methyl}-piper-
idin-1-yl,
4-{[(2-amino-cyclobutanecarbonyl)-amino]-methyl}-piperidin-1-yl- ,
3,9-diaza-spiro[5.5]undecane-3-carboxylic acid-9-yl tert-butyl
ester, 4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-8-yl, and
4-oxo-1,3,8-triaza-spiro[4.5]dec-8-yl;
[0130] wherein
[0131] substituent HetR.sup.a is a 4-7 membered heterocyclic ring
having a carbon member point of attachment and containing a member
>NR.sup.M as a heteroatom member, and said heteroatom member
being separated from said carbon member point of attachment by at
least 1 additional carbon member;
[0132] R.sup.K is selected from the group consisting of H,
--C.sub.1-4alkyl, --C.sub.0-4alkylR.sup.Ar each optionally
substituted with 1, 2, or 3 substituents R.sup.N;
[0133] R.sup.L is selected from the group consisting of
--CO.sub.2R.sup.S and --C(O)NR.sup.SR.sup.S';
[0134] R.sup.M is selected from the group consisting of R.sup.Z,
indol-7-yl, --SO.sub.2R.sup.Y, --C.sub.3-4alkylCO.sub.2R.sup.Y,
--CO.sub.2R.sup.Y, --C(O)NR.sup.ZOR.sup.Y, --C(O)R.sup.Y,
--C(O)C.sub.0-4alkylOR.sup.Y,
--C.sub.0-4alkylC(O)NR.sup.SR.sup.S'--, C.sub.0-4
alkylC(O)CO.sub.2R.sup.Y, 1,3-dihydro-indol-2-one-1-yl,
1,3-dihydro-benzoimidazol-2-one-1-yl, tetrazol-5-yl,
1-R.sup.Y-1H-tetrazol-5-yl,
[0135] R.sup.Y-triazolyl, 2-R.sup.Y-2H-tetrazol-5-yl and
--C.sub.0-4alkylC(O)N(R.sup.Y)(SO.sub.2R.sup.Y), each optionally
substituted with 1, 2 or 3 substituents R.sup.N;
[0136] R.sup.N is selected from the group consisting of OCH.sub.3,
Cl, F, Br, I, OH, NH.sub.2, CN, CF.sub.3, CH.sub.3, OC(O)CH.sub.3,
and NO.sub.2;
[0137] R.sup.P is selected from the group consisting of R.sup.Y,
--C.sub.2-4alkylOR.sup.Y, R.sup.Ar,
--C.sub.1-2alkylCO.sub.2R.sup.Y, --C.sub.1-2
alkylCONR.sup.SR.sup.S', indol-7-yl, and
--SO.sub.2C.sub.1-4alkyl;
[0138] R.sup.Q is selected from the group consisting of fluoro,
chloro, bromo, iodo, trifluoromethyl, trichloromethyl, --CN,
--C.sub.1-4alkyl, --C.sub.0-4alkylR.sup.Ar,
--C.sub.0-4alkylR.sup.Ar', --C.sub.0-4alkylOR.sup.Y,
--C.sub.0-4alkylCO.sub.2R.sup.Y, --C.sub.0-4alkylNR.sup.YR.sup.Z,
--C.sub.0-4alkylNR.sup.YCOR.sup.Y,
--C.sub.0-4alkylNR.sup.YCONR.sup.YR.sup.Z,
--C.sub.0-4alkylNR.sup.YSO.sub.2R.sup.Y, and --C.sub.0-4
alkylSR.sup.Y;
[0139] R.sup.S and R.sup.S' are independently selected from the
group consisting of H, --C.sub.1-4alkyl, and --C.sub.0-4
alkylphenyl; alternatively, R.sup.S and R.sup.S' are taken together
with the nitrogen member to which said R.sup.S and R.sup.S' are
attached to form a 4-7 membered heterocyclic ring having 0 or 1
additional heteroatom member selected from the group consisting of
O, S, and >NR.sup.Y, provided that said additional heteroatom
member is separated by at least two carbon members from said
nitrogen member to which said R.sup.S and R.sup.S' are attached,
and provided that where R.sup.Y is C.sub.0-4alkylR.sup.Ar, then
R.sup.Ar is not substituted with R.sup.L;
[0140] R.sup.W is selected from the group consisting of R.sup.Y,
and --C.sub.3-7cycloalkyl;
[0141] R.sup.X is selected from the group consisting of --OR.sup.Y,
--NR.sup.YR.sup.Z, --C.sub.1-4alkyl, and
--C.sub.0-4alkylR.sup.Ar;
[0142] R.sup.Y is selected from the group consisting of H,
--C.sub.1-4alkyl, --C.sub.0-4alkylR.sup.Ar and
--C.sub.0-4alkylR.sup.Ar', each optionally substituted with 1, 2,
or 3 substituents R.sup.N;
[0143] R.sup.Z is selected from the group consisting of R.sup.Y,
--C.sub.2-4alkylOR.sup.Y, --C.sub.1-2alkylCO.sub.2R.sup.Y,
--C.sub.1-2 alkylC(O)NR.sup.SR.sup.S', and
--C.sub.2-4akylNR.sup.SR.sup.S';
[0144] when R.sup.Y and R.sup.Z are attached to a nitrogen member,
R.sup.Y and R.sup.Z are selected as defined above, or R.sup.Y and
R.sup.Z are taken together with the R.sup.Y- and R.sup.Z-attached
nitrogen member to form a 4-7 membered heterocyclic ring HetR.sup.d
having 0 or 1 additional heteroatom members selected from the group
consisting of O, S, and >NR.sup.M, said 4-7 membered
heterocyclic ring HetR.sup.d having 0 or 1 carbonyl members, and
said 4-7 membered heterocyclic ring HetR.sup.d having 0 or 1
valence allowed carbon members substituted with at least one of
R.sup.M, --CO.sub.2H, and --C.sub.0-1alkylOR.sup.Y;
[0145] R.sup.Ar is a moiety with a carbon member attachment point
and said moiety is selected from the group consisting of phenyl,
pyridyl, pyrimidyl, and pyrazinyl, wherein each valence allowed
carbon member in each of said moieties is independently substituted
with at least one of 0, 1, 2 or 3 R.sup.N, and 0 or 1 R.sup.L;
[0146] R.sup.Ar' is a 3-8 membered ring, having 0, 1 or 2
heteroatom members selected from the group consisting of O, S, N,
and >NR.sup.Y, having 0, 1, or 2 unsaturated bonds, having 0 or
1 carbonyl members, wherein each valence allowed member in each of
said rings is independently substituted with 0, 1, or 2 R.sup.K;
and
[0147] R.sup.f is a linear 3- to 5-membered hydrocarbon moiety
having 0 or 1 unsaturated carbon-carbon bonds and having 0 or 1
carbonyl members.
[0148] In some embodiments, the compound of formula (III) is
selected from,
2-[4-(2-Piperidin-1-yl-ethoxy)-phenoxy]-benzooxazole,
(1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]ethyl}piperidin-4-yl)-methanol,
1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-ol, 2-[4
(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-dibutyl-amine,
(1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-piperidin-2-yl)-methanol,
1-{3-[4-(Benzooxazol-2-yloxy)-phenoxy]-propyl}-4
phenyl-piperidin-4-ol,
1-{3-[4-(Benzooxazol-2-yloxy)-phenoxy]-propyl}-4-benzyl-piperidin-4-ol,
2-[4-(2-Piperidin-1-yl-ethyl)-phenoxy]-benzooxazole,
3-[4-(Benzooxazol-2-yloxy)-phenyl]-propyl}-cyclohexyl-ethyl-amine,
1-{3-[4-(Benzooxazol-2-yloxy)-phenyl]-propyl}-piperidin-4-ol,
1-{3-[4-(Benzooxazol-2-yloxy)-phenoxy]-2-hydroxy-propyl}-4-phenyl-piperid-
in-4-ol,
1-[2-(4-Benzooxazol-2-ylmethyl-phenoxy)-ethyl]-piperidine-4-carbo-
xylic acid ethyl ester,
2-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenoxy]-benzooxazole,{3-[4-(Benzooxazol--
2-yloxy)-phenoxy]-propyl}-dimethyl-amine,
2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-dimethyl-amine,
2-[4-(2-Azepan-1-yl-ethoxy)-phenoxy]-benzooxazole,
1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-4-phenyl-piperidin-4-ol,
{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-cyclohexyl-ethyl-amine,
2-{4-[2-(2-Ethyl-piperidin-1-yl)-ethoxy]-phenoxy}-benzooxazole-1-{2-[4-(B-
enzooxazol-2-yloxy)-phenoxy]-ethyl}-4-phenyl-piperidine-4-carbonitrile,
1-(1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-4-phenyl-piperidin-4-yl)-
-ethanone,
2-{4-[2-(4-Methyl-piperidin-1-yl)-ethoxy]-phenoxy}-benzooxazole- ,
1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-4-(4-chloro-phenyl)-piperi-
din-4-ol,
1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-4-(4-bromo-phenyl)-
-piperidin-4-ol,
1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-4-(4-chloro-3-trifluorometh-
yl-phenyl)piperidin-4-ol,
1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-4-benzyl-piperidin-4-ol,
2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-cyclohexyl-methyl-amine,
{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-cyclopropylmethyl-propyl-amin-
e,{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-butyl-ethyl-amine,
2-({2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-benzyl-amino)-ethanol,
2-{4-[2-(4-Benzyl-piperidin-1-yl)-ethoxy]-phenoxy}-benzooxazole,
(1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-piperidin-3-yl)-methanol,
2-({2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-propyl-amino)-ethanol,
2-[4-(2-Azetidin-1-yl-ethoxy)-phenoxy]benzoxazole,
N-(1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-2-phenyl-
-acetamide,
1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-piperidine-3-carboxylic
acid ethyl ester,
2-{4-[3-(4-Phenyl-piperidin-1-yl)-propoxy]-phenoxy}-benzooxazole,
1-{2-[4-(Benzooxazol-2-yloxy)-phenyl]-ethyl}-4-phenyl-piperidin-4-ol,
{2-[4-(Benzooxazol-2-yloxy)-phenyl]-ethyl}-cyclohexyl-ethyl-amine,
2-[4-(2-Pyrrolidin-1-yl-ethyl)-phenoxy]-benzooxazole,
2-[4-(2-Azepan-1-yl-ethyl)-phenoxy]-benzooxazole,
2-[4-(Benzooxazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-propyl-amine,
{2-[4-(Benzooxazol-2-yloxy)-phenyl]-ethyl}-dibutyl-amine,
1-{2-[4-(Benzooxazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-ol,
1-{2-[4-(Benzooxazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylic
acid methyl ester,
1-{3-[4-(Benzooxazol-2-yloxy)-phenyl]-propyl}-4-phenyl-piperidin-4-ol,
2-[4-(3-Piperidin-1-yl-propyl)-phenoxy]-benzooxazole,
{3-[4-(Benzooxazol-2-yloxy)-phenyl]-propyl}-dibutyl-amine,
{3-[4-(Benzooxazol-2-yloxy)-phenyl]-propyl}-cyclopropylmethyl-propyl-amin-
e,
1-[4-(Benzooxazol-2-yloxy)-phenoxy]-3-pyrrolidin-1-yl-propan-2-ol,
1-[2-(4-Benzooxazol-2-ylmethyl-phenoxy)-ethyl]-4-phenyl-piperidin-4-ol,
1-[2-(4-Benzooxazol-2-ylmethyl-phenoxy)-ethyl]-piperidine-4-carboxylic
acid amide, 2-(4-Piperidin-1-ylmethyl-phenoxy)-benzooxazole,
2-[4-(2-Morpholin-4-yl-ethoxy)-phenoxy]-benzooxazole, and
{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-diethyl-amine and
pharmaceutically acceptable salts, prodrugs, and solvates thereof
of any of the foregoing compounds.
[0149] In some embodiments, the compound of formula (III) is
selected from,
{2-[4-(6-Chloro-benzothiazol-2-yloxy)-phenoxy]-ethyl}-diethyl-amine-
, 1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-ol,
1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carboxylic
acid ethyl ester,
1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carboxylic
acid,
(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-pyr-
rolidin-1-yl-methanone,
3-[(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carbonyl)-
-amino]-propionic acid ethyl ester,
1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carboxylic
acid amide,
1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-pyrroli-
din-2-one,
1'-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-[1,4']bipiperid-
inyl-2-one,
8-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-2,8-diaza-spiro[4.5]decan--
1-one, 2-[4-(3-Pyrrolidin-1-yl-propoxy)-phenoxy]-benzothiazole,
{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclohexyl-ethyl-amine,
1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-3-carboxylic
acid amide,
1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-3-methyl-
-1,3-dihydro-benzoimidazol-2-one,
1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylic
acid methyl ester,
(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-(4-methyl--
piperazin-1-yl)-methanone,
1-[2-(4-Benzothiazol-2-ylmethyl-phenoxy)-ethyl]-piperidine-4-carboxylic
acid methyl ester,
3-({2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-cyclopropyl-amino)-propio-
nic acid,
{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-dimethyl-amine,
2-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenoxy]-benzothiazole,
{3-[4-(Benzothiazol-2-yloxy)-phenoxy]-propyl}-dimethyl-amine,
2-[4-(2-Azepan-1-yl-ethoxy)-phenoxy]-benzothiazole,
2-[4-(2-Azepan-1-yl-ethoxy)-phenoxy]-6-methoxy-benzothiazole,
1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-4-phenyl-piperidin-4-ol,
{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-cyclohexyl-ethyl-amine,
1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-4-(4-chloro-phenyl)-piperi-
din-4-ol,
{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-dibutyl-amine,
1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-4-(4-bromo-phenyl)-piperid-
in-4-ol,
1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-4-(4-chloro-3-trif-
luoromethyl-phenyl)-piperidin-4-ol,
1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-4-benzyl-piperidin-4-ol,
{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-[1,4']bipiperidine,
(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-methanol,
N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-2-pheny-
l-acetamide,
1'-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-[1,4']bipiperidinyl-2-one-
,
2-(4-{2-[4-(2-Morpholin-4-yl-ethyl)-piperazin-1-yl]-ethoxy}-phenoxy)-ben-
zothiazole,
2-(4-{2-[4-(2-Morpholin-4-yl-ethyl)-piperazin-1-yl]-ethyl}-phenoxy)-benzo-
thiazole,
1-{3-[4-(Benzothiazol-2-yloxy)-phenoxy]-propyl}-4-phenyl-piperid-
in-4-ol,
1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-4-phenyl-piperidin--
4-ol, 2-[4-(2-Pyrrolidin-1-yl-ethyl)-phenoxy]-benzothiazole,
2-[4-(2-Azepan-1-yl-ethyl)-phenoxy]-benzothiazole,
{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-propyl-amin-
e, {2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-dibutyl-amine,
2-[4-(2-Piperidin-1-yl-ethyl)-phenoxy]-benzothiazole,
1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-ol,
1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylic
acid methyl ester,
1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylic
acid amide,
1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-3-carboxylic
acid ethyl ester,
1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-4-phenyl-piperidine-4-carbo-
xylic acid ethyl ester,
(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-acetic
acid ethyl ester,
1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-1,3-dihy-
dro-indol-2-one,
1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-pyrrolid-
in-2-one,
N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-
-2-phenyl-acetamide,
8-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-2,8-diaza-spiro[4.5]decan-1-
-one, 1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-3-ol,
1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylic
acid ethyl ester,
1'-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-[1,4']bipiperidine,
2-{4-[2-(4-Methyl-piperazin-1-yl)-ethyl]-phenoxy}-benzothiazole,
2-(4-{2-[4-(1-Benzyl-1H-tetrazol-5-yl)-piperidin-1-yl]-ethoxy}-phenoxy)-b-
enzothiazole,
4-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carbonyl)-p-
iperazine-1-carboxylic acid tert-butyl ester,
2-(4-{2-[4-(2-Morpholin-4-yl-ethyl)-piperazin-1-yl]-ethyl}-phenoxy)-benzo-
thiazole,
1-[2-(4-Benzothiazol-2-ylmethyl-phenoxy)-ethyl]-piperidine-4-car-
boxylic acid amide,
1-{1-[2-(4-Benzothiazol-2-ylmethyl-phenoxy)-ethyl]-piperidin-4-yl}-pyrrol-
idin-2-one,
1-[4-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carbonyl-
)-piperazin-1-yl]-ethanone,
1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylic
acid,
1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-p-
yrrolidine-2-thione,
2-(4-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperazin-1-yl)-ethanol-
,
2-(4-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperazin-1-yl)-1-pyrr-
olidin-1-yl-ethanone,
2-(4-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperazin-1-yl)-1-morph-
olin-4-yl-ethanone,
1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-3-carboxylic
acid,
1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-2-carboxyl-
ic acid,
(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-3-yl)-ac-
etic acid,
(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-
-acetic acid ethyl ester,
(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-carbamic
acid tert-butyl ester,
(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-acetic
acid,
(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-3-yl)-meth-
anol,
({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclohexyl-amino)-aceti-
c acid methyl ester,
(4-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperazin-1-yl)-acetic
acid,
1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-5-
-oxo-pyrrolidine-2-carboxylic acid ethyl ester,
1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-5-oxo-p-
yrrolidine-2-carboxylic acid,
4-(4-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperazin-1-yl)-phenol,
N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-4-chlor-
o-N-cyclopropyl-benzene sulfonamide,
3-({2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-cyclopropylmethyl-amino)--
propionic acid,
3-({2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-isopropyl-amino)-propioni-
c acid,
1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-ylamine-
,
3-[{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-(1-methyl-piperidin-4-yl-
)-amino]-propionic acid,
3-({2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-benzyl-amino)-propionic
acid,
3-((1-Acetyl-piperidin-4-yl)-{2-[4-(benzothiazol-2-yloxy)-phenoxy]--
ethyl}-amino)-propionic acid,
4-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-1H-tetrazol-5-yl)-piper-
idine-1-carboxylic acid tert-butyl ester,
3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propion-
ic acid,
3-((1-Acetyl-piperidin-4-yl)-{2-[4-(benzothiazol-2-yloxy)-phenyl]-
-ethyl}-amino)-propionic acid,
3-[{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-(1-methyl-piperidin-4-yl)--
amino]-propionic acid,
3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-amino)-p-
ropionic acid,
3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-isopropyl-amino)-propionic
acid,
2-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-1--
pyrrolidin-1-yl-ethanone,
(R)-1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-3-carboxylic
acid,
1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-1,-
3-dihydro-benzoimidazol-2-one,
2-(4-{2-[4-(6-Methyl-pyridin-2-yl)-piperazin-1-yl]-ethyl}-phenoxy)-benzot-
hiazole,
2-{4-[2-(4-Ethanesulfonyl-piperazin-1-yl)-ethyl]-phenoxy}-benzoth-
iazole,
2-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-1-
-morpholin-4-yl-ethanone,
3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-methyl-amino)-propionic
acid,
3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopentyl-amino)-p-
ropionic acid,
3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclobutyl-amino)-propioni-
c acid,
3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-benzyl-amino)-propi-
onic acid,
(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-
-(4-hydroxymethyl-piperidin-1-yl)-methanone,
{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amine,
(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-[4-(2-hyd-
roxy-ethyl)-piperazin-1-yl]-methanone,
(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-[4-(2-hyd-
roxy-ethyl)-piperidin-1-yl]-methanone,
2-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-ethanol-
,
3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propan-
-1-ol,
4-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-b-
utyric acid,
3-[(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carbonyl)-
-amino]-propionic acid,
4-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-butyron-
itrile,
3-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-p-
ropionic acid,
[(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carbonyl)-m-
ethyl-amino]-acetic acid,
3-(4-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperazin-1-yl)-phenol,
2-(4-{2-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-ethoxy}-phenoxy)-benzothiaz-
ole,
2-{4-[2-(5-Piperidin-4-yl-tetrazol-1-yl)-ethoxy]-phenoxy}-benzothiazo-
le,
(S)-1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)--
4-hydroxy-pyrrolidin-2-one,
2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-amine,
2-[({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-methyl-
]-cyclopropanecarboxylic acid ethyl ester,
4-(4-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperazine-1-carbonyl)--
benzoic acid ethyl ester,
2-[({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-methyl-
]-cyclopropanecarboxylic acid,
1-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propan--
2-ol,
3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-1,-
1,1-trifluoro-propan-2-ol,
3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propion-
amide,
3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-p-
ropane-1,2-diol,
2-{4-[2-(5-Phenyl-tetrazol-2-yl)-ethoxy]-phenoxy}-benzothiazole,
2-{4-[2-(5-Phenyl-tetrazol-1-yl)-ethoxy]-phenoxy}-benzothiazole,
N-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-N-cyclopropyl-2-(2H-tetrazo-
l-5-yl)-acetamide,
(S)-3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-2-m-
ethyl-propan-1-ol,
(R)-3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-2-m-
ethyl-propan-1-ol,
2-{4-[2-(5-Methylsulfanyl-tetrazol-2-yl)-ethoxy]-phenoxy}-benzothiazole,
2-{4-[2-(5-Methylsulfanyl-tetrazol-1-yl)-ethoxy]-phenoxy}-benzothiazole,
2-[4-(2-Tetrazol-2-yl-ethoxy)-phenoxy]-benzothiazole,
2-[4-(2-Tetrazol-1-yl-ethoxy)-phenoxy]-benzothiazole,
(1R,2R)-2-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethylamino}-cyclohexanecar-
boxylic acid,
(1S,2R)-2-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethylamino}-cyclohexanecar-
boxylic acid,
(1R,2R)-2-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethylamino}-cyclohexanol,
(1S,2R)-2-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethylamino}-cyclohexanol,
4-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-butyric
acid, 1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidine-4-carboxylic
acid,
1-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-pyrrolidin-2-one,
2-(2-Fluoro-4-piperidin-1-ylmethyl-phenoxy)-benzothiazole,
N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-2-hydroxy-acetamid-
e,
1-(2-{[4-(Benzothiazol-2-yloxy)-benzyl]-cyclopropyl-amino}-ethyl)-4-hyd-
roxy-pyrrolidin-2-one,
N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-N-methyl-methanesu-
lfonamide,
2-{4-[4-(1H-Tetrazol-5-yl)-piperidin-1-ylmethyl]-phenoxy}-benzo-
thiazole,
1-{4-[4-(Benzothiazol-2-yloxy)-benzyl]-piperazin-1-yl}-2-hydroxy-
-ethanone,
N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylmethyl}-me-
thanesulfonamide,
3-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-oxazolidin-2-one,
4-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-morpholin-3-one,
(R)
1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-4-h-
ydroxy-pyrrolidin-2-one,
2-(4-{2-[4-(1H-Tetrazol-5-yl)-piperidin-1-yl]-ethyl}-phenoxy)-benzothiazo-
le,
(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-2-yl)-methan-
ol,
(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-1H-tetrazol-5-yl)-acet-
ic acid ethyl ester,
(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-1H-tetrazol-5-yl)-acetic
acid ethyl ester,
2-{4-[2-(5-Piperidin-4-yl-tetrazol-2-yl)-ethoxy]-phenoxy}-benzothiazole
hydrochloride,
7-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-4-spiro-[3-phthalide]-pipe-
ridine,
1-{3-[4-(Benzothiazol-2-yloxy)-phenyl]-propyl}-piperidine-4-carbox-
ylic acid ethyl ester,
2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethylamine hydrochloride,
2-(4-{2-[4-(1H-Tetrazol-5-yl)-piperidin-1-yl]-ethoxy}-phenoxy)-benzothiaz-
ole, 2-(4-Piperidin-1-ylmethyl-phenoxy)-benzooxazole,
[4-(Benzothiazol-2-yloxy)-benzyl]-cyclohexyl-ethyl-amine,
[4-(Benzothiazol-2-yloxy)-benzyl]-cyclopropylmethyl-propyl-amine,
1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidine-4-carboxylic acid
amide,
1'-[4-(Benzothiazol-2-yloxy)-benzyl]-[1,4']bipiperidinyl-2-one,
{4-[4-(Benzothiazol-2-yloxy)-benzyl]-piperazin-1-yl}-pyridin-3-yl-methano-
ne,
{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylmethyl}-carbamic
acid tert-butyl ester,
{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylmethyl}-carbamic
acid methyl ester,
N--{C-[[4-(benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl]-methylamino
sulfonyl}-carbamic acid tert-butyl ester,
N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylmethyl}-sulfamide
hydrochloride,
N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylmethyl}-acetamide,{1-
-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-acetic acid,
Acetic acid
({1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylmethyl}-carbamoy-
l)-methyl ester,
[2-({1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylmethyl}-carbamoyl)-
-cyclobutyl]-carbamic acid tert-butyl ester,
2-Amino-cyclobutanecarboxylic acid
{1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylmethyl}-amide
dihydrochloride, 2-(4-Pyrrolidin-1-ylmethyl-phenoxy)-benzothiazole,
2-{[4-(Benzothiazol-2-yloxy)-benzyl]-ethyl-amino}-ethanol,
2-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-2-yl}-ethanol,
1-{4-[4-(Benzothiazol-2-yloxy)-benzyl]-piperazin-1-yl}-ethanone,
8-[4-(Benzothiazol-2-yloxy)-benzyl]-2,8-diaza-spiro[4.5]decan-1-one,
Spiro[isobenzofuran-1(3H), 4'-piperidin]-3-one,
1'-[4-(Benzothiazol-2-yloxy)-benzyl](R)-1-[4-(Benzothiazol-2-yloxy)-benzy-
l]-pyrrolidin-3-ol,
2-[4-(2-Methyl-piperidin-1-ylmethyl)-phenoxy]-benzothiazole,
[4-(Benzothiazol-2-yloxy)-benzyl]-diethyl-amine,
[4-(Benzothiazol-2-yloxy)-benzyl]-butyl-methyl-amine,
2-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-ethanol,
1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-ol,{1-[4-(Benzothiazol-2--
yloxy)-benzyl]-piperidin-2-yl}-methanol,
(R)-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-pyrrolidin-2-yl}-methanol,
2-(4-Azetidin-1-ylmethyl-phenoxy)-benzothiazole,
1-[4-(Benzothiazol-2-yloxy)-benzyl]-[1,4]diazepan-5-one,
{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-3-yl}-methanol,
1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidine-3-carboxylic acid
amide,
9-[4-(Benzothiazol-2-yloxy)-benzyl]-3,9-diaza-spiro[5.5]undecane-3-carbox-
ylic acid tert-butyl ester,
2-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-3-yl}-ethanol,
cis-4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethylamino}-cyclohexanecarboxy-
lic acid trifluoromethanesulfonate salt,
(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-(tetrahydr-
o-furan-2-yl)-methanone, propane-2-sulfonic acid
(1-{2-[4-(benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carbonyl)-am-
ide,
(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-oxo-ac-
etic methyl ester,
N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carbonyl)-b-
enzenesulfonamide trifluoromethanesulfonate salt,
N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carbonyl)-m-
ethanesulfonamide trifluoromethanesulfonate salt,
(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-oxo-acetic
acid trifluoromethanesulfonate salt,
(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-morpholin--
4-yl-methanone,
1-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-2-thioph-
en-2-yl-ethanone,
(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-pyridin-3--
yl-methanone,
(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-cyclopropy-
l-methanone,
1-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-2-methox-
y-ethanone,
1-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-2,2,2-tr-
ifluoro-ethanone,
4-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazine-1-carbonyl)-b-
enzoic acid,
(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-pyridin-4--
yl-methanone,
(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-(5-methyl--
pyrazin-2-yl)-methanone,
(R)-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-(tetra-
hydro-furan-2-yl)-methanone,
(S)-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-(tetra-
hydro-furan-2-yl)-methanone,
(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-(tetrahydr-
o-furan-3-yl)-methanone,
1-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-2-hydrox-
y-ethanone,
2-[2-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-2-oxo-
-ethyl]-cyclopentanone,
3-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-propioni-
c acid trifluoromethanesulfonate salt,
3-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-oxazolid-
in-2-one,
4-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-
-morpholin-3-one,
4-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-morphol-
in-3-one,
3-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl-
)-oxazolidin-2-one,
1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylic
acid benzyloxy-amide,
(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-acetic
acid,
(R)-1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl-
)-4-hydroxy-pyrrolidin-2-one,
1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylic
acid hydroxyamide,
(S)-1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-4-hy-
droxy-pyrrolidin-2-one,
(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-carbamic
acid tert-butyl ester,
2-{4-[2-(4-Fluoro-piperidin-1-yl)-ethyl]-phenoxy}-benzothiazole,
2-{4-[2-(4,4-Difluoro-piperidin-1-yl)-ethyl]-phenoxy}-benzothiazole,
(R)-1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-pyrrolidin-3-ol,
N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-Formamid-
e,
(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-urea,
1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-3-cyano--
2-phenyl-isourea,
1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-3-cyano--
2-methyl-isothiourea,
N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-methanes-
ulfonamide,
1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-3-cyano--
2-methyl-guanidine,
8-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-1-phenyl-1,3,8-triaza-spiro-
[4.5]decan-4-one,
8-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-1,3,8-triaza-spiro[4.5]deca-
ne-2,4-dione,
(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-methyl-car-
bamic acid tert-butyl ester,
N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-N-methyl-
-acetamide,
N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-N-methyl-
-methanesulfonamide, acetic acid
[(1-{2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-methyl-ca-
rbamoyl]-methyl ester,
N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-N-acetam-
ide, acetic acid
(1-{2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-ylcarbamoyl)-m-
ethyl ester,
2-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-methyl-amino)-3-(1H-imidaz-
ol-2-yl)-propionic acid,
2-(4-{2-[4-(3-Nitro-pyridin-2-yl)-[1,4]diazepan-1-yl]-ethyl}-phenoxy)-ben-
zothiazole, 2-(4-Piperidin-1-ylmethyl-phenoxy)-benzothiazole,
1-[4-(Benzothiazol-2-yloxy)-benzyl]-4-phenyl-piperidin-4-ol,
1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-ol,
{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-methanol,
N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-methanesulfonamide-
,
N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylmethyl}-2-hydroxy-a-
cetamide,
{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-carbamic acid
methyl ester,
{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylmethyl)-urea,
N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylmethyl}-2,2,2-triflu-
oro-acetamide,
{4-[4-(Benzothiazol-2-yloxy)-benzyl]-piperazin-1-yl}-acetic acid,
2-[4-(4-Methanesulfonyl-piperazin-1-ylmethyl)-phenoxy]-benzothiazol-
e,
1-{4-[4-(Benzothiazol-2-yloxy)-benzyl]-piperazin-1-yl}-2,2,2-trifluoro--
ethanone, 2-(4-Morpholin-4-ylmethyl-phenoxy)-benzothiazole,
{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-carbamic acid
phenyl ester,
N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-benzenesulf-
onamide, 3-[4-(Benzothiazol-2-yloxy)-benzylamino]-propionic acid
ethyl ester, 3-[4-(Benzothiazol-2-yloxy)-benzylamino]-propionic
acid,
[(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carbonyl)-m-
ethyl-amino]-acetic acid ethyl ester,
1'-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-[1,4']bipiperidinyl-4-car-
boxylic acid ethyl ester,
1'-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-[1,4']bipiperidinyl-4-car-
boxylic acid,
{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-ethyl-amine,
3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-2-methy-
l-propionic acid trifluoromethanesulfonic acid salt,
2-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-amino)-e-
thanol,
2-[2-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethy-
l-amino)-ethoxy]-ethanol,
3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-amino)-p-
ropan-1-01,
{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-(3-tetrazol-
-2-yl-propyl)-amine,
{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-(3-pyrrol-1-yl-pr-
opyl)-amine,
4-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-amino)-b-
utyronitrile,
1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylic
acid (2-cyano-ethyl)-amide,
{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-[3-(2H-tetr-
azol-5-yl)-propyl]-amine,
3-[5-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-tetra-
zol-1-yl]-propionitrile,
{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-[3-(2H-tetrazol-5-
-yl)-propyl]-amine,
1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylic
acid (2-hydroxy-1,1-dimethyl-ethyl)-amide,
{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-[3-(1H-[1,2-
,4]triazol-3-yl)-propyl]-amine,
{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-[3-(5-methy-
l-1H-[1,2,4]triazol-3-yl)-propyl]-amine,
{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-[3-(5-pheny-
l-1H-[1,2,4]triazol-3-yl)-propyl]-amine,
2-(4-{2-[4-(1-Methyl-1H-tetrazol-5-yl)-piperidin-1-yl]-ethyl}-phenoxy)-be-
nzothiazole,
2-(4-{2-[4-(2-Methyl-2H-tetrazol-5-yl)-piperidin-1-yl]-ethyl}-phenoxy)-be-
nzothiazole,
1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carbonitrile,
2-(4-{2-[4-(1H-[1,2,3]Triazol-4-yl)-piperidin-1-yl]-ethyl}-phenoxy)-benzo-
thiazole,
4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethylamino}-butyric acid
ethyl ester,
4-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-amino)-b-
utyric acid ethyl ester,
2-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-amino-
)-propyl]-isoindole-1,3-dione,
4-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}cyclopropylmethyl-amino)-bu-
tyric acid,
1-(3-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethylamino}-propyl)-pyrrolidin--
2-one,
N-1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-N1-cyclopropylmethy-
l-propane-1,3-diamine,
5-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-pentano-
ic acid methyl ester,
N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-amino-
)-propyl]-acetamide, morpholine-4-carboxylic acid
[3-({2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-amino)--
propyl]-amide,
N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-amino-
)-propyl]-methanesulfonamide,
5-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-pentano-
ic acid,
1-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-isopropyl-amino-
)-propyl]-pyrrolidin-2-one,
1-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-amino-
)-propyl]-pyrrolidin-2-one,
1-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-prop-
yl]-pyrrolidin-2-one,
1-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-propyl-amino)-propyl]-p-
yrrolidin-2-one,
4-((1-acetyl-piperidin-4-yl)-{2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyl}--
amino)-butyric acid ethyl ester,
4-((1-acetyl-piperidin-4-yl)-{2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyl}--
amino)-butyric acid ethyl ester,
4-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-methanesulfonyl-amino)-but-
yric acid,
({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-
-acetic acid,
6-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-hexanoi-
c acid ethyl ester,
7-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-heptano-
ic acid ethyl ester,
6-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-hexanoi-
c acid,
7-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)--
heptanoic acid,
N-1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-N1-cyclopropyl-propane-1,-
3-diamine,
N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-a-
mino)-propyl]-acetamide,
N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-prop-
yl]-isobutyramide,
N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-prop-
yl]-benzamide,
N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-prop-
yl]-4-chloro-benzamide,
N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-prop-
yl]-methanesulfonamide, propane-2-sulfonic acid
[3-({2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propyl-
]-amide trifluoromethanesulfonic acid salt,
8-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-octanoi-
c acid ethyl ester,
1-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-prop-
yl]-3-phenyl-urea,
8-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-octanoi-
c acid, tetrahydro-furan-2-carboxylic acid
[3-({2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propyl-
]-amide,
N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-ami-
no)-propyl]-2-hydroxy-acetamide,
4-({2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-cyclopropyl-amino)-butyri-
c acid,
1-{3-[4-(Benzothiazol-2-yloxy)-benzylamino]-propyl}-pyrrolidin-2-o-
ne,
1-(3-{[4-(Benzothiazol-2-yloxy)-benzyl]-methyl-amino}-propyl)-pyrrolid-
in-2-one,
1-(3-f[4-(Benzothiazol-2-yloxy)-benzyl]-isopropyl-amino}-propyl)-
-pyrrolidin-2-one,
1-(3-{[4-(Benzothiazol-2-yloxy)-benzyl]-ethyl-amino}-propyl)-pyrrolidin-2-
-one, [4-(Benzothiazol-2-yloxy)-benzyl]-cyclopropyl-amine,
N-1-[4-(Benzothiazol-2-yloxy)-benzyl]-N1-cyclopropyl-propane-1,3-diamine,
N-(3-{[4-(Benzothiazol-2-yloxy)-benzyl]-cyclopropyl-amino}-propyl)-isobut-
yramide,
1-(3-{[4-(Benzothiazol-2-yloxy)-benzyl]-cyclopropyl-amino}-propyl-
)-3-isopropyl-urea,
1-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-3-isopropyl-urea,
N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-oxalamic
acid methyl ester,
N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-isobutyramide,
tetrahydro-furan-2-carboxylic acid
{1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-amide,
1-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-4-hydroxy-pyrrolid-
in-2-one,
1-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-4-hydroxy-
-pyrrolidin-2-one,
{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-urea,
N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-oxalamic
acid,
N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-2-hydroxy-acetamid-
e,
N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]piperidin-4-yl}-2,2,2-trifluoro-a-
cetamide, 2-[4-(1,1-Dioxo-116-thiomorpholin-4-ylmethyl)
phenoxy]-benzothiazole,
N-{1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidin-4-amino
sulfonyl}-carbamic acid tert-butyl ester,
N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-acetamide,
N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-N,N-dimethylsulfam-
ide,
1-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-3-ethyl-urea,
1-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-3-ethyl-thiourea,
propane-1-sulfonic acid
{1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-amide,
propane-2-sulfonic acid
{1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-amide,
N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-sulfamide,
N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-formamide,
{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-carbamic acid
ethyl ester,
N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-propionamid-
e,
N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-butyramide,
1-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-3-propyl-urea,
{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-carbamic acid
propyl ester,
1-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-3-methyl-ur-
ea,
1-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-1,3-dimethyl-ur-
ea,
1-{1-[4-(Benzothiazol-2-yloxy)-benzyl]piperidin-4-yl}-1-methyl-urea,
N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-N-methyl-acetamide-
,
{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-methyl-carbamic
acid methyl ester,
N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-N-methyl-oxalamic
acid methyl ester,
N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-N-methyl-oxalamic
acid, Guanidine,
N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-N'-hydroxy,
{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-carbamic acid
isopropyl ester,
3-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-1,1-dimethyl-urea,
acetic acid
{1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylcarbamoyl}-methyl
ester,
{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-thiourea,
2-[4-(2-Morpholin-4-yl-ethoxy)-phenoxy]-benzothiazole; and
2-[4-(2-Piperidin-1-yl-ethoxy)-phenoxy]-benzothiazole and
pharmaceutically acceptable salts, prodrugs, and solvates thereof
of any of the foregoing compounds.
[0150] In some embodiments, the compound of formula (III) is
selected from,
1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-4-phenyl-piperid-
in-4-ol,
{2-[4-(1H-Benzoimidazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-
-propyl-amine,
cyclohexyl-ethyl-{2-[4-(1-methyl-1H-benzoimidazol-2-yloxy)-phenyl]-ethyl}-
-amine,
1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-4-(4-bromo-phen-
yl)-piperidin-4-ol,
1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-4-(4-chloro-phenyl)-pi-
peridin-4-ol,
1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-4-benzyl-piperidin-4-o-
l,
{2-[4-(1H-Benzoimidazol-2-yloxy)-phenyl]-ethyl}-cyclohexyl-ethyl-amine,
2-[4-(2-Pyrrolidin-1-yl-ethyl)-phenoxy]-1H-benzoimidazole,
2-[4-(2-Azepan-1-yl-ethyl)-phenoxy]-1H-benzoimidazole,
{2-[4-(1H-Benzoimidazol-2-yloxy)-phenyl]-ethyl}-dibutyl-amine,
1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-ol,
1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylic
acid methyl ester,
{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-cyclohexyl-ethyl-amine,
2-{4-[2-(4-Methyl-piperidin-1-yl)-ethoxy]-phenoxy}-1H-benzoimidazole,
2-{4-[2-(2-Ethyl-piperidin-1-yl)-ethoxy]phenoxy}-1H-benzoimidazole,
2-[4-(2-Piperidin-1-yl-ethoxy)-phenoxy]-1H-benzoimidazole,
(1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-metha-
nol,
1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-ol,
2-[4-(2-Azepan-1-yl-ethoxy)-phenoxy]-1H-benzoimidazole amide,
3-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-propyl}-dimethyl-amine,
2-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenoxy]-1H-benzoimidazole,
{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-diethyl-amine,
2-[4-(2-Morpholin-4-yl-ethoxy)-phenoxy]-1H-benzoimidazole,
2-[4-(2-Piperidin-1-yl-ethyl)-phenoxy]-1H-benzoimidazole,
1-(1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-pyr-
rolidin-2-one,
(1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-metha-
nol; and
1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-c-
arboxylic acid ethyl ester and pharmaceutically acceptable salts,
prodrugs, and solvates thereof of any of the foregoing
compounds.
[0151] In certain embodiments, the compound of formula (III) is the
compound known as JNJ26993135, which has the following
structure:
##STR00008##
[0152] JNJ26993135 analogs and derivatives useful in the methods of
the invention include the LTA4H inhibitor compounds described in US
Patent Application Publication Nos. 20080194630A1; 20050043379A1
and 20050043378A1, each of which is incorporated herein by
reference.
[0153] In certain cases, the LTA4H modulatory agent is a
heterocyclic compound comprising a thiazolopyridine group. In
certain embodiments the LTA4H modulatory agent is described by the
formula (IV):
##STR00009##
where:
[0154] X.sup.4, X.sup.5, X.sup.6, and X.sup.7 are defined as one of
the following a) and b):
a) one of X.sup.4, X.sup.5, X.sup.6 and X.sup.7 is N and the others
are CR.sup.a; where each R.sup.a is independently H, methyl,
chloro, fluoro, or trifluoromethyl; and b) each of X.sup.4 and
X.sup.7 is N and each of X.sup.5 and X.sup.6 is CH;
[0155] each of R.sup.7 and R.sup.8 is independently H,
--(CH.sub.2).sub.2-3OCH.sub.3, --CH.sub.2C(O)NH.sub.2,
--(CH.sub.2).sub.3NH.sub.2, --(CH.sub.2).sub.1-2 CO.sub.2H,
--CH.sub.2CO.sub.2CH.sub.2CH.sub.3, benzyl,
3-(2-oxo-pyrrolidin-1-yl)-propyl, 1-acetyl-azetidin-3-ylmethyl,
monocyclic cycloalkyl, 1-methyl-4-piperidinyl, or --C.sub.1-4alkyl
unsubstituted or substituted with phenyl, monocyclic cycloalkyl,
OH, or NR.sup.bR.sup.cC; where R.sup.b and R.sup.c are each
independently H, --C(O)CH.sub.3, or C.sub.1-4 alkyl, or R.sup.b and
R.sup.c taken together with the nitrogen to which they are attached
form a saturated monocyclic heterocycloalkyl ring; or
[0156] R.sup.7 and R.sup.8 taken together with the nitrogen to
which they are attached form:
[0157] i) a saturated monocyclic heterocycloalkyl ring, optionally
fused to a phenyl ring, and unsubstituted or substituted with one
or two R.sup.d substituents; where each R.sup.d substituent is
independently C.sub.1-4alkyl unsubstituted or substituted with
--OH; --OH; .dbd.O; --(CH.sub.2).sub.0-2N(CH.sub.3).sub.2;
--CF.sub.3; halo; --CO.sub.2C.sub.1-4 alkyl;
--(CH.sub.2).sub.0-2CO.sub.2H; --C(O)NH.sub.2; phenyl; benzyl;
morpholin-4-yl; pyridyl; pyrimidinyl; 1-piperidyl; phenoxy;
2-oxo-pyrrolidin-1-yl; 4-hydroxy-2-oxo-pyrrolidin-1-yl;
--C(O)NR.sup.fC.sub.1-4alkyl; --C(O)NHC(CH.sub.3).sub.2CH.sub.2OH;
--O-pyridinyl, --O-pyrimidinyl; --S-phenyl;
(4-methylphenyl)sulfanyl; --S-- pyridinyl; --C(O)--C.sub.1-4alkyl;
--C(O)-saturated monocyclic cycloalkyl;
--C(O)--(CH.sub.2).sub.0-1-2-thiophene-yl; --C(O)-2-furanyl;
--C(O)-4-morpholinyl; --C(O)-pyridyl; --C(O)-1-pyrrolidinyl;
--C(O)-phenyl optionally substituted with a chloro;
--C(O)-1-piperazinyl optionally substituted with C.sub.1-4alkyl;
--(CH.sub.2).sub.0-1NHC(O)--C.sub.1-4alkyl; --NHC(O)-saturated
monocyclic cycloalkyl; --NHS(OXO)CH.sub.3;
--NHC(O)--CH.sub.2OCH.sub.3; --NHC(O)-pyridinyl; or
--NHC(O)-2-thiophene-yl, where each phenyl in R.sup.d is
unsubstituted or substituted with --CF.sub.3, halo, or methoxy;
or
[0158] ii) one of the following moieties:
##STR00010##
where R.sup.e is --C.sub.1-4alkyl, C(O)C.sub.1-4alkyl,
--SO.sub.2CH.sub.3, --C( )CH.sub.2NH.sub.2, or C(O)NH.sub.2;
R.sup.f is H or --CH.sub.3; and A is --CH.sub.2--,
--CH.sub.2CH.sub.2--, or --OCH.sub.2CH.sub.2--.
[0159] In some embodiments, the compound of formula (IV) is
selected from,
2-(4-{2-[4-(Pyrimidin-2-yloxy)piperidin-1-yl]ethoxy}phenoxy)[1,3]thiazolo-
[4,5-b]pyridine,
2-{4-[2-(1,3-Dihydro-2H-isoindol-2-yl)ethoxy]phenoxy}[1,3]thiazolo[4,5-b]-
pyridine,
2-(4-{2-[4-(Phenylsulfanyl)piperidin-1-yl]ethoxy}phenoxy)[1,3]th-
iazolo[4,5-b]pyridine,
2-(4-{2-[4-(Pyridin-3-yloxy)piperidin-1-yl]ethoxy}phenoxy)[1,3]thiazolo[4-
,5-b]pyridine,
4-Pyridin-2-yl-1-{2-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl-
}piperidin-4-ol,
2-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}-1,2,3,4-tetra-
hydroisoquinoline,
1-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}-1,2,3,4-tetra-
hydroquinoline,
2-{4-[2-(4-Phenoxypiperidine-1-yl)ethoxy]phenoxy}[1,3]thiazolo[4,5-b]pyri-
dine,
2-[4-(2-Pyrrolidin-1-ylethoxy)phenoxy][1,3]thiazolo[4,5-b]pyridine,
2-[4-(2-Piperidin-1-ylethoxy)phenoxy][1,3]thiazolo[4,5-b]pyridine,
2-[4-(2-Morpholin-4-ylethoxy)phenoxy][1,3]thiazolo[4,5-b]pyridine,
2-(4-{2-[4-(Pyridin-2-yloxy)piperidin-1-yl]ethoxy}phenoxy)[1,3]thiazolo[4-
,5-b]pyridine,
2-(4-{2-[4-(Pyridin-4-yloxy)piperidin-1-yl]ethoxy}phenoxy)[1,3]thiazolo[4-
,5-b]pyridine,
2-(4-{2-[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]ethoxy}phenoxy-
)[1,3]thiazolo[4,5-b]pyridine,
(1S,4S)-5-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}-2,5-d-
iazabicyclo[2.2.1]heptane-2-carboxamide,
meso-N-[(3-endo)-8-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]eth-
yl}-8-azabicyclo[3.2.1]oct-3-yl]acetamide,
meso-N-[(3-exo)-8-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethy-
l}-8-azabicyclo[3.2.1]oct-3-yl]acetamide,
2-{4-[2-(5-Acetylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethoxy]phenoxy}[1-
,3]thiazolo[4,5-b]pyridine,
5-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}hexahydropyrro-
lo[3,4-c]pyrrole-2(1H)-carboxamide,
4-Phenyl-1-{2-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}piper-
idin-4-ol,
2-{4-[2-(4-Benzylpiperidin-1-yl(ethoxy]phenoxy}[1,3]thiazolo[4,-
5-b]pyridine,
2-{4-[2-(4-Pyridin-4-ylpiperidin-1-yl(ethoxy]phenoxy}[1,3]thiazolo[4,5-b]-
pyridine,
4-(4-Chlorophenyl)-1-{2-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)-
phenoxy]ethyl}piperidin-4-ol,
1-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}piperidine-4-c-
arboxamide,
1-(1-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}piperidin-4-
-yl)pyrrolidin-2-one,
1-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}-4-[3-(trifluo-
romethyl)phenyl]piperidin-4-ol,
2-{4-[2-(4-Pyridin-2-ylpiperidin-1-yl(ethoxy]phenoxy}[1,3]thiazolo[4,5-b]-
pyridine,
N-Benzyl-N-methyl-2-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)phen-
oxy]ethanamine,
(1S,4S)-5-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}-2,5-di-
azabicyclo[2.2.1]heptane-2-carboxamide,
1-(1-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}piperidin-4--
yl)pyrrolidin-2-one,
4-(4-Chlorophenyl)-1-{2-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)phenyl]et-
hyl}piperidin-4-ol,
2-{4-[2-(4-Pyridin-2-ylpiperidin-1-yl)ethyl]phenoxy}[1,3]thiazolo[4,5-b]p-
yridine,
meso-N-[(3-exo)-8-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phen-
yl]ethyl}-8-azabicyclo[3.2.1]oct-3yl]acetamide,
meso-1-[(3-exo)-8-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl-
}-8-azabicyclo[3.2.1]oct-3-yl]urea,
meso-8-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}-3,8-diaza-
bicyclo[3.2.1]octane-3-carboxamide,
meso-2-(4-{2-[3-Acetyl-3,8-diazabicyclo[3.2.1]oct-8-yl]ethyl}phenoxy)[1,3-
]thiazolo[4,5-b]pyridine,
2-(Ethyl{2-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}amino)eth-
anol,
N-(Cyclopropylmethyl)-N-{2-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)p-
henyl]ethyl}propan-1-amine,
(1R)--N-Methyl-1-phenyl-N-{2-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)phen-
yl]ethyl}ethanamine,
2-[4-(2-Morpholin-4-ylethyl)phenoxy][1,3]thiazolo[4,5-b]pyridine,
2-[4-(2-Piperidin-1-ylethyl)phenoxy][1,3]thiazolo[4,5-b]pyridine,
2-[4-(2-Pyrrolidin-1-ylethyl)phenoxy][1,3]thiazolo[4,5-b]pyridine,
4-Phenyl-1-{2-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}piperi-
din-4-ol,
2-{4-[2-(4-Benzylpiperidin-1-yl)ethyl]phenoxy}[1,3]thiazolo[4,5--
b]pyridine,
1-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}-4-[3-(trifluor-
omethyl)phenyl]piperidin-4-ol,
2-{4-[2-(4-Pyridin-4-ylpiperidin-1-yl)ethyl]phenoxy}[1,3]thiazolo[4,5-b]p-
yridine,
1-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}piperid-
ine-4-carboxamide,
2-{4-[2-(5-Acetylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl]phenoxy}[1,-
3]thiazolo[4,5-b]pyridine,
5-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}hexahydropyrrol-
o[3,4-c]pyrrole-2(1H)-carboxamide,
2-(4-{2-[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]ethyl}phenoxy)-
[1,3]thiazolo[4,5-b]pyridine,
meso-N-[(3-endo)-8-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethy-
l}-8-azabicyclo[3.2.1]oct-3-yl]acetamide,
meso-1-[(3-endo)-8-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethy-
l}-8-azabicyclo[3.2.1]oct-3-yl]urea,
2-(4-{2-[(1R,4R)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]ethyl}phenoxy)-
[1,3]thiazolo[4,5-b]pyridine,
(1R,4R)-5-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}-2,5-di-
azabicyclo[2.2.1]heptane-2-carboxamide,
1-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}piperidine-4-ca-
rboxylic acid,
{-4-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]morpholin-2-yl}methano-
l,
1-{1-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]piperidin-4-yl}pyrr-
olidin-2-one,
2-[4-(Pyrrolidin-1-ylmethyl)phenoxy][1,3]thiazolo[4,5-b]pyridine,
2-[4-(Piperidin-1-ylmethyl)phenoxy][1,3]thiazolo[4,5-b]pyridine,
2-[4-(Morpholin-4-ylmethyl)phenoxy][1,3]thiazolo[4,5-b]pyridine,
2-(4-{[(3R)-3-Fluoropyrrolidin-1-yl]methyl}phenoxy)[1,3]thiazolo[4,5-b]py-
ridine,
2-(4-{[(3S)-3-Methylmorpholin-4-yl]methyl}phenoxy)[1,3]thiazolo[4,-
5-b]pyridine,
2-{1-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]piperidin-4-yl}propan-
-2-ol,
2-(4-{[(2S)-2-Methylpiperidin-1-yl]methyl}phenoxy)[1,3]thiazolo[4,5-
-b]pyridine,
2-Piperidin-1-yl-N-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)benzyl]ethanam-
ine,
2-(4-{[4-(Trifluoromethyl)piperidin-1-yl]methyl}phenoxy)[1,3]thiazolo-
[4,5-b]pyridine,
2-{4-[(3,3-Difluoropyrrolidin-1-yl)methyl]phenoxy}[1,3]thiazolo[4,5-b]pyr-
idine,
(3R)-1-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]pyrrolidin-3--
ol,
{1-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]piperidin-4-yl}metha-
nol,
2-{4-[(4-Fluoropiperidin-1-yl)methyl]phenoxy}[1,3]thiazolo[4,5-b]pyri-
dine,
2-{4-[(4-Methylpiperidin-1-yl)methyl]phenoxy}[1,3]thiazolo[4,5-b]pyr-
idine,
2-(4-{[4-(Pyridin-3-yloxy)piperidin-1-yl]methyl}phenoxy)[1,3]thiazo-
lo[4,5-b]pyridine,
2-(4-{[4-(Pyrimidin-2-yloxy)piperidin-1-yl]methyl}phenoxy)[1,3]thiazolo[4-
,5-b]pyridine,
1-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]piperidine-4-carboxamide-
,
4-Pyridin-2-yl-1-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)benzyl]piperidi-
n-4-ol,
2-{4-[(4-Benzylpiperidin-1-yl)methyl]phenoxy}[13]thiazolo[4,5-b]py-
ridine,
1-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]-4-[3-(trifluorom-
ethyl)phenyl]piperidin-4-ol,
4-(4-Chlorophenyl)-1-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)benzyl]piper-
idin-4-ol,
4-Phenyl-1-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)benzyl]piper-
idin-4-ol,
(1S,4S)-5-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]-2,5-d-
iazabicyclo[2.2.1]heptane-2-carboxamide,
meso-2-(4-{[3-Acetyl-3,8-diazabicyclo[3.2.1]oct-8-yl]methyl}phenoxy)[1,3]-
thiazolo[4,5-b]pyridine,
{(2S)-1-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]pyrrolidin-2-yl}me-
thanol,
meso-N-{(3-exo)-8-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]--
8-azabicyclo[3.2.1]oct-3-yl}acetamide,
meso-1-{(3-exo)-8-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]-8-azabi-
cyclo[3.2.1]oct-3-yl}urea,
N-Ethyl-N-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)benzyl]ethanamine,
meso-N-{(3-endo)-8-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]-8-azab-
icyclo[3.2.1]oct-3-yl}acetamide,
meso-8-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]-3,8-diazabicyclo[3-
.2.1]octane-3-carboxamide,
2-(4-{[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}phenoxy)--
6-methyl[1,3]thiazolo[4,5-b]pyridine,
2-(4-{[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}phenoxy)--
6-chloro[1,3]thiazolo[4,5-b]pyridine,
2-(4-{[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}phenoxy)--
7-methyl[1,3]thiazolo[4,5-b]pyridine,
2-(4-{[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}phenoxy)--
5-methyl[1,3]thiazolo[4,5-b]pyridine,
1-{(1S,4S)-5-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]-2,5-diazabic-
yclo[2.2.1]hept-2-yl}ethenone,
2-(4-{[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}phenoxy)--
6-fluoro[1,3]thiazolo[4,5-b]pyridine,
6-Fluoro-2-[4-(piperidin-1-ylmethyl)phenoxy][1,3]thiazolo[4,5-b]pyridine,
Ethyl
1-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)benzyl]piperidine-4-carbo-
xylate,
1-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]piperidine-4-carb-
oxylic acid,
2-(4-{2-[4-(2-Methoxyphenyl)piperazin-1-yl]ethoxy}phenoxy)[1,3]thiazolo[4-
,5-b]pyridine,
2-[4-(2-{4-[(4-Chlorophenyl)sulfanyl]piperidin-1-yl}ethoxy)phenoxy][1,3]t-
hiazolo[4,5-b]pyridine,
1-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]piperidin-4-ol,
7-Methyl-2-[4-(piperidin-1-ylmethyl)phenoxy][1,3]thiazolo[4,5-b]pyridine,
N-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}cyclopropanami-
ne,
2-Methyl-N-[1-(2-{4-[(6-methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phe-
noxy}ethyl)piperidin-4-yl]propenamide,
meso-2-{4-[2-(3-Acetyl-3,8-diazabicyclo[3.2.1]oct-8-yl)ethoxy]phenoxy}[1,-
3]thiazolo[4,5-b]pyridine,
meso-1-[(3-exo)-8-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethy-
l}-8-azabicyclo[3.2.1]oct-3-yl]urea,
7-Methyl-2-(4-{2-[4-(pyridin-4-ylcarbonyl)piperazin-1-yl]ethoxy}phenoxy)[-
1,3]thiazolo[4,5-b]pyridine,
6-Methyl-2-(4-{2-[4-(morpholin-4-ylcarbonyl)piperidin-1-yl]ethoxy}phenoxy-
)[1,3]thiazolo[4,5-b]pyridine,
2-(4-{2-[5-(Cyclobutylcarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]eth-
oxy}phenoxy)-7-methyl[1,3]thiazolo[4,5-b]pyridine,
6-Chloro-2-(4-{2-[4-(furan-2-ylcarbonyl)piperazin-1-yl]ethoxy}phenoxy)[1,-
3]thiazolo[4,5-b]pyridine,
meso-3-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}-3,8-diaz-
abicyclo[3.2.1]octane-8-carboxamide,
N-[1-(2-{4-[(6-Methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phenoxy}ethyl)p-
iperidin-4-yl]acetamide,
1-{3-[(2-{4-[(6-Chloro[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phenoxy}ethyl)-
(methyl)amino]propyl}pyrrolidin-2-one,
1-(2-{4-[(7-Methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phenoxy}ethyl)-4-p-
yridin-2-ylpiperidin-4-ol,
meso-(3-endo)-8-acetyl-N-{2-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)pheno-
xy]ethyl}-8-azabicyclo[3.2.1]octan-3-amine,
N-Methyl-2-(methyloxy)-N-[2-({4-[(7-methyl[1,3]thiazolo[4,5-b]pyridin-2-y-
l)oxy]phenyl}oxy)ethyl]ethanamine,
meso-2-{[4-({2-[8-Acetyl-3,8-diazabicyclo[3.2.1]oct-3-yl]ethyl}oxy)phenyl-
]oxy}[1,3]thiazolo[4,5-b]pyridine,
N-[1-(2-1-{[4-[1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]oxy}ethyl)piperi-
din-4-yl]methanesulfonamide,
N-Methyl-1-[2-({4-[(7-methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phenyl}o-
xy)ethyl]piperidine-4-carboxamide,
meso-N-{(3-endo)-8-[2-({4-[(7-Methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]-
phenyl}oxy)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}glycinamide,
meso-3-{[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]methyl}-3,8-diazab-
icyclo[3.2.1]octane-8-carboxamide,
N,N-Dimethyl-1-({4-[(6-methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phenyl}-
methyl)piperidine-4-carboxamide,
N-Ethyl-N-(2-{4-[(6-methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phenyl}eth-
yl)butan-1-amine,
meso-(3-exo)-8-Acetyl-N-({4-[(6-methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)ox-
y]phenyl}methyl)-8-azabicyclo[3.2.1]octan-3-amine,
meso-N-[(3-endo)-8-{[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]methyl-
}-8-azabicyclo[3.2.1]oct-3-yl]methanesulfonamide,
2-({4-[(4-Cyclobutylpiperazin-1-yl)methyl]phenyl}oxy)-6-methyl[1,3]thiazo-
lo[4,5-b]pyridine,
meso-2-[(4-{[8-Acetyl-3,8-diazabicyclo[3.2.1]oct-3-yl]methyl}phenyl)oxy][-
1,3]thiazolo[4,5-b]pyridine,
6-Chloro-2-[(4-{[4-(2-thienylcarbonyl)piperazin-1-yl]methyl}phenyl)oxy][1-
,3]thiazolo[4,5-b]pyridine,
6-Chloro-2-{[(4-1-[5-(methylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)--
yl]methyl}phenyl)oxy][1,3]thiazolo[4,5-b]pyridine,
6-Chloro-2-{[4-(thiomorpholin-4-ylmethyl)phenyl]oxy}[1,3]thiazolo[4,5-b]p-
yridine,
(1R,4R)-5-({4-[(6-Chloro[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phen-
yl}methyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide,
(1S,4S)-5-({4-[(6-Chloro[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phenyl}methy-
l)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide,
6-Chloro-2-[(4-{2-[4-(cyclopropylcarbonyl)piperazin-1-yl]ethyl}phenyl)oxy-
][1,3]thiazolo[4,5-b]pyridine,
6-Methyl-2-[(4-{2-[4-(pyrrolidin-1-ylcarbonyl)piperidin-1-yl]ethyl}phenyl-
)oxy][1,3]thiazolo[4,5-b]pyridine,
meso-3-{4-[(7-Methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]benzyl}-3,8-diaz-
abicyclo[3.2.1]octane-8-carboxamide,
meso-7-Methyl-2-(4-{[3-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-8-yl]m-
ethyl}phenoxy)[1,3]thiazolo[4,5-b]pyridine,
N-(1-{4-[(7-Methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]benzyl}piperidin-4-
-yl)pyridine-4-carboxamide,
meso-2-(4-{2-[8-Acetyl-3,8-diazabicyclo[3.2.1]oct-3-yl]ethyl}phenoxy)-7-m-
ethyl[1,3]thiazolo[4,5-b]pyridine,
meso-3-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}-3,8-diaza-
bicyclo[3.2.1]octane-8-carboxamide,
meso-8-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}-3,8-diaz-
abicyclo[3.2.1]octane-3-carboxamide,
meso-2-(4-{2-[8-Acetyl-3,8-diazabicyclo[3.2.1]oct-3-yl]ethyl}phenoxy)[1,3-
]thiazolo[4,5-b]pyridine,
meso-2-(4-{2-[3-(Methylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-8-yl]ethoxy}p-
henoxy)[1,3]thiazolo[4,5-b]pyridine,
meso-(3-exo)-8-Acetyl-N-{2-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)phenyl-
]ethyl}-8-azabicyclo[3.2.1]octan-3-amine,
meso-(3-exo)-8-Acetyl-N-{2-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)phenox-
y]ethyl}-8-azabicyclo[3.2.1]octan-3-amine,
2-Methoxy-N-(1-{4-[(6-methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]benzyl}p-
iperidin-4-yl)acetamide,
2-{4-[(4-tert-Butylpiperidin-1-yl)methyl]phenoxy}-6-chloro[1,3]thiazolo[4-
,5-b]pyridine,
N-(1-{4-[(6-Methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]benzyl}piperidin-4-
-yl)thiophene-2-carboxamide,
1'-(2-{4-[(6-Chloro[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phenyl}ethyl)-1,4-
'-bipiperidine,
3-(4-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}piperazin-1--
yl)propanoic acid,
6-Methyl-2-(4-{[4-(piperazin-1-ylcarbonyl)piperidin-1-yl]methyl}phenoxy)[-
1,3]thiazolo[4,5-b]pyridine,
meso-3-(2-{4-[(6-Methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phenyl}ethyl)-
-3,8-diazabicyclo[3.2.1]octane-8-carboxamide,
meso-(3-exo)-8-Acetyl-N-(2-{4-[(6-methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)-
oxy]phenyl}ethyl)-8-azabicyclo[3.2.1]octan-3-amine,
meso-(3-exo)-8-Acetyl-N-methyl-N-(2-{4-[(6-methyl[1,3]thiazolo[4,5-b]pyri-
din-2-yl)oxy]phenyl}ethyl)-8-azabicyclo[3.2.1]octan-3-amine,
N2-(2-{4-[(6-Chloro[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phenoxy}ethyl)-N2-
-methylglycinamide,
meso-8-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]-8-azabicyclo[3.2.1-
]octane-3-carboxylic acid,
6-Chloro-2-(4-{2-[5-(1-methylethy)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-
ethoxy}phenoxy)[1,3]thiazolo[4,5-b]pyridine,
N-Methyl-N-(2-{4-[(6-methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phenoxy}e-
thyl)-beta-alanine,
N-(2-{4-[(6-Chloro[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phenyl}ethyl)-N,1--
dimethylpiperidin-4-amine,
6-Methyl-2-{4-[2-(4-pyridin-2-ylpiperidin-1-yl)ethyl]phenoxy}[1,3]thiazol-
o[4,5-b]pyridine,
1-(1-Acetylazetidin-3-yl)-N-{4-[(6-chloro[1,3]thiazolo[4,5-b]pyridin-2-yl-
)oxy]benzyl}-N-methylmethanamine,
meso-(3-exo)-3-{[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]amino}-8-a-
zabicyclo[3.2.1]octane-8-carboxamide,
2-[4-(2-{4-[(4-Methylphenyl)sulfanyl]piperidin-1-yl}ethoxy)phenoxy][1,3]t-
hiazolo[4,5-b]pyridine,
1'-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]-1,4'-bipiperidine,
2-{4-[(4-Morpholin-4-ylpiperidin-1-yl)methyl]phenoxy}[1,3]thiazolo[4,5-b]-
pyridine,
N,N-Dimethyl-2-{1-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)benzyl-
]piperidin-2-yl)ethanamine,
N,N-Dimethyl-1-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)benzyl]piperidin-4-
-amine,
2-{4-[(4-Phenoxypiperidin-1-yl)methyl]phenoxy}[1,3]thiazolo[4,5-b]-
pyridine,
2-(4-{[4-(Pyridin-2-yloxy)piperidin-1-yl]methyl}phenoxy)[1,3]thi-
azolo[4,5-b]pyridine,
2-(4-{[4-(Pyridin-4-yloxy)piperidin-1-yl]methyl}phenoxy)[1,3]thiazolo[4,5-
-b]pyridine,
2-(4-{[4-(Pyridin-2-ylsulfanyl)piperidin-1-yl]methyl}phenoxy)[1,3]thiazol-
o[4,5-b]pyridine,
2-(4-{[4-(Phenylsulfanyl)piperidin-1-yl]methyl}phenoxy)[1,3]thiazolo[4,5--
b]pyridine,
2-(4-{[(1R,4R)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}phenoxy)[-
1,3]thiazolo[4,5-b]pyridine,
(1R,4R)-5-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]-2,5-diazabicycl-
o[2.2.1]heptane-2-carboxamide,
2-(4-{2-[(1R,4R)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]ethoxy}phenoxy-
)[1,3]thiazolo[4,5-b]pyridine,
(1R,4R)-5-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}-2,5-d-
iazabicyclo[2.2.1]heptane-2-carboxamide, (4R)-4-Hydroxy-1-f
1-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)benzyl]piperidin-4-yl}pyrrolidi-
n-2-one,
(4R)-4-Hydroxy-1-{1-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)pheno-
xy]ethyl}piperidin-4-yl)pyrrolidin-2-one,
N-Methyl-2-piperidin-1-yl-N-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)benzy-
l]ethanamine,
N-(3-Methoxypropyl)-N-{2-[4-([1,3]thiazolo[4,5-b]pyridin-2yloxy)phenoxy]e-
thyl}cyclopropanamine, ethyl
N-benzyl-N-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)benzyl]glycinate,
N-Benzyl-N-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)benzyl]glycine,
N-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]-beta-alanine,
2-{4-[(5-Acetylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl]phenoxy}[1,3-
]thiazolo[4,5-b]pyridine,
5-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]hexahydropyrrolo[3,4-c]p-
yrrole-2(1H)-carboxamide,
meso-1-{(3-endo)-8-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]-8-azab-
icyclo[3.2.1]oct-3-yl}urea,
6-Chloro-2-(4-piperidin-1-ylmethyl-phenoxy)[1,3]thiazolo[4,5-b]pyridine,
1-{4-[(7-Methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]benzyl}piperidine-4-c-
arboxamide,
1-{4-[(6-Fluoro[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]benzyl}piperidine-4-c-
arboxamide,
1-{4-[(6-Chloro[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]benzyl}piperidine-4-c-
arboxamide,
meso-endo-N-[8-{4-[(6-Chloro[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]benzyl}--
8-azabicyclo[3.2.1]oct-3-yl]acetamide,
meso-endo-N-[8-{4-[(6-Fluoro[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]benzyl}--
8-azabicyclo[3.2.1]oct-3-yl]acetamide,
meso-endo-N-[8-{4-[(7-Methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]benzyl}--
8-azabicyclo[3.2.1]oct-3-yl]acetamide,
2-(4-{[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.2]oct-2-yl]methyl}phenoxy)[1-
,3]thiazolo[4,5-b]pyridine,
meso-N-{(3-endo)-8-[4-([1,3]Thiazolo[4,5-b]pyridin-2-ylmethyl)benzyl]-8-a-
zabicyclo[3.2.1]oct-3-yl}acetamide,
2-(4-{[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}benzyl)[1-
,3]thiazolo[4,5-b]pyridine,
meso-N-[(3-endo)-8-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-ylmethyl)phenoxy]-
ethyl}-8-azabicyclo[3.2.1]oct-3-yl]acetamide,
2-(4-{2-[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]ethoxy}benzyl)-
[1,3]thiazolo[4,5-b]pyridine,
2-[4-(Piperidin-1-ylmethyl)phenoxy][1,3]thiazolo[4,5-c]pyridine,
meso-N-{(3-endo)-8-[4-([1,3]Thiazolo[4,5-c]pyridin-2-yloxy)benzyl]-8-azab-
icyclo[3.2.1]oct-3-yl}acetamide,
N-(2-Hydroxy-1,1-dimethylethyl)-1-(2-{[4-([1,3]thiazolo[4,5-c]pyridin-2-y-
loxy)phenyl]oxy}ethyl)piperidine-4-carboxamide,
2-{[4-({2-[4-(Trifluoromethyl)piperidin-1-yl]ethyl}oxy)phenyl]oxy}[1,3]th-
iazolo[4,5-c]pyridine,
N-(Cyclopropylmethyl)-N-{[4-([1,3]thiazolo[4,5-c]pyridin-2-yloxy)phenyl]m-
ethyl}propan-1-amine,
2-({[4-[(4-Pyridin-4-ylpiperidin-1-yl]methyl]phenyl}oxy)[1,3]thiazolo[4,5-
-c]pyridine,
N-{1-[4-([1,3]Thiazolo[5,4-c]pyridin-2-yloxy)phenyl]ethyl}piperidin-4-yl)-
cyclopropanecarboxamide,
(4-Chlorophenyl)(1-{2-[4-([1,3]thiazolo[4,5-c]pyridin-2-yloxy)phenyl]ethy-
l}piperidin-4-yl)methanone,
N-Propyl-N-{2-[4-([1,3]thiazolo[4,5-c]pyridin-2-yloxy)phenyl]ethyl}propan-
-1-amine,
meso-3-[4-([1,3]Thiazolo[4,5-c]pyridin-2-yloxy)benzyl]-3,8-diaza-
bicyclo[3.2.1]octane-8-carboxamide,
2-[4-(2-Pyrrolidin-1-ylethyl)phenoxy][1,3]thiazolo[4,5-c]pyridine,
1-Methyl-4-[4-([1,3]thiazolo[4,5-c]pyridin-2-yloxy)benzyl]piperazin-2-one-
,
meso-(3-exo)-8-Acetyl-N-[4-([1,3]thiazolo[4,5-c]pyridin-2-yloxy)benzyl]--
8-azabicyclo[3.2.1]octan-3-amine,
meso-8-{2-[4-([1,3]Thiazolo[4,5-c]pyridin-2-yloxy)phenoxy]ethyl}-3,8-diaz-
abicyclo[3.2.1]octane-3-carboxamide,
N-(Cyclopropylmethyl)-N-{2-[4-([1,3]thiazolo[4,5-c]pyridin-2-yloxy)phenox-
y]ethyl}-beta-alanine,
meso-2-(4-{2-[3-Acetyl-3,8-diazabicyclo[3.2.1]oct-8-yl]ethoxy}phenoxy)[1,-
3]thiazolo[4,5-c]pyridine,
N-Ethyl-N-[4-([1,3]thiazolo[4,5-c]pyridin-2-yloxy)benzyl]cyclohexanamine,
2-[4-(Piperidin-1-ylmethyl)phenoxy][1,3]thiazolo[5,4-c]pyridine,
meso-N-{(3-endo)-8-[4-([1,3]Thiazolo[5,4-c]pyridin-2-yloxy)benzyl]-8-azab-
icyclo[3.2.1]oct-3-yl}acetamide,
1-(1-{2-[4-([1,3]Thiazolo[5,4-c]pyridin-2-yloxy)phenoxy]ethyl}piperidin-4-
-yl)pyrrolidin-2-one,
2-(4-{2-[(1R,4R)-5-(Methylsulfonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]etho-
xy}phenoxy)[1,3]thiazolo[5,4-c]pyridine,
3-[(Cyclopropylmethyl){2-[4-([1,3]thiazolo[5,4-c]pyridin-2-yloxy)phenoxy]-
ethyl}amino]propan-1-01,
N-Methyl-N-[4-([1,3]thiazolo[5,4-c]pyridin-2-yloxy)benzyl]cyclohexanamine-
,
2-{4-[2-(4-Acetylpiperazin-1-yl)ethyl]phenoxy}[1,3]thiazolo[5,4-c]pyridi-
ne,
meso-1-{(3-exo)-8-[4-([1,3]Thiazolo[5,4-c]pyridin-2-yloxy)benzyl]-8-az-
abicyclo[3.2.1]oct-3-yl}urea,
N-(Cyclopropylmethyl)-N-[4-([1,3]thiazolo[5,4-c]pyridin-2-yloxy)benzyl]pr-
opane-1,3-diamine,
3-(Cyclopropyl{2-[4-([1,3]thiazolo[5,4-c]pyridin-2-yloxy)phenoxy]ethyl}am-
ino)propan-1-ol,
2-(4-{[4-(Pyridin-2-ylcarbonyl)piperazin-1-yl]methyl}phenoxy)[1,3]thiazol-
o[5,4-c]pyridine,
2-{4-[(4-Acetyl-1,4-diazepan-1-yl)methyl]phenoxy}[1,3]thiazolo[5,4-c]pyri-
dine,
2-[4-({4-[(4-Methylpiperazin-1-yl)carbonyl]piperidin-1-yl}methyl)phe-
noxy][1,3]thiazolo[5,4-c]pyridine,
2-[4-(2-Azetidin-1-ylethoxy)phenoxy][1,3]thiazolo[5,4-c]pyridine,
5-{2-[4-([1,3]Thiazolo[5,4-c]pyridin-2-yloxy)phenyl]ethyl}hexahydropyrrol-
o[3,4-c]pyrrole-2(1H)-carboxamide,
2-(4-{[4-(Pyridin-3-yloxy)piperidin-1-yl]methyl}phenoxy)[1,3]thiazolo[5,4-
-c]pyridine,
meso-N-{(3-exo)-8-[4-([1,3]Thiazolo[5,4-c]pyridin-2-yloxy)benzyl]-8-azabi-
cyclo[3.2.1]oct-3-yl}methanesulfonamide,
N-[(1-{2-[4-([1,3]Thiazolo[5,4-c]pyridin-2-yloxy)phenoxy]ethyl}piperidin--
4-yl)methyl]acetamide,
2-(4-{2-[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]ethoxy}phenoxy-
)[1,3]thiazolo[5,4-b]pyridine,
(1S,4S)-5-{2-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)phenoxy]ethyl}-2,5-d-
iazabicyclo[2.2.1]heptane-2-carboxamide,
1-{2-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)phenoxy]ethyl}piperidine-4-c-
arboxamide,
1-{2-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)phenoxy]ethyl}-4-[3-(trifluo-
romethyl)phenyl]piperidin-4-01,
2-{4-[2-(4-Pyridin-2-ylpiperidin-1-yl(ethoxy]phenoxy}[1,3]thiazolo[5,4-b]-
pyridine,
4-(4-Chlorophenyl)-1-{2-[4-([1,3]thiazolo[5,4-b]pyridin-2-yloxy)-
phenoxy]ethyl}piperidin-4-ol,
4-Phenyl-1-{2-[4-([1,3]thiazolo[5,4-b]pyridin-2-yloxy)phenoxy]ethyl}piper-
idin-4-ol,
2-(4-{2-[4-(2-Methoxyphenyl)piperidin-1-yl]ethoxy}phenoxy)[1,3]-
thiazolo[5,4-b]pyridine,
2-{4-[2-(4-Pyridin-4-ylpiperidin-1-yl(ethoxy]phenoxy}[1,3]thiazolo[5,4-b]-
pyridine,
1-(1-{2-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)phenoxy]ethyl}pi-
peridin-4-yl)pyrrolidin-2-one,
1-{2-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)phenoxy]ethyl}piperidine-4-c-
arboxylic acid,
2-(4-{2-[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]ethyl}phenoxy)-
[1,3]thiazolo[5,4-b]pyridine,
meso-N-[(3-endo)-8-{2-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)phenyl]ethy-
l}-8-azabicyclo[3.2.1]oct-3-yl]acetamide,
meso-2-(4-{2-[3-Acetyl-3,8-diazabicyclo[3.2.1]oct-8-yl]ethyl}phenoxy)[1,3-
]thiazolo[5,4-b]pyridine,
1-{2-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)phenyl]ethyl}piperidine-4-ca-
rboxamide,
1-(1-{2-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)phenyl]ethyl}pi-
peridin-4-yl)pyrrolidin-2-one,
2-{4-[2-(5-Acetylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl]phenoxy}[1,-
3]thiazolo[5,4-b]pyridine,
5-{2-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)phenyl]ethyl}hexahydropyrrol-
o[3,4-c]pyrrole-2(1H)-carboxamide,
meso-8-{2-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)phenyl]ethyl}-3,8-diaza-
bicyclo[3.2.1]octane-3-carboxamide,
meso-1-[(3-endo)-8-{2-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)phenyl]ethy-
l}-8-azabicyclo[3.2.1]oct-3-yl]urea,
(1S,4S)-5-{2-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)phenyl]ethyl}-2,5-di-
azabicyclo[2.2.1]heptane-2-carboxamide,
1-{1-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)benzyl]piperidin-4-yl}pyrrol-
idin-2-one,
1-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)benzyl]piperidine-4-carboxamide-
,
2-(4-{[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}phenoxy)-
-5-methyl[1,3]thiazolo[5,4-b]pyridine,
meso-N-{(3-endo)-8-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)benzyl]-8-azab-
icyclo[3.2.1]oct-3-yl}acetamide,
2-(4-{[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}phenoxy)--
6-fluoro[1,3]thiazolo[5,4-b]pyridine,
2-(4-{[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}phenoxy)[-
1,3]thiazolo[5,4-b]pyridine,
1-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)benzyl]piperidine-4-carboxylic
acid,
2-{4-[2-(4-Methyl-1,4-diazepan-1-yl)ethoxy]phenoxy}[1,3]thiazolo[5,-
4-b]pyridine,
meso-N-[(3-exo)-8-{2-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)phenoxy]ethy-
l}-8-azabicyclo[3.2.1]oct-3-yl]acetamide,
2-[(Cyclopropylmethyl){2-[4-([1,3]thiazolo[5,4-b]pyridin-2-yloxy)phenoxy]-
ethyl}amino]ethanol,
7-Methyl-2-({4-[(4-pyridin-4-ylpiperazin-1-yl)methyl]phenyl}oxy)[1,3]thia-
zolo[4,5-b]pyridine,
meso-(3-endo)-8-Acetyl-N-{[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)phenyl]-
methyl}-8-azabicyclo[3.2.1]octan-3-amine,
meso-(3-exo)-8-Acetyl-N-{[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)phenyl]m-
ethyl}-8-azabicyclo[3.2.1]octan-3-amine,
N-Ethyl-N-{2-[4-([1,3]thiazolo[5,4-b]pyridin-2-yloxy)phenyl]ethyl}cyclopr-
opanamine,
meso-N-[(3-exo)-8-{2-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)ph-
enyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl]methanesulfonamide,
meso-(3-exo)-3-{[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)benzyl]amino}-8-a-
zabicyclo[3.2.1]octane-8-carboxamide,
4-Methyl-1-[4-([1,3]thiazolo[5,4-b]pyridin-2-yloxy)benzyl]-1,4-diazepan-5-
-one,
N-{1-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)benzyl]piperidin-4-yl}p-
ropenamide,
2-(4-{2-[4-(Cyclopropylcarbonyl)-1,4-diazepan-1-yl]ethyl}phenoxy)[1,3]thi-
azolo[5,4-b]pyridine,
meso-N-Methyl-N-{(3-exo)-8-[4-([1,3]thiazolo[5,4-b]pyridin-2-yloxy)benzyl-
]-8-azabicyclo[3.2.1]oct-3-yl}acetamide,
2-(Cyclopropyl{2-[4-([1,3]thiazolo[5,4-b]pyridin-2-yloxy)phenoxy]ethyl}am-
ino)ethanol,
2-{4-[(4-Pyridin-2-ylpiperazin-1-yl)methyl]phenoxy}[1,3]thiazolo[5,4-b]py-
ridine,
2-(4-{2-[(1R,4R)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]ethyl}p-
henoxy)[1,3]thiazolo[5,4-b]pyridine,
7-Methyl-2-[4-(piperidin-1-ylmethyl)phenoxy][1,3]thiazolo[5,4-b]pyridine,
2-(4-{[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]ethyl}phenoxy)-7-
-methyl[1,3]thiazolo[5,4-b]pyridine,
1-{4-[(7-Methyl[1,3]thiazolo[5,4-b]pyridin-2-yl)oxy]benzyl}piperidine-4-c-
arboxamide,
4-Phenyl-1-{2-[4-([1,3]thiazolo[4,5-b]pyrazin-2-yloxy)phenoxy]ethyl}piper-
idin-4-ol,
2-{4-[2-(4-Benzylpiperidin-1-yl(ethoxy]phenoxy}[1,3]thiazolo[4,-
5-b]pyrazine,
1-{2-[4-([1,3]Thiazolo[4,5-b]pyrazin-2-yloxy)phenoxy]ethyl}-4-[3-(trifluo-
romethyl)phenyl]piperidin-4-ol,
4-(4-Chlorophenyl)-1-{2-[4-([1,3]thiazolo[4,5-b]pyrazin-2-yloxy)phenoxy]e-
thyl}piperidin-4-ol,
1-{2-[4-([1,3]Thiazolo[4,5-b]pyrazin-2-yloxy)phenoxy]ethyl}piperidine-4-c-
arboxamide,
2-(4-{[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}phenoxy)[-
1,3]thiazolo[4,5-b]pyrazine,
meso-N-[(3-endo)-8-{2-[4-([1,3]Thiazolo[4,5-b]pyrazin-2-yloxy)phenoxy]eth-
yl}-8-azabicyclo[3.2.1]oct-3-yl]acetamide,
2-[4-(2-Morpholin-4-ylethoxy)phenoxy][1,3]thiazolo[4,5-b]pyrazine,
2-({4-[(4-Pyrimidin-2-ylpiperazin-1-yl)methyl]phenyl}oxy)[1,3]thiazolo[4,-
5-b]pyrazine,
2-[(4-{[4-(2-Thienylacetyl)piperazin-1-yl]methyl}phenyl)oxy][1,3]thiazolo-
[4,5-b]pyrazine,
1-{2-[4-([1,3]Thiazolo[4,5-b]pyrazin-2-yloxy)phenyl]ethyl}-1,4-diazepan-5-
-one,
2-{[4-(2-Azepan-1-ylethyl)phenyl]oxy}[1,3]thiazolo[4,5-b]pyrazine,
2-({4-[2-(4-Fluoropiperidin-1-yl)ethyl]phenyl}oxy)[1,3]thiazolo[4,5-b]pyr-
azine,
2-[(4-{[4-(Pyrimidin-2-yloxy)piperidin-1-yl]methyl}phenyl)oxy][1,3]-
thiazolo[4,5-b]pyrazine,
meso-1-{(3-exo)-8-[4-([1,3]Thiazolo[4,5-b]pyrazin-2-yloxy)benzyl]-8-azabi-
cyclo[3.2.1]oct-3-yl}urea,
2-(4-{2-[4-(Pyridin-2-yloxy)piperidin-1-yl]ethyl}phenoxy)[1,3]thiazolo[4,-
5-b]pyrazine,
3-Acetyl-9-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)benzyl]-3,9-diazaspiro-
[5.5]undecane, and
1-[4-([1,3]Thiazolo[4,5-b]pyrazin-2-yloxy)benzyl]piperidine-4-carboxamide-
, and pharmaceutically acceptable salts, prodrugs, and solvates
thereof of any of the foregoing compounds.
[0160] In certain embodiments, the compound of formula (IV) is the
compound known as JNJ-40929837, which has the following
structure:
##STR00011##
[0161] JNJ40929837 analogs and derivatives useful in the methods of
the invention include the LTA4H inhibitor compounds described in
U.S. Pat. Nos. 7,939,527; and 8,357,684, which are incorporated
herein by reference.
[0162] In certain embodiments, the LTA4H modulatory agent is a
diazabicyclo[2.2.1]heptane derivative. In some embodiments, the
LTA4H modulatory agent is described by the formula (V):
##STR00012##
where:
[0163] r is 0 to 4;
[0164] R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d and R.sup.1e are each
independently selected from hydrogen, --R.sup.13a--OR.sup.10a,
--R.sup.13a--C(.dbd.O)OR.sup.10a, --R.sup.13a--C(.dbd.O)R.sup.10a,
alkyl, halo, haloalkyl, cyano, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heterocyclyl, and optionally substituted
heterocyclylalkyl;
[0165] R.sup.16 is a direct bond, --O--, --R.sup.12a--O--,
--O--R.sup.12a, --O--R.sup.12a--O--, an optionally substituted
straight or branched alkylene chain, an optionally substituted
straight or branched alkenylene chain, or an optionally substituted
straight or branched alkynylene chain;
[0166] R.sup.14 is a direct bond, --O--R.sup.12b--, an optionally
substituted straight or branched alkylene chain, an optionally
substituted straight or branched alkenylene chain, or an optionally
substituted straight or branched alkynylene chain;
[0167] R.sup.13 is hydrogen, alkyl, haloalkyl, haloalkenyl,
haloalkynyl, hydroxyalkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
aryl, optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, --R.sup.13a--OR.sup.10a,
--R.sup.13a--O--R.sup.14a--C(.dbd.O)OR.sup.10a,
--R.sup.13a--C(.dbd.O)R.sup.10a, --R.sup.13a--C(.dbd.O)OR.sup.10a,
--R.sup.13a--C(.dbd.O)--R.sup.14a--C(.dbd.O)OR.sup.10a,
--R.sup.13a--C(.dbd.O)--R.sup.13a--N(R.sup.10a)R.sup.11a,
--R.sup.13a,
--C(.dbd.O)--R.sup.14a--S(O).sub.tN(R.sup.10a)R.sup.11a (where t is
1 or 2), or --R.sup.14a--S(.dbd.O).sub.pR.sup.10a (where p is 0, 1
or 2);
[0168] or R.sup.13 is aralkyl optionally substituted with one or
more substituents selected from the group consisting of halo,
nitro, cyano, optionally substituted heteroaryl, hydroxyiminoalkyl,
--R.sup.13a--OR.sup.10a, --R.sup.13a--C(.dbd.O)R.sup.10a,
--R.sup.13a--C(.dbd.O)OR.sup.10a,
--R.sup.13a--C(.dbd.O)--R.sup.13a--N(R.sup.10a)R.sup.11a,
--R.sup.10a--C(.dbd.O)N(R.sup.10a)--R.sup.14a--N(R.sup.10a)R.sup.11a,
--R.sup.13a--S(.dbd.O).sub.tN(R.sup.10a)R.sup.11a,
--R.sup.13a--N(R.sup.10a)R.sup.11a,
--R.sup.13a--N(R.sup.10a)C(.dbd.O)R.sup.10a,
--R.sup.13a--N(R.sup.10a)C(.dbd.O)--R.sup.13a--N(R.sup.10a)R.sup.11a,
--R.sup.13a--N(R.sup.10a)--R.sup.13a--C(.dbd.O)OR.sup.10a,
--R.sup.13a,
--N(R.sup.10a)C(.dbd.O)--R.sup.14a--S(.dbd.O).sub.tN(R.sup.10a)R.sup.11a,
--R.sup.13a--N(R.sup.10a)C(.dbd.O)--R.sup.13a--N(R.sup.10a)C(.dbd.O)R.sup-
.10a, --R.sup.13a,
--N(R.sup.10a)C(.dbd.O)--R.sup.13a--N(R.sup.10a)--R.sup.14a--N(R.sup.10a)-
R.sup.11a,
--R.sup.13a--N(R.sup.10a)S(.dbd.O).sub.tN(R.sup.10a)R.sup.11a, and
--R.sup.13a--O--R.sup.14a--C(.dbd.O)OR.sup.10a, where t is 1 or
2;
[0169] each R.sup.15 is independently selected from --O--R.sup.10a,
alkyl, hydroxyalkyl, halo, haloalkyl, aryl or aralkyl;
[0170] each R.sup.10a and R.sup.11a is independently hydrogen,
alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heterocyclyl, or optionally substituted heterocyclylalkyl;
[0171] or R.sup.10a and R.sup.11a, together with the nitrogen to
which they are attached, form an optionally substituted
N-heterocyclyl or an optionally substituted N-heteroaryl;
[0172] each R.sup.12a is an optionally substituted straight or
branched alkylene chain, an optionally substituted straight or
branched alkenylene chain, or an optionally substituted straight or
branched alkynylene chain;
[0173] R.sup.12b is an optionally substituted straight or branched
alkylene chain, an optionally substituted straight or branched
alkenylene chain, or an optionally substituted straight or branched
alkynylene chain;
[0174] each R.sup.13a is a direct bond, an optionally substituted
straight or branched alkylene chain, an optionally substituted
straight or branched alkenylene chain, or an optionally substituted
straight or branched alkynylene chain;
[0175] and each R.sup.14a is an optionally substituted straight or
branched alkylene chain, an optionally substituted straight or
branched alkenylene chain, or an optionally substituted straight or
branched alkynylene chain.
[0176] In certain embodiments of formula (V), the compound is
selected from
4-[[(1S,4S)-5-[(4-phenoxyphenyl)methyl]-2,5-diazabicyclo[2.2.1]hept--
2-yl]methyl]benzoic acid,
4-[[(1S,4S)-5-[[(4-fluorophenoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]he-
pt-2-yl]methyl]-benzoic acid,
4-[[(1S,4S)-5-[(4-(2-phenylethoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]h-
ept-2-yl]methyl]benzoic acid,
4-[[(1S,4S)-5-[3-(4-phenoxyphenyl)propyl]-2,5-diazabicyclo[2.2.1]hept-2-y-
l]methyl]benzoic acid,
4-[[(1S,4S)-5-[[4-(4-chlorophenoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]-
hept-2-yl]methyl]benzoic acid,
4-[[(1S,4S)-5-[2-(4-phenoxyphenyl)ethyl]-2,5-diazabicyclo[2.2.1]hept-2-yl-
]methyl]benzoic acid,
4-[[(1S,4S)-5-[[4-(2-phenoxyethoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]-
hept-2-yl]methyl]benzoic acid,
4-[[(1S,4S)-5-[[4-(4-bromophenoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]h-
ept-2-yl]methyl]benzoic acid,
4-[[(1S,4S)-5-[[4-[(2'-fluoro[1,1'-biphenyl]-4-yl)oxy]phenyl]methyl]-2,5--
diazabicyclo[2.2.1]hept-2-yl]methyl]benzoic acid,
4-[[(1S,4S)-5-[[4-[4-(3-furanyl)phenoxy]phenyl]methyl]-2,5-diazabicyclo[2-
.2.1]hept-2-yl]methyl]benzoic acid,
4-[[(1S,4S)-5-[[4-[4-(trifluoromethyl)phenoxy]phenyl]methyl]-2,5-diazabic-
yclo[2.2.1]hept-2-yl]methyl]benzoic acid,
4-[[(1S,4S)-5-[[4-]4-acetylphenoxy]phenyl]methyl]-2,5-diazabicyclo[2.2.1]-
hept-2-yl]methyl]benzoic acid,
4-[[(1S,4S)-5-[[4-[4-(3-thienyl)phenoxy]phenyl]methyl]-2,5-diazabicyclo[2-
.2.1]hept-2-yl]methyl]benzoic acid,
4-[[(1S,4S)-5-[[4-[4-(3,5-dimethyl-4-isoxazolyl)phenoxy]phenyl]methyl]-2,-
5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoic acid,
4-[[(1S,4S)-5-[(3-fluoro-4-phenoxyphenyl)methyl]-2,5-diazabicyclo[2.2.1]h-
ept-2-yl]methyl]benzoic acid,
4-[[(1S,4S)-5-[[3-(2-phenylethoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]h-
ept-2]yl]methyl]benzoic acid,
4-[[(1S,4S)-5-[[4-[4-(2-oxazolyl)phenoxy]phenyl]methyl]-2,5-diazabicyclo[-
2.2.1]hept-2-yl]methyl]benzoic acid,
4-[[(1S,4S)-5-[(4-fluoro-2-phenoxyphenyl)methyl]-2,5-diazabicyclo[2.2.1]h-
ept-2-yl]methyl]benzoic acid,
4-[[(1S,4S)-5-[(3-phenoxyphenyl)methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]-
methyl]benzoic acid,
4-[[(1S,4S)-5-[(2-fluoro-4-phenoxyphenyl)methyl]-2,5-diazabicyclo[2.2.1]h-
ept-2-yl]methyl]benzoic acid,
4-[[(1S,4S)-5-[(2,4-diphenoxyphenyl)methyl]-2,5-diazabicyclo[2.2.1]hept-2-
-yl]methyl]benzoic acid,
4-[[(1S,4S)-5-([1.1'-biphenyl]-4-ylmethyl)-2,5-diazabicyclo[2.2.1]hept-2--
yl]methyl]benzoic acid,
4-[[(1S,4S)-5-[(4-phenoxyphenyl)methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]-
methyl]benzeneacetic acid,
4-[[(1S,4S)-5-[[4-(2-phenoxyethoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]-
hept-2-yl]methyl]benzeneacetic acid,
4-[[(1S,4S)-5-[[4-(2-phenylethoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]h-
ept-2-yl]methyl]benzeneacetic acid, methyl
4-[[(1S,4S)-5-[[4-[4-(2-oxazolyl)phenoxy]phenyl]methyl]-2,5-diazabicyclo[-
2.2.1]hept-2-yl]methyl]benzoate,
4-[[(1S,4S)-5-[[4-[4-(2-thiazolyl)phenoxy]phenyl]methyl]-2,5-diazabicyclo-
[2.2.1]hept-2-yl]methyl]benzoic acid, and methyl
4-[[(1S,4S)-5-[[4-[4-(2-thiazolyl)phenoxy]phenyl]methyl]-2,5-diazabicyclo-
[2.2.1]hept-2-yl]methyl]benzoate.
[0177] In some embodiments of formula (V), the compound is selected
from
4-[[(1S,4S)-5-[[4-[4-(2-oxazolyl)phenoxy]phenyl]methyl]-2,5-diazabicyclo[-
2.2.1]hept-2-yl]methyl]benzoic acid, and methyl
4-[[(1S,4S)-5-[[4-[4-(2-oxazolyl)phenoxy]phenyl]methyl]-2,5-diazabicyclo[-
2.2.1]hept-2-yl]methyl]benzoate.
[0178] In some embodiments of formula (V), the compound is selected
from
4-[[(1S,4S)-5-[[4-[4-(2-thiazolyl)phenoxy]phenyl]methyl]-2,5-diazabicyclo-
[2.2.1]hept-2-yl]methyl]benzoic acid, and methyl
4-[[(1S,4S)-5-[[4-[4-(2-thiazolyl)phenoxy]phenyl]methyl]-2,5-diazabicyclo-
[2.2.1]hept-2-yl]methyl]benzoate.
[0179] In certain embodiments, the compound of formula (V) is the
compound known as Acebilustat (CTX-4430), which has the following
structure:
##STR00013##
[0180] Acebilustat analogs and derivatives useful in the methods of
the invention include the compounds described in US. Pat. Nos.
7,737,145; and U.S. Patent Application Publication No.
20100210630A1, the contents of each of which are incorporated by
reference herein. LTA4H inhibitor compounds also include those
described in U.S. Pat. Nos. 9,822,106; 9,856,249; and 9,777,006,
the contents of each of which are incorporated by reference
herein.
[0181] In some embodiments the LTA4H modulatory agent is a
heterocyclic compound described by the formula (VI):
##STR00014##
[0182] where:
[0183] Ar is selected from aryl, heteroaryl, aryl substituted with
from one to three substituents independently selected from the
group consisting of halogen, loweralkyl, loweracyl, loweralkoxy,
fluoroloweralkyl, fluoroloweralkoxy, hydroxy,
hydroxy(C.sub.1-C.sub.4) alkyl, formyl,
formyl(C.sub.1-C.sub.4)alkyl, cyano, cyano(C.sub.1-C.sub.4)alkyl,
benzyl, benzyloxy, phenyl, substituted phenyl, heteroaryl,
heterocyclylalkyl, substituted heteroaryl, and nitro, and
heteroaryl substituted with from one to three substituents
independently selected from the group consisting of halogen,
loweralkyl, loweracyl, loweralkoxy, fluoroloweralkyl,
fluoroloweralkoxy, formyl, cyano, benzyl, benzyloxy, phenyl,
heteroaryl, heterocyclylalkyl and nitro;
[0184] X is selected from direct bond, O, SO, S(O.sub.2),
NR.sup.1f, CH.sub.2, CF.sub.2, CH.sub.2CH.sub.2, CH.sub.2NR.sup.1f,
NR.sup.1fCH.sub.2, CH.dbd.CH, C.dbd.O, CH.sub.2C.dbd.O,
CR.sup.1aaR.sup.1bb, OCR.sup.1aaR.sup.1bbCR.sup.1aaR.sup.1bbO;
SO.sub.2NR.sup.1f, NR.sup.1fSO.sub.2, C(.dbd.O)NR.sup.1f and
NR.sup.1fC(.dbd.O);
[0185] R.sup.1f is selected separately in each occurrence from H
and lower alkyl;
[0186] R.sup.1aa is selected from H, OH and lower alkyl;
[0187] R.sup.1bb is selected from H and lower alkyl, or R.sup.1aa
and R.sup.1bb taken together may form a 3-6 membered ring, which
may optionally contain a heteroatom chosen from O, S, and N;
[0188] HetAr is an aryl or heteroaryl ring attached via a ring
carbon to Q, further characterized in that Q and X cannot be on
adjacent positions in said aryl or heteroaryl ring;
[0189] Q is chosen from --O--, --NR.sup.1f-- and S(O).sub.p;
[0190] Q and X cannot be on adjacent positions in said benzene or
pyridine ring;
[0191] p is zero, 1 or 2;
[0192] n is an integer selected from 1-5;
[0193] HET is selected from 4-7-membered saturated nitrogenous
heterocycle, and 4-7-membered saturated nitrogenous heterocycle
substituted with one or two substituents independently selected
from halogen, hydroxyl, amino, carboxy, loweralkyl, loweracyl,
loweralkoxy, N-oxide, fluoroloweralkyl, fluoroloweralkoxy, formyl,
cyano, benzyl, benzyloxy, phenyl, heteroaryl and nitro; and
[0194] taken together ZW is H or Z is (CH.sub.2).sub.1-10, in which
one or two (CH.sub.2) may optionally be replaced by --O--,
--NR.sup.1f--, --SO--, --S(O).sub.2--, --C(.dbd.O)-- or
--C.dbd.O(NH)--, provided that said --O--, --NR.sup.1f--, --SO--,
--S(O).sub.2--, --C(.dbd.O)-- or --C.dbd.O(NH)-- are not at the
point of attachment to HET and are separated by at least one
--(CH.sub.2)--;
[0195] W is selected from acyl, hydroxyl, carboxyl, amino,
--C(O)NHR.sup.4a, aminoacyl, --COOalkyl, --CHO, heterocyclyl,
substituted aryl, substituted heterocyclyl, sulfonamide,
--C(O)fluoroalkyl, --C(O)CH.sub.2C(O)Oalkyl,
--C(O)CH.sub.2C(O)Ofluoroalkyl, --SH, --C(O)NH(OH),
--C(O)N(OH)R.sup.4a, --N(OH)C(O)OH, --N(OH)C(O)R.sup.4a; and
[0196] R.sup.4a is selected from H, (C.sub.1-C.sub.4) alkyl and
phenyl(C.sub.1-C.sub.4) alkyl.
[0197] In some embodiments of formula (VI), the compound is
described by formula (VIa):
##STR00015##
[0198] Where:
[0199] X is selected from the group consisting of direct bond, O,
SO, S(O.sub.2), NR.sup.1, CH.sub.2, CF.sub.2, CH.sub.2O, C.dbd.O
and CH.sub.2C.dbd.O;
[0200] R.sup.17 is chosen from halogen, CF.sub.3, methyl, methoxy,
CF.sub.3O;
[0201] n is 1 or 2;
[0202] Z is (CH.sub.2).sub.1-10, in which one or two (CH.sub.2) may
optionally be replaced by --O--, --NR.sup.1f--, --SO--,
--S(O).sub.2--, --C(.dbd.O)-- or --C.dbd.O(NH)--, provided that
said --O--, --NR.sup.1f--, --SO--, --S(O).sub.2--, --C(.dbd.O)-- or
--C.dbd.O(NH)-- are not at the point of attachment to HET and are
separated by at least one --(CH.sub.2)--;
[0203] W is selected from acyl, hydroxyl, carboxyl, amino,
--C(O)NHR.sup.4a, aminoacyl, --COOalkyl, --CHO, heterocyclyl,
substituted aryl, substituted heterocyclyl, sulfonamide,
--C(O)fluoroalkyl, --C(O)CH.sub.2C(O)Oalkyl,
--C(O)CH.sub.2C(O)Ofluoroalkyl, --SH, --C(O)NH(OH), --C(O)N(OH)R*,
--N(OH)C(O)OH, --N(OH)C(O)R.sup.4a; and
[0204] R.sup.4a is selected from H, (C.sub.1-C.sub.4) alkyl and
phenyl(C.sub.1-C.sub.4) alkyl.
[0205] In certain embodiments of formula (VIa), X is O or CH.sub.2,
n is 1 or 2, Z is C.sub.1-4 alkylene and W is COOH.
[0206] In certain embodiments, the compound of formula (VI) or
(VIa) is the compound known as DG-051, which has the following
structure:
##STR00016##
[0207] DG051 analogs and derivatives useful in the methods of the
invention include the LTA4H inhibitor compounds described in U.S.
Pat. No. 7,402,684; and Sandanayaka et al. J Med. Chem. Jan. 28,
2010; 53(2):573-85; Bio-org Med Chem. Lett. 2009 Nov. 15;
19(22):6275-9, each of which is incorporated herein by
reference.
[0208] In some embodiments the LTA4H modulatory agent is described
by the formula (VII):
Ar.sup.1-Q.sup.1-AR.sup.2--Y.sup.1--Z.sup.1 (VII)
[0209] where:
[0210] Ar.sup.1 is an aryl moiety selected from phenyl, mono-, di-,
or tri-substituted phenyl with the substituents selected from the
Cl, Br, F, CF.sub.3, lower alkyl, lower alkoxy, NH.sub.2, NO.sub.2
and OH;
[0211] Ar.sup.2 is
##STR00017##
wherein R.sup.19 is selected from H, halogen, lower alkyl, lower
alkoxy, nitro or hydroxy, R.sup.20 and R.sup.21 are each
independently selected from H, halogen, lower alkyl, lower alkoxy,
amino, nitro or hydroxy;
[0212] Q.sup.1 is --O--, or --CH.sub.2--, --OCH.sub.2--,
--CH.sub.2O--, --NH--, --NHCH.sub.2--, --CH.sub.2NH--,
--CF.sub.2--, --CH.dbd.CH--, --CH.sub.2--CH.sub.2--, and a
carbon-carbon single bond;
[0213] Y.sup.1 is selected from --O--, --S--, --NH--, --S(O)--, and
--S(O.sub.2)--;
[0214] R.sup.18 is selected from linear or branched C.sub.2-C.sub.6
alkylenyl, or C(R.sup.22)(R.sup.23)--(CH.sub.2)m, wherein R.sup.22
and R.sup.23 are each independently selected from H and lower
alkyl, and m is 1, 2 or 2; and
[0215] Z is
##STR00018##
wherein at least one of R.sup.24 and R.sup.25 is
--(CH.sub.2).sub.aCOR.sup.26 and the other is selected from H,
lower alkyl, allyl, benzyl, --(CH.sub.2).sub.aCOR.sup.26, and
--(CH.sub.2).sub.a--OH;
[0216] R.sup.26 is --OR.sup.27, where R.sup.27 is H, lower alkyl or
benzyl; and
[0217] a is an integer from 0 to 5, provided that when R.sup.24 and
R.sup.25 are both --(CH.sub.2).sub.aCOR.sup.26, then a is not
0.
[0218] In certain embodiments of formula (VII),
Ar.sup.1-Q.sup.1-AR.sup.2 --Y.sup.1 is:
##STR00019##
[0219] Where:
[0220] Q is --O-- or --CH.sub.2--;
[0221] R.sup.20 and R.sup.28 are each independently selected from
H, lower alkyl, lower alkoxy, halogen, amino and nitro.
[0222] In certain embodiments of formula (VII), the compound is
selected from 3-[[3-[4(phenylmethyl)phenoxy]propyl]amino]propanoic
acid, 3-[methyl[3-[4(phenylmethyl)phenoxy]propyl]amino]propanoic
acid, 3-[[4-[4(phenylmethyl)phenoxy]butyl]amino]propanoic acid,
3-[[3-(4-phenoxyphenoxy)propyl]amino]propanoic acid,
3-[methyl[3-(4-phenoxyphenoxy)propyl]amino]propanoic acid,
3-[[4-(4-phenoxyphenoxy)butyl]amino]propanoic acid; and
3-[[3-[4-[(4-fluorophenyl)methyl]phenoxy]propyl]methylamino]propanoic
acid, monohydrochloride. In certain embodiments of formula (VII),
the compound is selected from ethyl
3-[[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoate,
phenylmethyl
3[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoate, ethyl
3-[[3-(4-phenoxyphenoxy)propyl]-amino]propanoate, ethyl
3-[[methyl-[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoate,
methyl
3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoate,
hydrate, ethyl
3-[4-[4-(phenylmethyl)phenoxy]butyl]amino]propanoate, phenylmethyl
3-[4-[4-(phenylmethyl)phenoxy]butyl]amino]propanoate, phenylmethyl
3-[[3-(4-phenoxyphenoxy)propyl]amino]propanoate, phenylmethyl
3-[methyl[3-(4-phenoxyphenoxy)propyl]amino]propanoate, phenylmethyl
3-[[4-(4-phenoxyphenoxy)butyl]amino]propanoate, methyl
3-[3-[4-[(4-fluorophenyl)methyl]phenoxy]propyl]methylamino]propanoate,
ethyl 3-[[4-[4-phenoxyphenoxy]butyl]amino]propanoate, and methyl
3-[[3-[4-(4-fluorophenoxy)phenoxy]propyl]methylamino]propanoate.
[0223] In certain embodiments, the compound of formula (VII) is the
compound known as SC-57461A, which has the following structure:
##STR00020##
[0224] SC-57461A analogs and derivatives useful in the methods of
the invention include the LTA4H inhibitor compounds described in
U.S. Pat. Nos. 5,723,492; 6,162,823; 5,585,492; and 5,719,306, each
of which is incorporated herein by reference.
[0225] In certain embodiments, the LTA4H modulatory agent is of the
formula (VIII):
##STR00021##
[0226] where:
[0227] Y.sup.2 is selected from N, or CR.sup.32, wherein R.sup.32
is selected from hydrogen, alkyl or substituted alkyl;
[0228] Y.sup.3 is selected from S, O, NR.sup.33, wherein R.sup.33
is selected from H, alkyl or substituted alkyl;
[0229] each R.sup.29 and R.sup.30 are independently selected from
halogen, lower alkyl, lower alkoxy, amino, nitro, and hydroxy;
[0230] R.sup.31 is selected from H, halogen, lower alkyl, lower
alkoxy, amino, nitro, and hydroxy;
[0231] n is an integer from 0 to 5; and
[0232] m is an integer from 0 to 4.
[0233] In some embodiments the compound of formula (VIII) is
4-(4-benzylphenyl)thiazol-2-amine (ARM1), or an analog thereof.
ARM1 has the following structure:
##STR00022##
[0234] In certain embodiments, ARM1 is in the form of a salt (e.g.,
a hydrogen bromide salt or a hydrogen chloride salt).
[0235] In some embodiments, the LTA4H modulatory agent is a proline
derivative. In some embodiments, the LTA4H modulatory agent is
described by the formula (IX):
##STR00023##
[0236] where:
[0237] R.sup.34 is hydroxy or lower alkoxy;
[0238] R.sup.35 is hydrogen or lower alkyl;
[0239] R.sup.36 is hydrogen or lower alkanoyl; and
[0240] n is 0, 1 or 2, or pharmaceutically acceptable salts
thereof, wherein said lower alkoxy, lower alkyl and lower alkanoyl
groups having up to 7 carbon atoms.
[0241] In certain embodiments of a compound of formula (IX),
R.sup.34 is hydroxy. In certain cases, R.sup.34 is hydroxy,
R.sup.35 is methyl and R.sup.36 is H. In certain cases, the
compound of formula (IX) is a proline derivative in the L-form.
[0242] In some embodiments the compound of formula (IX) is
captopril, or an analog thereof. The structure of captopril is as
follows:
##STR00024##
[0243] Captopril analogs and derivatives useful in the methods of
the invention include the compounds described in U.S. Pat. Nos.
4,046,889, and 4,105,776, each of which is incorporated herein by
reference.
[0244] In some embodiments, the LTA4H modulatory agent is a
resveratrol derivative. In some embodiments, the LTA4H modulatory
agent is described by the formula (X):
##STR00025##
[0245] where:
[0246] R.sup.37, R.sup.38 and R.sup.39 are each independently
--OR.sup.40, wherein each R.sup.40 is independently selected from
hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy.
[0247] In some embodiments compound of formula (X) is pinostilbene
hydrate, or an analog thereof. The structure of pinostilbene
hydrate is as follows:
##STR00026##
[0248] Pinostilbene hydrate analogs useful in the methods of the
invention include the LTA4H inhibitor compounds described in Low et
al. Scientific Reports, (2017) 7:44449, which is incorporated
herein by reference.
[0249] In some embodiments, the LTA4H modulatory agent is an
arylpyrazole, or a pharmaceutically acceptable salt thereof. In
certain embodiments, the LTA4H modulatory agent is of the formula
(XI):
##STR00027##
or a pharmaceutically acceptable salt thereof, wherein:
[0250] A.sup.1 and A.sup.2 are each independently selected from the
group consisting of CH and N;
[0251] L.sup.1 is a linker selected from the group consisting of
--O-- and --CH.sub.2--; B is a 9- or 10-membered ring selected
from:
##STR00028## ##STR00029## ##STR00030## ##STR00031##
wherein each B ring may optionally be further substituted by
--(C.sub.1-C.sub.6)alkyl;
[0252] L.sup.2 is absent or a --(CH.sub.2).sub.n-linker, wherein n
is an integer selected from 1, 2 and 3, and wherein one
--(CH.sub.2)-- moiety of said L2 linker may optionally be replaced,
where possible, by --O-- and wherein each --(CH.sub.2)-- of said L2
linker may be substituted with one to two groups selected from the
group consisting of --OH, -halo, .dbd.O, --(C.sub.1-C.sub.6)alkyl,
--(C.sub.3-C.sub.6)cycloalkyl, -(4- to 7-membered)heterocyclyl, and
phenyl; wherein two --(C.sub.1-C.sub.6)alkyls groups, when attached
to the same carbon atom of said L.sup.2 linker moiety may join to
form a --(C.sub.3-C.sub.6)cycloalkyl;
[0253] R.sup.1 is selected from:
[0254] (a) a group of formula --N(R.sup.2)(R.sup.3), wherein
R.sup.2 and R.sup.3 are each independently selected from the group
consisting of --H, --(C.sub.1-C.sub.6)alkyl,
--(C.sub.3-C.sub.6)cycloalkyl, and -(4- to 7-membered)heterocyclyl,
wherein each of said --(C.sub.1-C.sub.6)alkyl,
--(C.sub.3-C.sub.6)cycloalkyl, and -(4- to 7-membered)heterocyclyl
of said R.sup.2 and R.sup.3 may optionally be independently
substituted by 1 to 3 R.sup.4 groups;
[0255] R.sup.4 is selected from the group consisting of halo, --OH,
.dbd.O, --(C.sub.1-C.sub.6)alkyl, --O(C.sub.1-C.sub.6)alkyl,
--N(R.sup.5).sub.2, --C(O)--R, --N(R)--C(O)--R,
--C(O)--N(R.sup.5).sub.2, --(C.sub.3-C.sub.6)cycloalkyl optionally
substituted by --C(O)--(C.sub.1-C.sub.6)alkyl, -(4- to
7-membered)heterocyclyl optionally substituted by
--C(O)--(C.sub.1-C.sub.6)alkyl, and phenyl; and
[0256] each R.sup.5 is independently selected from the group
consisting of --H, --(C.sub.1-C.sub.6)alkyl,
--(C.sub.3-C.sub.6)cycloalkyl, and -(4- to
7-membered)heterocyclyl;
[0257] (b) a 4- to 9-membered N-heterocyclic ring, wherein said 4-
to 9-membered N-heterocyclic ring is optionally independently
substituted with one or more substituents selected from the group
consisting of (i) 1 G.sup.1 group or (ii) 1 to 3 G2 groups; wherein
G.sup.1 is selected from the group consisting of
-L.sup.4-(C.sub.1-C.sub.6)alkyl,
-L.sup.4-(C.sub.3-C.sub.6)cycloalkyl,
-L.sup.4-(C.sub.3-C.sub.6)heterocyclyl, and -L.sup.4-phenyl;
wherein each of said --(C.sub.1-C.sub.6)alkyl,
--(C.sub.3-C.sub.6)cycloalkyl, -(4- to 7-membered)heterocyclyl, and
phenyl substituents may optionally be individually substituted by 1
to 4 R.sup.6 groups;
[0258] L.sup.4 is absent or selected from the group consisting of
--O--, --C(O)--, --N(R')--, --C(O)--N(R.sup.7)--,
--N(R.sup.7)--C(O)--, and --N(R.sup.7)--S(O).sub.j--;
--R.sup.6 is selected from the group consisting of halo, --OH,
.dbd.O, --CN, --(C.sub.1-C.sub.6)alkyl, --O(C.sub.1-C.sub.6)alkyl,
--N(R.sup.7).sub.2, --C(O)--R.sup.7, --C(O)--O--R.sup.7,
--N(R.sup.7)--C(O)--R.sup.7, --C(O)--N(R.sup.7).sub.2,
--S(O).sub.1--R, --(C.sub.3-C.sub.6)cycloalkyl, -(4- to
7-membered)heterocyclyl, and phenyl optionally substituted with
--C(O)--O--R.sup.7;
[0259] each R.sup.7 is independently selected from the group
consisting of --H, --(C.sub.1-C.sub.6)alkyl,
--(C.sub.3-C.sub.6)cycloalkyl, and -(4- to 7-membered)heterocyclyl;
and
G2 is independently selected from the group consisting of -halo,
--OH, .dbd.O, --CN, --O(C.sub.1-C.sub.6)alkyl and
--(C.sub.1-C.sub.6)alkyl optionally substituted with
--O(C.sub.1-C.sub.6)alkyl; or (c) a group selected from the group
consisting of a tetrahydro-2H-pyranyl, --C(O)--OH and OH, wherein j
is an integer selected from 0, 1 and 2.
[0260] In some embodiments, the LTA4H modulatory agent is a
compound selected from
2-Methoxy-1-(4-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-naphthalen-2-ylme-
thyl}-piperazin-1-yl)-ethanone,
1-(4-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-naphthalen-2-ylmethyl}-pipe-
razin-1-yl)-ethanone,
5-(2H-Pyrazol-3-yl)-2-(6-pyrrolidin-1-ylmethyl-naphthalen-2-yloxy)-pyridi-
ne,
1-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-naphthalen-2-ylmethyl}-pipe-
ridin-4-ol,
1-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-naphthalen-2-ylmethyl}-piperid-
ine-4-carboxylic acid amide,
N-(1-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-naphthalen-2-ylmethyl}-pipe-
ridin-4-yl)-acetamide,
(S)-3-Hydroxy-1-(1-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-naphthalen-2--
ylmethyl}-piperidin-4-yl)-pyrrolidin-2-one,
Dimethyl-{6-[4-(2H-pyrazol-3-yl)-phenoxy]-chroman-2-ylmethyl}-amine,
1-{7-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-chroman-2-ylmethyl}-piperidine-
-4-carboxylic acid amide,
2-Hydroxy-1-(4-{6-[4-(2H-pyrazol-3-yl)-phenoxy]-quinolin-2-ylmethyl}-pipe-
razin-1-yl)-ethanone,
3-(1-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-piperi-
din-4-yl)-oxazolidin-2-one,
1-(4-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-quinolin-2-ylmethyl}-piperazin-1-yl-
)-propan-1-one,
(S)-2-Hydroxy-1-(4-{6-[4-(2H-pyrazol-3-yl)-phenoxy]-quinolin-2-ylmethyl}--
piperazin-1-yl)-propan-1-one,
2-Morpholin-4-ylmethyl-6-[4-(2H-pyrazol-3-yl)-phenoxy]-pyrazolo[1,5-a]pyr-
idine,
(1-Hydroxy-cyclopropyl)-(4-{6-[4-(2H-pyrazol-3-yl)-phenoxy]-quinoli-
n-2-ylmethyl}-piperazin-1-yl)-methanone,
(S)-7-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-hexah-
ydro-oxazolo[3,4-a]pyrazin-3-one,
2-(2,2-Dioxo-2-.lamda.-6-thia-5-aza-bicyclo[2.2.1]hept-5-ylmethyl)-6-[4-(-
2H-pyrazol-3-yl)-phenoxy]-quinoline,
2-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-hexahydro-
-pyrrolo[1,2-a]pyrazin-6-one,
6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-2-pyrrolidin-1-ylmethyl-quinoline-
,
2-(2-Oxa-6-aza-spiro[3.4]oct-6-ylmethyl)-6-[5-(2H-pyrazol-3-yl)-pyridin--
2-yloxy]-quinoline,
2-Azetidin-1-ylmethyl-6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinoline,
2-Azepan-1-ylmethyl-6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinoline,
2-Piperidin-1-ylmethyl-6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinoline,
1-(8-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-3,8-di-
aza-bicyclo[3.2.1]oct-3-yl)-ethanone,
Methyl-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-amin-
e,
2-Methyl-1-(4-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmet-
hyl}-piperazin-1-yl)-propan-1-one,
2-Hydroxy-1-(4-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmeth-
yl}-piperazin-1-yl)-ethanone,
2-Methoxy-1-(4-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmeth-
yl}-piperazin-1-yl)-ethanone,
1-(4-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-pipera-
zin-1-yl)-propan-1-one,
8-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-1,8-diaza-
-spiro[4.5]decan-2-one,
3-Oxo-3-(4-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}--
piperazin-1-yl)-propionitrile,
1-(5-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-hexahy-
dro-pyrrolo[3,4-c]pyrrol-2-yl)-ethanone,
2-Hydroxy-N-methyl-N-(1-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-
-2-ylmethyl}-piperidin-4-yl)-acetamide,
(R)-2-({6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-amin-
o)-propionamide,
(1.alpha.,5.alpha.,6.alpha.)-3-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-q-
uinolin-2-ylmethyl}-3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid
amide,
1-{3-[(Methyl-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethy-
l}-amino)-methyl]-azetidin-1-yl}-ethanone,
N-Methyl-N-(1-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethy-
l}-piperidin-4-yl)-acetamide,
2-Hydroxy-1-((R)-3-methyl-4-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quin-
olin-2-ylmethyl}-piperazin-1-yl)-ethanone,
2-Methanesulfonyl-1-(4-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin--
2-ylmethyl}-piperazin-1-yl)-ethanone,
(1.alpha.,5.alpha.,6.alpha.)-3-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-q-
uinolin-2-ylmethyl}-3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid
(2-hydroxy-2-methyl-propyl)-amide,
N-((1.alpha.,5.alpha.,6.alpha.)-3-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy-
]-quinolin-2-ylmethyl}-3-aza-bicyclo[3.1.0]hex-6-ylmethyl)-acetamide,
1-((S)-3-Hydroxymethyl-4-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinoli-
n-2-ylmethyl}-piperazin-1-yl)-ethanone,
4-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-piperazin-
e-1-carboxylic acid amide,
2-Hydroxy-1-(3-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmeth-
yl}-3,8-diaza-bicyclo[3.2.1]oct-8-yl)-ethanone,
2-({6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-amino)-1-
-pyrrolidin-1-yl-ethanone,
2-Hydroxy-N-(4-methyl-1-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-
-2-ylmethyl}-piperidin-4-yl)-acetamide,
2-(Methyl-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-a-
mino)-acetamide,
2-(2-Oxa-6-aza-spiro[3.5]non-6-ylmethyl)-6-[5-(2H-pyrazol-3-yl)-pyridin-2-
-yloxy]-quinoline,
(S)-3-({6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-amin-
o)-pyrrolidin-2-one,
2-Hydroxy-1-(8-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmeth-
yl}-1,8-diaza-spiro[4.5]dec-1-yl)-ethanone,
(S)-2-Phenyl-2-({6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmet-
hyl}-amino)-acetamide,
5-[4-(2H-Pyrazol-3-yl)-phenoxy]-2-pyrrolidin-1-ylmethyl-1H-benzoimidazole-
,
2-((2R,6S)-2,6-Dimethyl-morpholin-4-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phe-
noxy]-1H-benzoimidazole,
6-[4-(2H-Pyrazol-3-yl)-benzyl]-2-pyrrolidin-1-ylmethyl-1H-benzoimidazole,
2-((3S,5S)-3,5-Dimethyl-morpholin-4-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phen-
oxy]-1H-benzoimidazole,
2-((2S,6S)-2,6-Dimethyl-morpholin-4-ylmethyl)-6-[4-(2H-pyrazol-3-yl)-benz-
yl]-1H-benzoimidazole,
2,2,2-Trifluoro-1-(4-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2--
ylmethyl}-piperazin-1-yl)-ethanone,
(1S,5S)-3-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-8-
-oxa-3-aza-bicyclo[3.2.1]octane,
2-(1-Morpholin-4-yl-cyclopropyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzo-
imidazole,
2-Morpholin-4-ylmethyl-6-[4-(2H-pyrazol-3-yl)-benzyl]-1H-benzoi-
midazole,
2-[4-(2-Methoxy-ethyl)-piperazin-1-ylmethyl]-5-[4-(2H-pyrazol-3--
yl)-phenoxy]-1H-benzoimidazole,
2-((S)-3-Methyl-morpholin-4-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H--
benzoimidazole,
5-[4-(2H-Pyrazol-3-yl)-phenoxy]-2-[4-(2,2,2-trifluoro-ethyl)-piperazin-1--
ylmethyl]-1H-benzoimidazole,
2-(4-Isopropyl-piperazin-1-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-b-
enzoimidazole,
2-[4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-ylmethyl]-5-[4-(2H-pyra-
zol-3-yl)-phenoxy]-1H-benzoimidazole,
(S)-1-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-pyrro-
lidin-3-ol,
5-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-imidazo[1,2-a]pyridin-2-yl}-piperidin--
2-one,
(S)-5-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-quinolin-2-yloxy}-piperidin--
2-one,
5-[4-(1H-Pyrazol-3-yl)-phenoxy]-1H-benzoimidazole-2-carboxylic
acid,
2,2-Dimethyl-1-(4-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-
-2-ylmethyl}-piperazin-1-yl)-propan-1-one,
2,2,2-Trifluoro-1-(1-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2--
ylmethyl}-piperidin-4-yl)-ethanol,
2-(2-Oxa-6-aza-spiro[3.3]hept-6-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-
-1H-benzoimidazole,
5-[4-(2H-Pyrazol-3-yl)-phenoxy]-2-pyridin-3-ylmethyl-1H-benzoimidazole,
((S)-sec-Butyl)-methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol--
2-ylmethyl}-amine,
5-[4-(2H-Pyrazol-3-yl)-phenoxy]-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazole,
Methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-[(S)-
-1-(tetrahydro-furan-2-yl)methyl]-amine,
Methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-(S)--
tetrahydro-furan-3-yl-amine,
Methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-(R)--
tetrahydro-furan-3-yl-amine,
5-[4-(2H-Pyrazol-3-yl)-phenoxy]-1-(3-pyrrolidin-1-yl-propyl)-1H-indazole,
((R)-sec-Butyl)-methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol--
2-ylmethyl}-amine,
Methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-[(R)-
-1-(tetrahydro-furan-2-yl)methyl]-amine,
((S)-2-Methoxy-1-methyl-ethyl)-methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-
-benzoimidazol-2-ylmethyl}-amine,
5-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-1-(2-pyrrolidin-1-yl-ethyl)-1H-in-
dazole,
2-(3-Morpholin-4-yl-propyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-2H-ind-
azole,
Methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl-
}-(tetrahydro-furan-2-ylmethyl)-amine,
Ethyl-((S)-2-methoxy-1-methyl-ethyl)-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H--
benzoimidazol-2-ylmethyl}-amine,
[1,4]Dioxan-2-ylmethyl-methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoim-
idazol-2-ylmethyl}-amine,
N-[1-(2-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-indazol-1-yl}-ethyl)-piperidin-4-
-yl]-acetamide,
2-((S)-1-Methyl-pyrrolidin-2-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-
-benzoimidazole,
1-[4-(2-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-indazol-1-yl}-ethyl)-piperazin-1-
-yl]-ethanone,
(2-Methoxy-ethyl)-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylm-
ethyl}-amine,
Methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-(tet-
rahydro-pyran-3-ylmethyl)-amine,
1-[4-(2-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-indazol-2-yl}-ethyl)-piperazin-1-
-yl]-ethanone,
1-[4-(2-{5-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-indazol-1-yl}-ethyl)-pip-
erazin-1-yl]-ethanone,
1-[4-(3-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-indazol-2-yl}-propyl)-piperazin--
1-yl]-ethanone,
(1-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-piperidi-
n-4-yl)-acetonitrile,
{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-(tetrahydro-
-furan-2-ylmethyl)-amine,
5-[4-(2H-Pyrazol-3-yl)-phenoxy]-2-thiomorpholin-4-ylmethyl-1H-benzoimidaz-
ole,
1-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-piper-
idine-4-carbonitrile,
{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-[(S)-1-(tet-
rahydro-furan-2-yl)methyl]-amine,
{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-[(R)-1-(tet-
rahydro-furan-2-yl)methyl]-amine,
1-(2-Morpholin-4-yl-ethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-indazole,
N--((S)-sec-Butyl)-N-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2--
ylmethyl}-acetamide,
Methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-(tet-
rahydro-furan-3-ylmethyl)-amine,
5-[4-(2H-Pyrazol-3-yl)-phenoxy]-2-(3-pyrrolidin-1-yl-propyl)-2H-indazole,
{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-(tetrahydro-
-pyran-4-ylmethyl)-amine,
(R)-1-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-pyrro-
lidine-3-carbonitrile,
1-[4-(2-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-yl}-ethyl)-pi-
perazin-1-yl]-ethanone,
N-[1-(3-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-indazol-1-yl}-propyl)-piperidin--
4-yl]-acetamide,
1-[4-(Methyl-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl-
}-amino)-piperidin-1-yl]-ethanone,
1-(2-Morpholin-4-yl-ethyl)-5-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-1H-ind-
azole,
2-Hydroxy-2-methyl-N-[1-(2-{5-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-
-indazol-2-yl}-ethyl)-piperidin-4-yl]-propionamide,
3-Morpholin-4-ylmethyl-6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-1H-indazol-
e,
2-Morpholin-4-ylmethyl-6-[4-(2H-pyrazol-3-yl)-phenoxy]-benzooxazole,
1-(4-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-yl}-piperazin-1--
yl)-ethanone,
N-[l-(3-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-indazol-2-yl}-propyl)-piperidin--
4-yl]-acetamide,
(S)-5-{5-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-indazol-1-ylmethyl}-pyrrol-
idin-2-one,
3-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-indazol-1-yl}-propan-1-01,
(S)-5-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-isoquinolin-1-yloxymethyl}-pyrroli-
din-2-one,
2-(2-Morpholin-4-yl-ethoxy)-6-[5-(2H-pyrazol-3-yl)-pyridin-2-yl-
oxy]-quinoline,
N-[2-({6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-amino-
)-ethyl]-acetamide,
(2-Methoxy-ethyl)-methyl-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinoli-
n-2-ylmethyl}-amine,
Dimethyl-{6-[4-(2H-pyrazol-3-yl)-phenoxy]-quinolin-2-ylmethyl}-amine,
4-(1-{1-[4-(2H-Pyrazol-3-yl)-benzyl]-1H-indol-5-ylmethyl}-piperidin-4-yl)-
-benzoic acid,
N-(1-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-2,3-dihydro-benzofuran-2-yl-
methyl}-piperidin-4-yl)-acetamide,
5-(2H-Pyrazol-3-yl)-2-(2-pyrrolidin-1-ylmethyl-2,
3-dihydro-benzofuran-6-yloxy)-pyridine,
5-(2H-Pyrazol-3-yl)-2-(2-pyrrolidin-1-ylmethyl-benzofuran-6-yloxy)-pyridi-
ne,
N-(1-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-2,3-dihydro-benzofuran-2-
-ylmethyl}-piperidin-4-ylmethyl)-acetamide,
1-(1-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-2,3-dihydro-benzofuran-2-yl-
methyl}-piperidin-4-yl)-pyrrolidin-2-one,
3-[1-(2-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-benzofuran-3-yl}-ethyl)--
piperidin-4-yl]-oxazolidin-2-one,
N-((endo)-8-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-2,
3-dihydro-benzofuran-2-ylmethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-acetamide,
2-Hydroxy-1-(8-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmeth-
yl}-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-ethanone,
N-[1-(2-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-benzofuran-3-yl}-ethyl)--
piperidin-4-yl]-acetamide,
1-[4-(2-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-benzofuran-3-yl}-ethyl)--
[1,4]diazepan-1-yl]-ethanone,
1-[4-(2-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-2,3-dihydro-benzofuran-3-
-yl}-ethyl)-[1,4]diazepan-1-yl]-ethanone,
1-[4-(2-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-benzofuran-3-yl}-ethyl)--
piperazin-1-yl]-ethanone,
1-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-2,3-dihydro-benzofuran-2-ylmethyl}-pip-
eridine-4-carboxylic acid methylamide,
1-(2-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-benzofuran-3-yl}-ethyl)-pip-
eridine-4-carboxylic acid methylamide,
2-Hydroxy-1-((1S,4S)-5-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin--
2-ylmethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethanone,
2-Hydroxy-1-(4-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmeth-
yl}-[1,4]diazepan-1-yl)-ethanone,
N-[1-(2-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-benzofuran-3-yl}-ethyl)--
piperidin-4-yl]-methanesulfonamide,
N-((exo)-8-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-2,3-dihydro-benzofuran-2-ylme-
thyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-acetamide,
1-[4-(2-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-2,3-dihydro-benzofuran-3-
-yl}-ethyl)-piperazin-1-yl]-ethanone,
1-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-2,3-dihydro-benzofuran-2-ylmethyl}-pip-
eridine-4-carboxylic acid amide,
2-Hydroxy-1-((1R,4R)-5-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin--
2-ylmethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethanone,
2-Hydroxy-1-(5-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmeth-
yl}-2,5-diaza-bicyclo[2.2.2]oct-2-yl)-ethanone,
1-((1R,4R)-5-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl-
}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethanone,
1-(5-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-2,5-di-
aza-bicyclo[2.2.2]oct-2-yl)-ethanone,
1-(4-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-benzofuran-3-ylmethyl}-pipe-
razin-1-yl)-ethanone,
4-((1S,4S)-5-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl-
}-2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-benzoic acid methyl
ester,
4-(1-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-piperi-
din-4-yl)-benzoic acid methyl ester,
Diethyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-ami-
ne,
2-(4-Methyl-piperidin-1-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-b-
enzoimidazole,
Ethyl-methyl-(2-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-indazol-2-yl}-ethyl)-ami-
ne,
Ethyl-(2-methoxy-ethyl)-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimida-
zol-2-ylmethyl}-amine,
2-(3-Methoxymethyl-piperidin-1-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]--
1H-benzoimidazole,
2-(3-Methoxy-pyrrolidin-1-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-be-
nzoimidazole,
Dimethyl-(2-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-indazol-2-yl}-ethyl)-amine,
Methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-(tet-
rahydro-pyran-4-ylmethyl)-amine,
N--[(R)-1-(2-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-indazol-1-yl}-ethyl)-pyrrol-
idin-3-yl]-acetamide,
((S)-sec-Butyl)-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmet-
hyl}-amine,
Dimethyl-(2-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-indazol-1-yl}-ethyl)-amine,
2-Azepan-1-ylmethyl-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazole,
Cyclopentyl-methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-yl-
methyl}-amine,
2-((R)-2-Methyl-piperidin-1-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H--
benzoimidazole,
2-(3-Methoxymethyl-pyrrolidin-1-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-
-1H-benzoimidazole,
2-((R)-2-Methoxymethyl-pyrrolidin-1-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phen-
oxy]-1H-benzoimidazole,
2-(2-Methoxymethyl-piperidin-1-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]--
1H-benzoimidazole,
N,N-Dimethyl-2-(1-{6-[4-(2H-pyrazol-3-yl)-phenoxy]-2,3-dihydro-benzofuran-
-2-ylmethyl}-piperidin-4-yl)-acetamide,
2-Methoxy-N-(1-{6-[4-(2H-pyrazol-3-yl)-phenoxy]-2,3-dihydro-benzofuran-2--
ylmethyl}-piperidin-4-yl)-acetamide,
2-((S)-2-Methyl-piperidin-1-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H--
benzoimidazole,
2-(3-Methoxy-piperidin-1-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-ben-
zoimidazole,
2-((S)-2-Methoxymethyl-pyrrolidin-1-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phen-
oxy]-1H-benzoimidazole,
3-Methyl-1-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}--
azetidin-3-ol,
2-[1,4]Oxazepan-4-ylmethyl-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidaz-
ole,
2-[2-(1,1-Dioxo-1-6-thiomorpholin-4-yl)-ethyl]-5-[4-(2H-pyrazol-3-yl)-
-phenoxy]-2H-indazole,
1-[1-(2-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-indazol-1-yl}-ethyl)-piperidin-4-
-yl]-pyrrolidin-2-one,
2-[(1S,4S)-1-(2-Oxa-5-aza-bicyclo[2.2.1]hept-5-yl)methyl]-6-[5-(2H-pyrazo-
l-3-yl)-pyridin-2-yloxy]-quinoline,
Cyclopropyl-methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-yl-
methyl}-amine,
((R)-sec-Butyl)-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmet-
hyl}-amine,
{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-(tetrahydro-
-pyran-3-yl)-amine,
2-(3,3-Dimethyl-morpholin-4-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H--
benzoimidazole,
Isopropyl-(2-methoxy-ethyl)-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimid-
azol-2-ylmethyl}-amine,
(2-Methoxy-ethyl)-propyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazo-
l-2-ylmethyl}-amine,
{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-2,3-dihydro-benzofuran-2-ylmethyl}-(tetr-
ahydro-pyran-4-ylmethyl)-amine,
Bis-(2-methoxy-ethyl)-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-
-ylmethyl}-amine,
Morpholin-4-yl-(1-{6-[4-(2H-pyrazol-3-yl)-phenoxy]-2,3-dihydro-benzofuran-
-2-ylmethyl}-piperidin-4-yl)-methanone,
Cyclopentyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-
-amine,
((S)-2-Methoxy-1-methyl-ethyl)-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-
-benzoimidazol-2-ylmethyl}-amine,
3-(1-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-piperi-
din-4-yl)-[1,3]oxazinan-2-one,
Ethyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-amine-
,
2-(Ethyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-a-
mino)-ethanol,
2-(4-Ethoxymethyl-piperidin-1-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1-
H-benzoimidazole,
{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-(S)-tetrahy-
dro-furan-3-yl-amine,
(1-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-piperidi-
n-2-yl)-methanol,
5-[4-(2H-Pyrazol-3-yl)-phenoxy]-2-(3-trifluoromethyl-pyrrolidin-1-ylmethy-
l)-1H-benzoimidazole,
1-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-2,3-dihydro-benzofuran-2-ylmethyl}-pip-
eridine-4-carboxylic acid dimethylamide,
1-(1-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-2,3-dihydro-benzofuran-2-ylmethyl}--
piperidin-4-yl)-pyrrolidin-2-one,
2-(Propyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-a-
mino)-ethanol,
N--[(R)-1-(2-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-indazol-2-yl}-ethyl)-pyrrol-
idin-3-yl]-acetamide,
2-Methoxy-N-[1-(2-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-indazol-1-yl}-ethyl)-p-
iperidin-4-yl]-acetamide,
5-[4-(2H-Pyrazol-3-yl)-phenoxy]-2-(tetrahydro-pyran-4-ylmethyl)-1H-benzoi-
midazole,
3-(1-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-2,3-dihydro-benzofuran-2-y-
lmethyl}-piperidin-4-yl)-oxazolidin-2-one,
1-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-piperidin-
-4-ol,
2-((R)-3-Methoxy-pyrrolidin-1-ylmethyl)-6-[5-(2H-pyrazol-3-yl)-pyri-
din-2-yloxy]-quinoline,
(2-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-indazol-2-yl}-ethyl)-(tetrahydro-pyra-
n-4-ylmethyl)-amine,
5-[4-(2H-Pyrazol-3-yl)-phenoxy]-2-(S)-1-pyrrolidin-2-ylmethyl-1H-benzoimi-
dazole,
2-((S)-3-Methoxy-pyrrolidin-1-ylmethyl)-6-[5-(2H-pyrazol-3-yl)-pyr-
idin-2-yloxy]-quinoline,
1'-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl-[1,4']bip-
iperidinyl-2-one,
(S)-1-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-pyrro-
lidin-3-ol,
4-(1-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-piperi-
din-4-yl)-morpholin-3-one,
2-(4-Methoxy-piperidin-1-ylmethyl)-6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy-
]-quinoline,
(1R,5S)-3-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-1-
,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one,
{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-[2-(tetrahy-
dro-pyran-4-yl)-ethyl]-amine,
6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-2-[4-(pyridin-2-yloxy)-piperidin--
1-ylmethyl]-quinoline,
1-{1-[4-(2H-Pyrazol-3-yl)-benzyl]-1H-indol-5-ylmethyl}-azetidin-3-ol,
5-[4-(2H-Pyrazol-3-yl)-phenoxy]-2-(2-pyrrolidin-1-yl-ethyl)-2H-indazole,
5-[4-(2-Pyrrolidin-1-ylmethyl-2,3-dihydro-benzofuran-6-yloxy)-phenyl]-1H--
pyrazole,
N-(1-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-2,3-dihydro-benzofuran-2-y-
lmethyl}-piperidin-4-yl)-acetamide,
6-[5-(2H-Pyrazol-3-yl)-pyrimidin-2-yloxy]-2-pyrrolidin-1-ylmethyl-quinoli-
ne,
1-(4-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-1H-indol-2-ylmethyl}-pip-
erazin-1-yl)-ethanone,
1-(4-{5-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-1H-indol-2-ylmethyl}-pipera-
zin-1-yl)-ethanone,
1-(4-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-isoquinolin-3-ylmethyl}-pip-
erazin-1-yl)-ethanone,
1-[4-(2-{5-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-indol-1-yl}-ethyl)-piper-
azin-1-yl]-ethanone,
2-(4-Morpholin-4-ylmethyl-piperidin-1-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-ph-
enoxy]-1H-benzoimidazole,
2-((S)-3-Methoxy-pyrrolidin-1-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1-
H-benzoimidazole,
3-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-8-oxa-3-a-
za-bicyclo[3.2.1]octane,
2-(4-Methoxy-piperidin-1-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-ben-
zoimidazole,
(1S,2S)-2-(Methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylm-
ethyl}-amino)-cyclohexanol,
Methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-(tet-
rahydro-pyran-4-yl)-amine,
1-(4-{6-[5-(1H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-pipera-
zin-1-yl)-ethanone,
2-(2-Morpholin-4-yl-ethoxy)-6-[4-(1H-pyrazol-3-yl)-phenoxy]-benzothiazole-
, Cyclopropanecarboxylic acid
methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-amid-
e,
3,3-Dimethyl-1-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylme-
thyl}-pyrrolidin-2-one, Cyclopropanecarboxylic acid
ethyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-amide-
,
2-Methoxy-N-(1-{6-[5-(1H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmet-
hyl}-piperidin-4-yl)-acetamide,
N-(1-{6-[5-(1H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-piperi-
din-4-yl)-acetamide,
N-((endo)-8-{6-[5-(1H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-
-8-aza-bicyclo[3.2.1]oct-3-yl)-acetamide,
N-((exo)-8-{6-[5-(1H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}--
8-aza-bicyclo[3.2.1]oct-3-yl)-acetamide,
1-((S)-5-{6-[5-(1H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-2,-
5-diaza-bicyclo[2.2.1]hept-2-yl)-ethanone,
1-(4-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-quinoxalin-2-ylmethyl}-piperazin-1--
yl)-ethanone,
2-(1,1-Dioxo-1-.lamda.-6-thiomorpholin-4-ylmethyl)-6-[5-(1H-pyrazol-3-yl)-
-pyridin-2-yloxy]-quinoline,
6-[4-(2H-Pyrazol-3-yl)-phenoxy]-2-pyrrolidin-1-ylmethyl-quinoline,
2-Azetidin-1-ylmethyl-6-[4-(2H-pyrazol-3-yl)-phenoxy]-quinoline,
1-(8-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-quinolin-2-ylmethyl}-3,8-diaza-bicy-
clo[3.2.1]oct-3-yl)-ethanone,
6-[4-(2H-Pyrazol-3-yl)-phenoxy]-2-pyrrolidin-1-ylmethyl-imidazo[1,2-a]pyr-
idine,
1-(4-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-quinolin-2-ylmethyl}-piperazi-
n-1-yl)-ethanone,
N-((exo)-8-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-quinolin-2-ylmethyl}-8-aza-bi-
cyclo[3.2.1]oct-3-yl)-acetamide,
3-Morpholin-4-ylmethyl-6-[4-(2H-pyrazol-3-yl)-phenoxy]-quinoline,
2-Morpholin-4-ylmethyl-6-[4-(2H-pyrazol-3-yl)-phenoxy]-imidazo[1,2-a]pyri-
dine,
(S)-5-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-indazol-2-ylmethyl}-pyrrolidi-
n-2-one,
2-Morpholin-4-ylmethyl-6-[4-(2H-pyrazol-3-yl)-benzyl]-imidazo[1,2-
-a]pyridine,
(S)-5-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-indazol-1-ylmethyl}-pyrrolidin-2-o-
ne,
2-Morpholin-4-ylmethyl-6-[4-(2H-pyrazol-3-yl)-phenoxy]-quinoline,
3-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-imidazo[1,2-a]pyridin-2-ylmethyl}-oxaz-
olidin-2-one,
2-Methyl-6-[4-(2H-pyrazol-3-yl)-phenoxy]-3-pyrrolidin-1-ylmethyl-quinolin-
e,
2-Morpholin-4-ylmethyl-7-[4-(2H-pyrazol-3-yl)-phenoxy]-imidazo[1,2-a]py-
ridine,
Morpholin-4-yl-{7-[4-(2H-pyrazol-3-yl)-phenoxy]-imidazo[1,2-a]pyri-
din-2-yl}-methanone,
1-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-imidazo[1,2-a]pyridin-2-ylmethyl}-pipe-
ridine-4-carboxylic acid, and
(R)-5-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-imidazo[1,2-a]pyridin-2-ylmethoxy}-
-piperidin-2-one, and pharmaceutically acceptable salts
thereof.
[0261] In some embodiments, the LTA4H modulatory agent is a
compound selected from
2-Hydroxy-1-(4-{7-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmeth-
yl}-piperazin-1-yl)-ethanone,
1-(4-{7-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethyl}-pipera-
zin-1-yl)-ethanone,
1-{7-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethyl}-azetidin--
3-ol,
2-Methoxy-1-(4-{7-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-y-
lmethyl}-piperazin-1-yl)-ethanone,
(S)-3-Hydroxy-1-(1-{7-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-yl-
methyl}-piperidin-4-yl)-pyrrolidin-2-one,
3-(1-{7-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethyl}-piperi-
din-4-yl)-oxazolidin-2-one,
1-{7-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethyl}-piperidin-
-4-ol,
3-Methyl-1-{7-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylme-
thyl}-azetidin-3-ol,
2-Hydroxy-1-[(R)-3-(methyl-{7-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quino-
lin-3-ylmethyl}-amino)-pyrrolidin-1-yl]-ethanone,
2-Hydroxy-1-[(S)-3-(methyl-{7-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quino-
lin-3-ylmethyl}-amino)-pyrrolidin-1-yl]-ethanone,
2-Hydroxy-N-methyl-N--((S)-1-{7-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-qui-
nolin-3-ylmethyl}-pyrrolidin-3-yl)-acetamide,
2-Hydroxy-N-methyl-N--((R)-1-{7-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-qui-
nolin-3-ylmethyl}-pyrrolidin-3-yl)-acetamide,
(S)-1-{7-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethyl}-pyrro-
lidin-3-ol,
1-(4-{7-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethyl}-pipera-
zin-1-yl)-propan-1-one,
2-Hydroxy-N-methyl-N-(1-{7-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-
-3-ylmethyl}-piperidin-4-yl)-acetamide,
1-{3-[(Methyl-{7-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethy-
l}-amino)-methyl]-azetidin-1-yl}-ethanone,
(R)-1-{7-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethyl}-pyrro-
lidin-3-ol,
(S)-2-Hydroxy-1-(4-{7-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-yl-
methyl}-piperazin-1-yl)-propan-1-one,
1-{7-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethyl}-piperidin-
e-4-carboxylic acid dimethylamide,
2-Hydroxy-2-methyl-1-(4-{7-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-
-3-ylmethyl}-piperazin-1-yl)-propan-1-one,
2,2-Dimethyl-1-(4-{7-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylm-
ethyl}-piperazin-1-yl)-propan-1-one,
Cyclopropyl-(4-{7-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmeth-
yl}-piperazin-1-yl)-methanone, and
2-Methyl-1-(4-{7-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethy-
l}-piperazin-1-yl)-propan-1-one, and pharmaceutically acceptable
salts thereof.
[0262] In certain embodiments, the LTA4H modulatory agent is of the
formula (XII):
##STR00032##
or a pharmaceutically acceptable salt thereof,
[0263] where:
[0264] A.sup.3, A.sup.4 and A.sup.5 are each independently CH or
N;
[0265] L.sup.1 is a linker selected from --O-- and
--CH.sub.2--;
[0266] L.sup.3 is absent or a --(C.sub.1-C.sub.6)alkylene-linker;
wherein said --(C.sub.1-C.sub.6)alkylene-linker is optionally
substituted with one to three groups selected from --OH, halo,
--(C.sub.1-C.sub.6)alkyl;
[0267] D is a ring selected from
[0268] (a) --(C.sub.3-C.sub.7)cycloalkyl, (C.sub.6-C.sub.10)aryl,
and -(5- to 11-membered)heteroaryl;
[0269] (b) -(4- to 11-membered)heterocycloalkyl, comprising an O or
S ring atom and optionally 1 to 3 additional ring heteroatoms
selected from N, O, and S;
[0270] (c) 4-8 member monocyclic heterocyclic comprising a N ring
atom and 1 to 3 additional ring heteroatoms selected from N, O, and
S;
[0271] (d) a 6 to 11-membered fused bicyclic, bridged bicyclic or
spirocyclic heterocyclic radical comprising a N ring atom and
optionally 1 to 3 additional ring heteroatoms selected from N, O,
and S; and
[0272] (e) a group selected from 2-oxo-pyrrolidin-1-yl,
2-oxo-pyrrolidin-3-yl, 2-oxo-pyrrolidin-5-yl,
1-methyl-2-oxo-pyrrolidin-4-yl, and 2-oxo-piperidin-5-yl wherein
each of said D rings is optionally substituted with one to three
R.sup.1 groups; and wherein each of said D rings is further
optionally substituted, where possible, by one or two groups
independently selected from (.dbd.O) and (.dbd.S);
[0273] each R.sup.1 is independently selected from halo, --OH,
--CF.sub.3, --CN, --(C.sub.1-C.sub.6)alkyl,
--O(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.2, --C(O)OR.sup.2,
--C(O)N(R.sup.2).sub.2, --N(R.sup.2).sub.2,
--N(R.sup.2)C(O)R.sup.2, --S(O).sub.2R.sup.2,
--N(R.sup.2)--S(O).sub.2--R.sup.2, --(C.sub.3-C.sub.6)cycloalkyl,
-(5- to 11-membered)heterocycloalkyl, --(C.sub.6-C.sub.10)aryl, and
-(5- to 11-membered)heteroaryl; wherein each of said,
--(C.sub.1-C.sub.6)alkyl, --O(C.sub.1-C.sub.6)alkyl,
--(C.sub.3-C.sub.6)cycloalkyl, -(5- to
11-membered)heterocycloalkyl, --(C.sub.6-C.sub.10)aryl, and -(5- to
11-membered)heteroaryl of said R.sup.1 group is optionally
substituted with one to three groups selected from halo, --OH,
--CF.sub.3, --(C.sub.1-C.sub.6)alkyl, --C(O)OH,
--C(O)OC.sub.1-C.sub.6)alkyl, --C(O)(C.sub.1-C.sub.6)alkyl),
--NH.sub.2, --NH(C.sub.1-C.sub.6)alkyl,
N((C.sub.1-C.sub.6)alkyl).sub.2 and --CN;
[0274] each R.sup.2 is independently selected from the group
consisting of --H, --(C.sub.1-C.sub.6)alkyl,
--(C.sub.3-C.sub.6)cycloalkyl, -(5- to
11-membered)heterocycloalkyl, --(C.sub.6-C.sub.10)aryl, and -(5- to
11-membered)heteroaryl; wherein each of said,
--(C.sub.1-C.sub.6)alkyl, --O(C.sub.1-C.sub.6)alkyl,
--(C.sub.3-C.sub.6)cycloalkyl, -(5- to
11-membered)heterocycloalkyl, --(C.sub.6-C.sub.10)aryl, and -(5- to
11-membered)heteroaryl of said R.sup.2 group is optionally
independently substituted by one to three groups selected from
halo, --OH, --CF.sub.3, --(C.sub.1-C.sub.6)alkyl, --NH.sub.2,
--NH(C.sub.1-C.sub.6)alkyl, --N((C.sub.1-C.sub.6)alkyl).sub.2 and
--CN.
[0275] In some embodiments of formula (XII), L3-D taken together
are described by a group selected from
(1-methyl-pyrrolidin-2-on-4-yl)methyl, (pyrrolidin-2-on-3yl)oxy,
(pyrrolidin-2-on-5-yl)methyloxy, 2-(pyrrolidin-2-on-1-yl)ethyloxy,
3-(pyrrolidin-2-on-1-yl)propyloxy, (tetrahydrofuran-3-yl)oxy,
(tetrahydrofuran-2-yl)methyloxy, (tetrahydrofuran-3-yl)methyloxy;
(piperidin-2-on-5-yl)oxy, (1,3-oxazolidin-2-on-4-yl)methyloxy,
(1,3-oxazolidin-2-on-5-yl)methyloxy, (morpholin-3-yl)methyloxy,
(morpholin-4-yl)ethyloxy, 1H-pyrazol-5-yl,
(1H-pyrazol-5-yl)methyloxy, (1H-pyrazol-3-yl)methyloxy,
(1-methyl-1H-pyrazol-3-yl)methyloxy,
(1-methyl-1H-pyrazol-5-yl)methyloxy,
(1-methyl-2-(2-furyl)-pyrazol-5-yl)methyloxy,
3-(1H-pyrazol-1-yl)-ethyloxy, 2-(1H-pyrazol-4-yl)-ethyloxy,
3-(1H-pyrazol-1-yl)-3-methylpropyloxy, (furan-2-yl)methyloxy,
(furan-3-yl)methyloxy, (dihydrofuran-2(3H)-on-3-yl)oxy,
(dihydrofuran-2(3H)-on-5-yl)methyloxy, (pyridin-3-yl)methyloxy,
(pyridin-4-yl)methyloxy,
(2-(1H-pyrazol-1-yl)-pyridin-5-yl)methyloxy,
1-(pyridin-2-yl)-ethyloxy, 2-(pyridin-2-yl)ethyloxy,
2-(pyridin-3-yl)ethyloxy, 2-(pyridin-4-yl)-ethyloxy,
(pyrimidin-2-yl)methyloxy, (thien-3-yl)methyloxy,
2-(thien-2-yl)ethyloxy, (tetrahydro-2H-pyran-3-yl)oxy,
(tetrahydro-2H-pyran-4-yl)oxy),
(tetrahydro-2H-pyran-2-yl)methyloxy,
(tetrahydro-2H-pyran-3-yl)methyloxy,
(tetrahydro-2H-pyran-4-yl)methyloxy,
2-(tetrahydro-2H-pyran-2-yl)ethyloxy,
2-(tetrahydro-2H-pyran-4-yl)ethyloxy,
(2-methyl-1H-imidazol-1-yl)ethyloxy, (pyrazin-2-yl)methyloxy,
benzyloxy, (4-(methylsulfonyl)benzyl)oxy,
(1,3-thiazol-2-yl)methyloxy, (1,3-thiazol-5-yl)methyloxy,
2-(1,3-thiazol-5-yl)ethyloxy,
(4-methyl-1,2,3-thiadiazol-5-yl)methyloxy,
(isoxazol-5-yl)methyloxy, 2-(isoxazol-4-yl)ethyloxy,
(1-methyl-1,2,4-triazol-5-yl)methyloxy, (1,3-oxazol-4-yl)methyloxy,
(1,3-oxazol-5-yl)methyloxy, (2-methyl-1,3-oxazol-4-yl)methyloxy,
(4-methyl-1,3-oxazol-5-yl)methyloxy,
(1H-benzimidazol-2-yl)methyloxy, (1H-benzimidazol-5-yl)methyloxy,
(1H-benzimidazol-1-yl)ethyloxy, (1H-benzimidazol-2-yl)ethyloxy,
2-((1H-benzimidazol-2-yl)-amino)ethyloxy,
(imidazo[2,1-b][1,3]thiazol-2-yl)methyloxy,
(1H-pyrrolo[2,3-b]pyridin-5-yl)methyloxy,
(6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)oxy,
2-(1H-pyrrolo[3,2-b]pyridin-6-yl)-ethyloxy,
(imidazo[1,2-a]pyridin-2-yl)methyloxy,
(1,3-benzothiazol-2-yl)methyloxy; and
(imidazo[1,2-a]pyridin-6-yl)methyloxy.
[0276] In some embodiments the LTA4H modulatory agent includes an
arylpyrazole small molecule described in any of U.S. Pat. Nos.
9,573,957; 9,403,830; 9,303,018; and 9,139,567, each of which is
incorporated herein by reference.
[0277] In some embodiments, the LTA4H modulatory agent is a
benzodioxane, or a pharmaceutically acceptable salt thereof. In
certain embodiments, the LTA4H modulatory agent is of the formula
(XIII):
##STR00033##
[0278] where:
[0279] X.sup.a is N or CH;
[0280] n is an integer from 0 to 3;
[0281] R.sup.42 is selected from halo, --OH, --CN,
--(C.sub.1-C.sub.6)alkyl, --O(C.sub.1-C.sub.6)alkyl, and
--(C.sub.3-C.sub.6)cycloalkyl;
[0282] R.sup.40 and R.sup.41 are each independently selected from
--H and --(C.sub.1-C.sub.6)alkyl; wherein R.sup.40 and R.sup.41 may
join to form a 3- to 6-membered ring optionally comprising one to
three heteroatoms, and further optionally substituted with one to
three groups selected from halo, --OH, (.dbd.O),
--(C.sub.1-C.sub.6)alkyl, --O(C.sub.1-C.sub.6)alkyl, --C(O)O--H,
--C(O)(C.sub.1-C.sub.6)alkyl, and --C(O)NH.sub.2;
[0283] A is a group of formula --NR.sup.43R.sup.44, wherein
R.sup.43 and R.sup.44 are each independently selected from --H,
--(C.sub.1-C.sub.6)alkyl, --(C.sub.3-C.sub.6)cycloalkyl, -(4- to
14-membered)heterocycloalkyl, --(C.sub.6-C.sub.10)aryl, and -(5- to
11-membered)heteroaryl; wherein each of the foregoing
--(C.sub.1-C.sub.6)alkyl, --(C.sub.3-C.sub.6)cycloalkyl, -(4- to
14-membered)heterocycloalkyl, --(C.sub.6-C.sub.10)aryl, and -(5- to
11-membered)heteroaryl of said R.sup.4 and R.sup.5 groups is
optionally independently substituted by one to three R.sup.6
groups; wherein two R.sup.6 groups when attached to the same carbon
atom of said --(C.sub.1-C.sub.6)alkyl may join to form a 3- to
6-membered ring optionally comprising one to three heteroatoms, and
further optionally substituted with one to three groups selected
from halo, --OH, (.dbd.O), --(C.sub.1-C.sub.6)alkyl,
--O(C.sub.1-C.sub.6)alkyl, --C(O)O--H,
--C(O)(C.sub.1-C.sub.6)alkyl, and --C(O)NH.sub.2;
[0284] A is a (4- to 14-membered)N-heterocyclic ring of formula
B:
##STR00034##
[0285] wherein said ring B is:
[0286] (a) a non-aromatic 4-8 membered monocyclic radical; or
[0287] (b) a bridged bicyclic radical, a spirocyclic radical, or a
6 to 11-membered fused bicyclic radical, wherein each of said
bridged bicyclic radical, spirocyclic radical, and 6 to 11-membered
fused bicyclic radical comprises at least a nonaromatic
N-heterocyclic ring which is attached to the carbon atom 1 of the
compound of formula (I); wherein each of said bridged bicyclic
radical, spirocyclic radical, and 6 to 11-membered fused bicyclic
radical may optionally comprise an aromatic ring;
[0288] wherein said ring B may additionally comprise one to three
additional ring heteroatoms independently selected from N, O and
S;
[0289] wherein said ring B may be further optionally substituted by
one to three groups selected from halo, --OH, (.dbd.O), --C(O)O--H,
--C(O)O--(C.sub.1-C.sub.6)alkyl, and --(C.sub.1-C.sub.6)alkyl;
and
[0290] wherein L is absent or a linker selected from
--(C.sub.1-C.sub.6)alkylene-;
[0291] each R.sup.6 is independently selected from halo,
--OR.sup.7, --CF.sub.3, --CN, --(C.sub.1-C.sub.6)alkyl,
--O(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.7, --C(O).sub.2R.sup.7,
--C(O)N(R.sup.7).sub.2, --N(R.sup.7).sub.2, --NHC(O)R.sup.7,
--NHC(O)N(R.sup.7).sub.2, --S(O).sub.2R.sup.7,
--NH--S(O).sub.2--R.sup.7, --(C.sub.3-C.sub.6)cycloalkyl, -(4- to
14-membered)heterocycloalkyl, --(C.sub.6-C.sub.10)aryl, and -(5- to
11-membered)heteroaryl; wherein each of said,
--(C.sub.1-C.sub.6)alkyl, --O(C.sub.1-C.sub.6)alkyl,
--(C.sub.3-C.sub.6)cycloalkyl, -(4- to
14-membered)heterocycloalkyl, --(C.sub.6-C.sub.10)aryl, and -(5- to
11-membered)heteroaryl of said R.sup.6 group is optionally
substituted where possible with one to three groups selected from
halo, --OH, --CF.sub.3, --CN, (.dbd.O), --(C.sub.1-C.sub.6)alkyl,
--C(O)O--H, --C(O)O--(C.sub.1-C.sub.6)alkyl, --NH.sub.2,
--NH(C.sub.1-C.sub.6)alkyl, --N((C.sub.1-C.sub.6)alkyl).sub.2,
--S(O).sub.2(C.sub.1-C.sub.6)alkyl, --(C.sub.3-C.sub.6)cycloalkyl,
-(4- to 14-membered)heterocycloalkyl, --(C.sub.6-C.sub.10)aryl, and
-(5- to 11-membered)heteroaryl; and
[0292] each R.sup.7 is independently selected from --H,
--(C.sub.1-C.sub.6)alkyl, --(C.sub.1-C.sub.6)alkyl-OH,
--(C.sub.1-C.sub.6)alkyl-0-(C.sub.1-C.sub.6)alkyl,
--O(C.sub.1-C.sub.6)alkyl, --(C.sub.3-C.sub.6)cycloalkyl,
--(C.sub.3-C.sub.6)cycloalkyl-OH, -(4- to
14-membered)heterocycloalkyl, --(C.sub.6-C.sub.10)aryl, and -(5- to
11-membered)heteroaryl; wherein each of said R.sup.7 group is
optionally substituted where possible with a group selected from
--OH, --NH(C.sub.1-C.sub.6)alkyl, --NHC(O)(C.sub.1-C.sub.6)alkyl,
--C(O)NH.sub.2, --S(O).sub.2(C.sub.1-C.sub.6)alkyl, and -(4- to
14-membered)heterocycloalkyl; wherein said -(4- to
14-membered)heterocycloalkyl group is optionally substituted where
possible with a (.dbd.O) group.
[0293] In some embodiments, the LTA4H modulatory agent is a
compound selected from
3-[(4-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperazin-1-yl)met-
hyl]benzoic acid,
7-[(S)-4-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-5,6,7,8-te-
trahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-carboxylic acid ethyl
ester,
7-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-5,6,7,8-te-
trahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-carboxylic acid amide,
7-[(S)-4-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-5,6,7,8-te-
trahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-carboxylic acid
methylamide,
7-[(S)-4-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-5,6,7,8-te-
trahydro-imidazo[1,2-a]pyrazine-2-carboxylic acid amide,
7-[(S)-4-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-5,6,7,8-te-
trahydro-imidazo[1,2-a]pyrazine-2-carboxylic acid methylamide,
6-[(S)-4-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-5,6,7,8-te-
trahydro-4H-1,2,3a,6-tetraaza-azulene-3-carboxylic acid amide,
6-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-5,6,7,8-te-
trahydro-4H-1,2,3a,6-tetraaza-azulene-3-carboxylic acid
methylamide,
[(1a,5a,6a)-3-[(S)-4-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl-
]-3-aza-bicyclo[3.1.0]hexane]-6-carboxylic acid
((S)-2-hydroxy-propyl)-amide,
[(1.alpha.,5.alpha.,6.alpha.)-3-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]py-
ridin-3-yl)-benzyl]-3-aza-bicyclo[3.1.0]hexane]-6-carboxylic acid
((S)-2-hydroxy-1-methyl-ethyl)-amide,
7-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-5,6,7,8-te-
trahydro-imidazo[1,2-a]pyrazine-3-carbonitrile,
N-{(1a,5a,6a)-3-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benz-
yl]-3-aza-bicyclo[3.1.0]hex-6-yl}-acetamide,
[(1.alpha.,5.alpha.,6.alpha.)-3-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]py-
ridin-3-yl)-benzyl]-3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid
(2-hydroxy-2-methyl-propyl)]-amide,
N-{1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperid-
in-4-yl}-2-methoxy-acetamide,
1-{4-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperaz-
in-1-yl}-2-hydroxy-ethanone,
4-{1-[(S)-4-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-benzyl]-azetidin-3-yl}-be-
nzoic acid,
1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperidine-
-4-carboxylic acid (2-hydroxy-2-methyl-propyl)-amide,
1-{(1S,4S)-5-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-
-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-2-methanesulfonyl-ethanone,
1-{4-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-[1,4]di-
azepan-1-yl}-2-methoxy-ethanone,
5-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-4,5,6,7-te-
trahydro-thiazolo[5,4-c]pyridin-2-ylamine,
{(endo)-8-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-8--
aza-bicyclo[3.2.1]oct-3-yl}-urea,
2-{1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperid-
in-4-yl}-N-methoxy-acetamide,
(R)--N-{1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-pi-
peridin-4-yl}-2-methylamino-propionamide,
N-{1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperid-
in-4-ylmethyl}-2-hydroxy-2-methyl-propionamide,
N--{(1.alpha.,5.alpha.,6.alpha.)-3-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b-
]pyridin-3-yl)-benzyl]-3-aza-bicyclo[3.1.0]hex-6-ylmethyl}-methanesulfonam-
ide,
1-{(1S,4S)-5-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-ben-
zyl]-2,5-diaza-bicyclo[2.2.2]oct-2-yl}-ethanone,
4-{1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperid-
in-4-yl}-cyclohexanecarboxylic acid,
1-[(S)-4-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-benzyl]-azepane-4-carboxylic
acid,
[(1.alpha.,5.alpha.,6.alpha.)-3-[(S)-4-(2,3-Dihydro-benzo[1,4]dioxi-
n-2-yl)-benzyl]-3-aza-bicyclo[3.1.0]hexane]-6-carboxylic acid,
(1S,4S)-5-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-2,-
5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid amide,
1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-4-phenyl-p-
iperidin-4-ol,
1-{5-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-hexahyd-
ro-pyrrolo[3,4-c]pyrrol-2-yl}-ethanone,
1-{8-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-3,8-dia-
za-bicyclo[3.2.1]oct-3-yl}-ethanone,
5-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-hexahydro--
pyrrolo[3,4-c]pyrrole-2-carboxylic acid amide,
{(exo)-8-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-8-a-
za-bicyclo[3.2.1]oct-3-yl}-urea,
2-{1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperid-
in-4-yloxy}-acetamide,
(S)-3-[4-(1,1-Dioxo-1lambda-6-[1,4]thiazepan-4-ylmethyl)-phenyl]-2,3-dihy-
dro-[1,4]dioxino[2,3-b]pyridine,
1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-4-methyl-p-
iperidin-4-ol,
1-{(1S,4S)-5-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-
-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-2-hydroxy-ethanone,
N-{(endo)-8-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]--
8-aza-bicyclo[3.2.1]oct-3-yl}-acetamide,
N-{1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperid-
in-4-ylmethyl}-acetamide,
[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-(1,1-dioxo-t-
etrahydro-1lambda-6-thiophen-3-yl)-methyl-amine,
1-{(1S,4S)-5-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-
-2,5-diaza-bicyclo[2.2.2]oct-2-yl}-2-hydroxy-ethanone,
{1-[(S)-4-(2,3-dihydro-[1,4]dioxino-[2,3-b]pyridin-3-yl)-benzyl]-spiro-[3-
H-indole-3,4'-piperidine]-1 (2H)-urea,
{1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperidin-
-4-ylmethyl}-urea,
{4-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperazin-
-1-yl}-acetonitrile,
(R)-7-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-hexahy-
dro-oxazolo[3,4-a]pyrazin-3-one,
{1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperidin-
-4-yl}-(3-hydroxy-azetidin-1-yl)-methanone,
1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperidine-
-4-carboxylic acid [(S)-1-(tetrahydro-furan-2-yl)methyl]-amide,
N-[3-[4-[[4-[(3S)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl]phenyl]meth-
yl]piperazin-1-yl]-3-oxo-propyl]acetamide,
N-[1-[[4-[(3S)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl]phenyl]methyl]-
-4-piperidyl]-2-(2-oxopyrrolidin-1-yl)acetamide,
N-[1-[[4-[(3S)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl]phenyl]methyl]-
-4-piperidyl]tetrahydropyran-4-carboxamide,
3-{1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperid-
in-4-yl}-[1,3]oxazinan-2-one,
1-{(1S,4S)-5-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-
-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-ethanone,
(S)-3-{4-[4-(Pyridin-3-yloxy)-piperidin-1-ylmethyl]-phenyl}-2,3-dihydro-[-
1,4]dioxino[2,3-b]pyridine,
1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-4-phenyl-p-
iperidine-4-carboxylic acid, (S)-3-[4-(1-Oxo-1
lambda-4-thiomorpholin-4-ylmethyl)-phenyl]-2,3-dihydro-[1,4]dioxino[2,3-b-
]pyridine, and
(S)-7-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-hexahy-
dro-oxazolo[3,4-a]pyrazin-3-one.
[0294] In some embodiments, the LTA4H modulatory agent is a
compound selected from
1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]pyrrolidine,
4-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]morpholine,
1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-4,4-dimethylpiperidine,
8-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-2,8-diazaspiro[4,5]decan-1-
-one,
1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-4-fluoropiperidine,
(1
s,4s)-7-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-7-azabicyclo[2.2.-
1]heptane,
4-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]thiomorpholine
1,1-dioxide,
1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-N,N-dimethylpiperidin-
e-4-carboxamide,
(3S)-1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]pyrrolidin-3-ol,
1-({1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]piperidin-3-yl}methyl)p-
yrrolidin-2-one,
1-{4-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]piperazin-1-yl}ethenone,
2-{[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]amino}-1-(pyrrolidin-1-yl)-
ethenone,
N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-N-methyl-1-(-
methylsulfonyl)piperidin-4-amine,
1-{4-[{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}(methyl)amino]pipe-
ridin-1-yl}ethenone,
3-[4-(pyrrolidin-1-ylmethyl)phenyl]-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-
e,
7-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-5,6,7,8-tetrahydro[1,2,4-
]triazolo[4,3-a]pyrazine,
3-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}-2,3-dihydro[1,4]dioxi-
no[2,3-b]pyridine,
3-[4-(morpholin-4-ylmethyl)phenyl]-2,3-dihydro[1,4]dioxino[2,3-b]pyridine-
,
(3R)-1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidine-3-car-
boxylic acid,
(3S)-1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidine-3-carb-
oxylic acid,
1-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-yl)-2,2-
,2-trifluoroethanol,
2-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-yl)-1,1-
,1,3,3,3-hexafluoropropan-2-ol,
N-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-2-methylpropan-2-amine,
(2R)--N-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]butan-2-amine,
1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-N-methylpiperidine-4-carbo-
xamide,
4-{1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]piperidin-4-yl}bu-
tanoic acid,
{1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]piperidin-4-yl}methanol,
2-{1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]piperidin-4-yl}propan-2--
ol,
3-{1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]piperidin-4-yl}propan-
-1-ol,
1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-4-methyl-1,4-diazepa-
ne,
1-{4-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-1,4-diazepan-1-yl}et-
henone,
4-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-1,4-oxazepane,
N-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-2-methoxy-N-methylethanami-
ne,
(3R)-1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]pyrrolidin-3-ol,
8-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-1,3,8-triazaspiro[4.5]deca-
ne-2,4-dione,
1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-3-methoxyazetidine,
{1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]piperidin-4-yl}(morpholin--
4-yl)methanone,
2-{1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]piperidin-4-yl}-N,N-dime-
thylacetamide,
1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-4-(methylsulfonyl)piperidi-
ne, 1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]azepane,
N-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]cyclopentanamine,
N-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-N-methyl-2-(pyridin-2-yl)e-
thanamine,
1-cyclopropyl-N-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]met-
hanamine,
1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-4-phenylpiperidin-
-4-ol,
N-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-N-ethylethanamine,
1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]azetidine-3-carbonitrile,
1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-3-methoxypyrrolidine,
N-{1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]piperidin-4-yl}methanesu-
lfonamide,
N-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-2-methyl-1-(pyrr-
olidin-1-yl)propan-2-amine,
1-({1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]piperidin-4-yl}methyl)p-
yrrolidin-2-one,
1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-N,N-dimethylpiperidine-4-c-
arboxamide,
1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-N-(2-hydroxyethyl)piperidi-
ne-4-carboxamide,
1-{1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]piperidin-4-yl}urea,
1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)phenyl]-Nyridin-3-ylmethyl)methana-
mine,
1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)phenyl]-N-[(1-methyl-1H-imida-
zol-4-yl)methyl]methanamine,
2-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-1,2,3,4-tetrahydroiso-
quinoline-4-carboxylic acid,
(1R,3S)-3-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)cyclope-
ntanecarboxylic acid,
3-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)-4,4-dimethylpe-
ntanoic acid,
1-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)cyclopentanecar-
boxylic acid,
N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-N-methylglycine,
1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}pyrrolidine-3-carboxyl-
ic acid,
trans-4-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)c-
yclohexanecarboxylic acid,
cis-4-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)cyclohexane-
carboxylic acid,
1-[(3R)-3-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)pyrroli-
din-1-yl]ethenone,
1-[(3S)-3-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)pyrroli-
din-1-yl]ethenone,
trans-4-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)cyclohexa-
necarboxamide,
N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-N-methylcyclohexanami-
ne,
(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-3-yl)met-
hanol,
2-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-y-
l)ethanol,
N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}propan-2-ami-
ne,
N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-1-methoxypropan-2--
amine,
N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}propan-1-amine,
N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-N-methylethanamine,
1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]phenyl}-N,N-dimethylmethanami-
ne,
trans-4-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)cycloh-
exanol,
1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-3-ol,
N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-N,N',N'-trimethyletha-
ne-1,2-diamine, 2-(cyclohexyl
{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)ethanol,
(1R,2R,4S)--N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}bicyclo[2.-
2.1]heptan-2-amine,
(4aR,8aS)-1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}decahydroqui-
noline,
(1S,2R)-2-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)-
cyclohexanecarboxamide,
[(1S,2R)-2-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)cycloh-
exyl]methanol,
(3R)-1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}pyrrolidin-3-ol,
[(1R,2R)-2-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)cycloh-
exyl]methanol,
(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-yl)methan-
ol,
(3S)-1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}pyrrolidin-3-o-
l,
1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}imidazolidin-4-one,
1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-N,N-dimethylpyrrolidi-
n-3-amine,
1'-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-1,4'-bipip-
eridin-2-one,
N-(cyclopropylmethyl)-N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-
cyclohexanamine,
(1R,2R)-2-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)cyclohe-
xanol,
1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-4-methoxypiperi-
dine,
1-[(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-y-
l)methyl]pyrrolidin-2-one,
trans-N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-4-methylcyclohe-
xanamine,
(1S,2R)-2-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amin-
o)cyclopentanol,
(1S,2S)-2-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)cyclope-
ntanol,
N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}tetrahydro-2H-p-
yran-3-amine,
(1S,2S)-2-[{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}(methyl)amino-
]cyclohexanol,
(1R,2S)-2-[{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}(methyl)amino-
]cyclohexanol,
4-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-3-methylmorpholine,
5-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)-1-methylpiperi-
din-2-one,
N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-N,1-dimethy-
lpiperidin-4-amine,
4-[({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)methyl]phenol,
2-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-1,2,3,4-tetrahydroiso-
quinolin-6-ol,
1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]piperidine-3-carboxylic
acid,
1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]piperidine-3-carboxam-
ide,
(3S)-1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-3-fluoropyrrolidi-
ne,
9-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-2,9-diazaspiro[5.5-
]undecan-1-one,
1-(7-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-1,7-diazaspiro[4.4-
]non-1-yl)ethenone,
9-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-2-methyl-2,9-diazaspi-
ro[5.5]undecan-1-one,
8-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-2-methyl-2,8-diazaspi-
ro[4.5]decan-1-one,
7-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-1-(methylsulfonyl)-1,-
7-diazaspiro[4.4]nonane,
2-(7-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-1,7-diazaspiro[4.4-
]non-1-yl)acetamide,
(7-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-1,7-diazaspiro[4.4]n-
on-1-yl)acetonitrile,
1-(7-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-1,7-diazaspiro[4.4-
]non-1-yl)-2-methoxyethanone,
9-[(S)-4-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-benzyl]-2-methyl-2,9-diaza-s-
piro[5.5]undecan-1-one,
1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-1,4-diazepan-5-one,
1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-1,4-diazepa-
n-5-one,
N-[2-({4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-
amino)ethyl]acetamide,
3-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-yl)prop-
anoic acid,
N-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}cyclopentana-
mine,
N-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-N-meth-
ylethanamine,
(3S)-3-{4-[(1s,4s)-7-azabicyclo[2.2.1]hept-7-ylmethyl]phenyl}-2,3-dihydro-
[1,4]dioxino[2,3-b]pyridine,
(3S)-1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}pyrroli-
din-3-ol,
4-(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-
piperidin-4-yl)butanoic acid,
1-[4-({4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}amino)pi-
peridin-1-yl]ethenone,
(3S)-3-{4-(5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-ylmethyl)phenyl-
}-2,3-dihydro[1,4]dioxino[2,3-b]pyridine,
(3S)-3-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}-2,3-dihydro[1,4]-
dioxino[2,3-b]pyridine,
4-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperazine-1-
-carboxamide,
(3S)-3-{4-[(3-methoxyazetidin-1-yl)methyl]phenyl}-2,3-dihydro[1,4]dioxino-
[2,3-b]pyridine,
N-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-N-methyl-1--
(methylsulfonyl)piperidin-4-amine,
(3S)-3-(4-{[4-(2-methoxyethoxyl)piperidin-1-yl]methyl}phenyl)-2,3-dihydro-
[1,4]dioxino[2,3-b]pyridine,
2-(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-
-4-yl)-N,N-dimethylacetamide,
(3S)-3-(4-{[4-(methylsulfonyl)piperidin-1-yl]methyl}phenyl)-2,3-dihydro[1-
,4]dioxino[2,3-b]pyridine,
N-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}cyclobutanam-
ine,
N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-1-(methylsulfonyl-
)piperidin-4-amine,
1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidine-4-carbonitr-
ile,
N-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-yl)-
acetamide,
[(3S)-1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperi-
din-3-yl]acetic acid,
[(3R)-1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}pyrrolidin-3-yl]-
acetic acid,
1-(4-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperazin-
-1-yl)ethenone,
1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4--
ol,
1-(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperi-
din-4-yl)urea,
(3S)-3-(4-{[4-(methylsulfonyl)piperazin-1-yl]methyl}phenyl)-2,3-dihydro[1-
,4]dioxino[2,3-b]pyridine,
1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidine-4-
-carboxylic acid,
(1S,3R)-3-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)cyclope-
ntanecarboxylic acid,
1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-ol,
1-{4-[(2R)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-ol,
8-{4-[(2R)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-2,8-diazaspiro[4.5]de-
can-1-one,
1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}pyrrolidine,
1-{4-[(2R)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}pyrrolidine,
4-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}morpholine,
4-{4-[(2R)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}morpholine,
1-{4-[(2R)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidine-4-carboxyli-
c acid,
4-[4-(7-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]morpholine,
1-[4-(7-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]pyrrolidine,
(3R)-3-[4-(morpholin-4-ylmethyl)phenyl]-2,3-dihydro[1,4]dioxino[2,3-b]pyr-
idine,
1-{4-[(3R)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperi-
dine-4-carboxamide,
1-[4-(2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl)benzyl]pyrrolidin-2-one,
3-[4-(2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl)benzyl]-1,3-oxazolidin-2-
-one,
1-[4-(2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl)phenyl]methanamine,
1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-4-methylpiperidine-4--
carboxylic acid,
(3R,4R)-1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-3-methylpiper-
idine-4-carboxylic acid,
1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-4-fluoropiperidine-4--
carboxylic acid,
(3R)-1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}pyrrolidine-3-car-
boxylic acid,
(3S)-1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}pyrrolidine-3-car-
boxylic acid,
1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-4-(1H-tetrazol-5-yl)p-
iperidine,
1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4--
amine,
N-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-y-
l)-2-hydroxyacetamide,
N-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-yl)-2-m-
ethoxyacetamide,
N-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-yl)-2-h-
ydroxy-2-methylpropanamide,
1-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]phenyl}ethyl)pyrrolidine,
4-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]phenyl}ethyl)morpholine,
1-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]phenyl}ethyl)piperidine-4--
carboxylic acid,
1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-4-methylpip-
eridine-4-carboxylic acid,
2-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-yl)-2-m-
ethylpropanoic acid,
2-(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-
-4-yl)-2-methylpropanoic acid,
2-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-1,2,3,4-tetrahydroiso-
quinoline-7-carboxylic acid,
4-{[{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}(ethyl)amino]methyl}-
benzoic acid,
4-[(butyl{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)methyl]be-
nzoic acid,
3-{[{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}(ethyl)amino]methyl}-
benzoic acid, and
3-[(4-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperazin-1-yl)met-
hyl]benzoic acid, or a pharmaceutically salt thereof of each of the
foregoing.
[0295] In some embodiments, the LTA4H modulatory agent is a
compound selected from
4-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-yl)buta-
noic acid,
4-(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl-
}piperidin-4-yl)benzoic acid,
(3S)-3-{4-[(1s,4s)-7-azabicyclo[2.2.1]hept-7-ylmethyl]phenyl}-2,3-dihydro-
[1,4]dioxino[2,3-b]pyridine,
N-(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-
-4-yl)methanesulfonamide,
(3S)-3-[4-(azepan-1-ylmethyl)phenyl]-2,3-dihydro[1,4]dioxino[2,3-b]pyridi-
ne,
1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-2-methylpiperidine-
,
7-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-1,7-diazaspiro[4.4]n-
onane-1-carboxamide,
7-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-1,7-diazasp-
iro[4.4]nonan-2-one,
1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidine-4-carboxyli-
c acid,
(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-yl-
)(morpholin-4-yl)methanone,
8-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-1,3,8-triaz-
aspiro[4.5]decane-2,4-dione,
(3S)-3-{4-[(3-methoxypiperidin-1-yl)methyl]phenyl}-2,3-dihydro[1,4]dioxin-
o{2,3-b}pyridine,
N-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}pyrrolidin-3-yl)-N--
methylacetamide,
1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-4-(1,1-dioxido-1,2-th-
iazolidin-2-yl)piperidine,
(3R)-1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}pyrroli-
din-3-ol,
N-(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-
piperidin-4-yl)-2-hydroxyacetamide,
4-{(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidi-
n-4-yl)methyl)benzoic acid,
(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-
-yl)(morpholin-4-yl)methanone,
(3S)-3-[4-(morpholin-4-ylmethyl)phenyl]-2,3-dihydro[1,4]dioxino[2,3-b]pyr-
idine,
8-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-2,8-diazaspiro[-
4.5]decan-1-one,
1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidine-4-
-carbonitrile,
1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-N-methylpiperidine-4--
carboxamide,
8-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-2,8-diazasp-
iro[4.5]decan-1-one,
N-(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-
-4-yl)-2-hydroxy-2-methylpropanamide,
N-(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-
-4-yl-1-hydroxycyclopropanecarboxamide,
N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-N-ethylcyclopentanami-
ne,
1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-N-methyl-
piperidine-4-carboxamide,
N-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-N-methylcyc-
lopentanamine,
1-{(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidi-
n-3-yl)methyl}pyrrolidin-2-one,
1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-2-methylpyrrolidine,
N-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-2-methyl-1--
(pyrrolidin-1-yl)propan-2-amine,
N-cyclohexyl-N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-N',N'-di-
methylethane-1,2-diamine,
N-(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-
-4-yl)acetamide,
N-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-N-methyl-2--
(pyridin-2-yl)ethanamine,
(3S)-3-[4-(pyrrolidin-1-ylmethyl)phenyl]-2,3-dihydro[1,4]dioxino[2,3-b]py-
ridine,
1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piper-
idine-3-carboxamide,
1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidine-4-
-carboxamide,
N-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}pyrrolidin-3-yl)ace-
tamide,
1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-N-(2-
-hydroxyethyl)piperidine-4-carboxamide,
(3S)-3-[4-(1,4-oxazepan-4-ylmethyl)phenyl]-2,3-dihydro[1,4]dioxino[2,3-b]-
pyridine,
1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-N-(2-hydroxy-
ethyl)piperidine-4-carboxamide,
4-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-yl)benz-
oic acid,
1-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin--
4-yl)urea,
7-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-1,7-diazasp-
iro[4.4]nonan-2-one,
8-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-2-methyl-2,-
8-diazaspiro[4.5]decan-1-one,
1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4--
ol,
N-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-yl)m-
ethanesulfonamide,
3-(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-
-4-yl)propan-1-ol,
(3S)-3-{4-[(4-methylpiperidin-1-yl)methyl]phenyl}-2,3-dihydro[1,4]dioxino-
{2,3-b}pyridine,
N-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-N-ethyletha-
namine,
N-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-1-(m-
ethylsulfonyl)piperidin-4-amine,
(3S)-3-{4-[(4-fluoropiperidin-1-yl-methyl]phenyl}-2,3-dihydro[1,4]dioxino-
{2,3-b}pyridine,
1-(4-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-1,4-diaz-
epan-1-yl)ethenone,
[(3R)-1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-3-yl]a-
cetic acid,
(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-
-yl-methanol,
4-[(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-yl-met-
hyl]benzoic acid,
(3S)-3-(4-[(4-methyl-1,4-diazepan-1-yl)methyl]phenyl}-2,3-dihydro[1,4]dio-
xino {2,3-b}pyridine,
(3S)-3-{4-[(3-methoxypyrrolidin-1-yl)methyl]phenyl}-2,3-dihydro[1,4]dioxi-
no {2,3-b}pyridine, and
N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-N,2-dimethylpropan-2--
amine, or a pharmaceutically salt thereof of each of the
foregoing.
[0296] In some embodiments, the LTA4H modulatory agent is
4-{4-[(3S)-2,3-Dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperazine-1-
-carboxamide, or a pharmaceutically acceptable salt thereof. In
some embodiments, the LTA4H modulatory agent is
4-{4-[(3S)-2,3-Dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperazine-1-
-carboxamide. In some cases, the LTA4H modulatory agent is
1-{4-[(2S)-2,3-Dihydro-1,4-benzodioxin-2-yl]benzyl}piperidine-4-carboxyli-
c acid, or a pharmaceutically acceptable salt thereof. In some
cases, the LTA4H modulatory agent is
1-{4-[(2S)-2,3-Dihydro-1,4-benzodioxin-2-yl]benzyl}piperidine-4-carboxyli-
c acid. In some cases, the LTA4H modulatory agent is
[(3R)-1-{4-[(2S)-2,3-Dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-3-yl]a-
cetic acid, or a pharmaceutically acceptable salt thereof. In some
cases, the LTA4H modulatory agent is
[(3R)-1-{4-[(2S)-2,3-Dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-3-yl]a-
cetic acid.
[0297] In some embodiments the LTA4H modulatory agent includes an
benzodioxane small molecule described in any of U.S. Pat. Nos.
9,133,146; 8,551,982; 8,946,203; 9,133,146 and 9,662,339; each of
which is incorporated herein by reference.
[0298] In some embodiments, the LTA4H modulatory agent is a
biarylamide, or a pharmaceutically acceptable salt thereof. In
certain embodiments, the LTA4H modulatory agent is of the formula
(XIX):
##STR00035##
[0299] or a pharmaceutically acceptable salt thereof, wherein:
[0300] A is selected from pyrazolyl, imidazolyl, pyrrolyl, thienyl,
thiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl,
pyridazinyl, indolyl, pyrrolopyridinyl, dihydropyrrolopyridinyl,
imidazopyridinyl, pyrazolopyridinyl and quinolinyl;
[0301] B is selected from phenyl, pyridinyl, pyrimidinyl, pyrazinyl
and pyridazinyl;
[0302] C is pyridinyl;
[0303] R.sup.1a and R.sup.1b are each independently selected from
--H, C.sub.1-6 alkyl, C.sub.1-3alkoxyl, --C.sub.1-3 alkyl --OH,
hydroxy, --C(O)--C.sub.1-3 alkyl and --NR.sup.5R.sup.6;
[0304] R.sup.2 and R.sup.3 together with the carbon atom to which
they are attached form a cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, tetrahydrofuranyl or a tetrahydropyranyl ring;
[0305] R.sup.4a and R.sup.4b are each independently selected from
--H, C.sub.1-3 alkyl, C.sub.1-3alkoxyl, --C.sub.1-3 alkyl-OH,
phenyl, --O-phenyl, thiazolyl, oxazolyl, isoxazolyl, furanyl,
thienyl, pyrrolyl, thiadiazolyl, tetrazolyl, pyridinyl,
pyrimidinyl, pyridazinyl, pyrazinyl, cyclopropyl, cyclopbutyl,
cyclopenyl, cyclohexyl, pyrrolidinyl, tetrahydrothienyl,
piperidinyl, piperazinyl, morpholinyl, --C.sub.1-3alkyl-phenyl,
--(C.sub.1-3 alkyl-pyridinyl, --C.sub.1-3 alkyl-pyrimidinyl,
--C.sub.1-3 alkyl-pyridazinyl, --C.sub.1-3 alkyl-pyrazinyl,
--C.sub.1-3 alkyl-heterocyclyl, --O--C.sub.1-3 alkyl-phenyl,
--O--C.sub.1-3 alkyl-pyridinyl, --OC.sub.1-3 alkyl, CF.sub.3,
O--(CF.sub.3, --(COO R.sup.5, --C(O) C.sub.1-3 alkyl
--S(O).sub.2--NR.sup.5R.sup.6, --S(O).sub.2CF.sub.3,
--S(O).sub.2C.sub.1-3 alkyl, --C(O) NR.sup.7R.sup.8, hydroxy,
halogen, and cyano, wherein each group is optionally independently
substituted with 1-3 substituents chosen from C.sub.1-6 alkyl,
C.sub.1-6 alkoxyl, hydroxy and halogen;
[0306] R.sup.5 and R.sup.6 are each independently chosen from H,
C.sub.1-5 alkyl, --C.sub.1-3alkylhydroxy and C.sub.1-3
alkyl-O--C.sub.1-3 alkyl;
[0307] or, R.sup.5 and R.sup.6 together with the nitrogen atom to
which they are attached form a piperidinyl, morpholinyl or
thiomorpholinyl ring;
[0308] R.sup.7 and R.sup.8 are each independently chosen from H,
C.sub.1-6 alkyl, --S(O).sub.2C.sub.1-3 alkyl, and
--C(NH)--NH.sub.2.
[0309] In some embodiments the LTA4H modulatory agent includes a
biarylamide small molecule described in U.S. Pat. No. 9,073,895,
which is incorporated herein by reference.
[0310] In some instances, the LTA4H modulatory agent is not a
compound disclosed in U.S. Pat. Nos. 8,569,303; 9,822,106;
9,856,249; 9,777,006; and 9,856,249; or United States Published
Patent Application Publication Nos. 20180118735; 20180162854 and
20180162854.
[0311] In some cases, the modulating agent exhibits an affinity
(Kd) for LTA4H that is sufficient to provide for the desired
modulation of LTA4H. The affinity of the agent can be at least
1-fold greater, at least 2-fold greater, at least 3-fold greater,
at least 4-fold greater, at least 5-fold greater, at least 6-fold
greater, at least 7-fold greater, at least 8-fold greater, at least
9-fold greater, at least 10-fold greater, at least 20-fold greater,
at least 30-fold greater, at least 40-fold greater, at least
50-fold greater, at least 60-fold greater, at least 70-fold
greater, at least 80-fold greater, at least 90-fold greater, at
least 100-fold greater, or at least 1000-fold greater, or more,
than the affinity of the agent for unrelated transporter. In some
cases, the affinity of an agent to LTA4H can be, for example, from
about 100 nanomolar (nM) to about 1 nM, from about 100 nanomolar
(nM) to about 0.1 nM, from about 100 nM to about 1 picomolar (pM),
or from about 100 nM to about 1 femtomolar (fM), or from about 10
nanomolar (nM) to about 0.1 nM. In some embodiments, the affinity
between the agent and LTA4H is characterized by a Kd (dissociation
constant) of 10.sup.-6 M or less, such as 10.sup.-7 M or less,
including 10.sup.-8 M or less, e.g., 10.sup.-9 M or less,
10.sup.-10 M or less, 10.sup.-11 M or less, 10.sup.-12 M or less,
10.sup.-13 M or less, 10.sup.-14 M or less, including 10.sup.-15 M
or less. Modulating agents include antibodies that specifically
bind to LTA4H. In some cases, the antibody specifically binds an
epitope of LTA4H that provides for inhibition of the function of
LTA4H. Antibodies that can be used as modulating agents in
connection with the present disclosure can encompass, but are not
limited to, monoclonal antibodies, polyclonal antibodies,
bispecific antibodies, Fab antibody fragments, F(ab).sub.2 antibody
fragments, Fv antibody fragments (e.g., VH or VL), single chain Fv
antibody fragments and dsFv antibody fragments. Furthermore, the
antibody molecules can be fully human antibodies, humanized
antibodies, or chimeric antibodies. The antibodies that can be used
in connection with the present disclosure can include any antibody
variable region, mature or unprocessed, linked to any
immunoglobulin constant region. Minor variations in the amino acid
sequences of antibodies or immunoglobulin molecules are encompassed
by the present disclosure, providing that the variations in the
amino acid sequence maintain 75% or more, e.g., 80% or more, 90% or
more, 95% or more, or 99% or more of the sequence. In particular,
conservative amino acid replacements are contemplated. Conservative
replacements are those that take place within a family of amino
acids that are related in their side chains. Whether an amino acid
change results in a functional peptide can be determined by
assaying the specific activity of the polypeptide derivative.
"Antibody fragments" comprise a portion of an intact antibody, for
example, the antigen binding or variable region of the intact
antibody. Examples of antibody fragments include Fab, Fab',
F(ab').sub.2, and Fv fragments; diabodies; linear antibodies
(Zapata et al., Protein Eng. 8(10): 1057-1062 (1995)); single-chain
antibody molecules; and multispecific antibodies formed from
antibody fragments. Papain digestion of antibodies produces two
identical antigen-binding fragments, called "Fab" fragments, each
with a single antigen-binding site, and a residual "Fc" fragment, a
designation reflecting the ability to crystallize readily. Pepsin
treatment yields an F(ab').sub.2 fragment that has two
antigen-combining sites and is still capable of cross-linking
antigen. Antibodies that can be used in connection with the present
disclosure thus can encompass monoclonal antibodies, polyclonal
antibodies, bispecific antibodies, Fab antibody fragments,
F(ab).sub.2 antibody fragments, Fv antibody fragments (e.g., VH or
VL), single chain Fv antibody fragments and dsFv antibody
fragments. Furthermore, the antibody molecules can be fully human
antibodies, humanized antibodies, or chimeric antibodies. In some
embodiments, the antibody molecules are monoclonal, fully human
antibodies. The antibodies that can be used in connection with the
present disclosure can include any antibody variable region, mature
or unprocessed, linked to any immunoglobulin constant region. If a
light chain variable region is linked to a constant region, it can
be a kappa chain constant region. If a heavy chain variable region
is linked to a constant region, it can be a human gamma 1, gamma 2,
gamma 3 or gamma 4 constant region, more preferably, gamma 1, gamma
2 or gamma 4 and even more preferably gamma 1 or gamma 4. As such,
additional LTA4H modulatory agents include antibodies, including
monoclonal antibodies, which selectively bind to the LTA4H enzyme
to modulate its activity. Such antibodies may reduce one or more of
the LTA4H enzyme's activities including, for example, its epoxide
hydrolase and/or aminopeptidase activities.
[0312] In some instances, the agent modulates the activity of a
LTA4H following expression, such that the agent is one that changes
the activity of the protein encoded by the target gene following
expression of the protein from the target gene. In other
embodiments, the modulating agent modulates expression of the RNA
and/or protein from the gene encoding the LTA4H, such that it
changes the expression of the RNA or protein from the target gene
in some manner. In these instances, the agent may change expression
of the RNA or protein in a number of different ways. As would be
readily understood by one of ordinary skill in the art, one can
reduce expression (protein production) of an endogenous gene at the
DNA, RNA, or protein level. For example, expression can be reduced
by reducing the total amount of wild type protein made by the
endogenous locus, and this can be accomplished either by changing
the nature of the protein produced (e.g., via gene mutation to
generate a loss of function allele such as a null allele or an
allele that encodes a protein reduced function) or by reducing the
overall levels of protein produced without changing the nature of
the protein itself. In certain embodiments, the agent is one that
reduces, including inhibits, expression of functional LTA4H.
Inhibition of protein expression may be accomplished using any
convenient means, and one of ordinary skill in the art will be
aware of multiple suitable methods. For example, in order to
reduce/inhibit expression, one can reduce protein levels
post-translationally; one can block production of protein by
blocking/reducing translation of mRNA (e.g., using an RNAi agent
such as an shRNA or siRNA that targets the mRNA of an endogenous
gene); one can reduce mRNA levels post-transcriptionally (e.g.,
using an RNAi agent such as an shRNA or siRNA that targets the mRNA
of an endogenous gene); one can reduce mRNA levels by blocking
transcription (e.g., using gene editing tools to either alter a
promoter and/or enhancer sequence or to modulate transcription, or
by using modified gene editing tools, e.g., CRISPRi, that can
modify transcription without cutting the target DNA). Additionally,
one can alter the nature of the protein made from an endogenous
locus by inducing (e.g., using gene editing technology) a loss of
function mutation, which can range from an allele with reduced wild
type activity to a dead protein or no protein (e.g., catalytically
inactive mutant, a frameshift allele, a gene knockout, etc.).
Moreover, one can reduce mRNA levels via gene editing methods that
result in low net transcript levels (e.g., frameshift mutations can
trigger nonsense mediated mRNA decay). Any convenient inhibitor of
expression can be utilized as an antagonist in the subject methods.
Such antagonists can act to inhibit expression at a
transcriptional, translational, or post-translational level. In
some embodiments, the inhibitors are nucleic-acid based, including,
without limitation, DNA, RNA, chimeric RNA/DNA, protein nucleic
acid, and other nucleic acid derivatives. In some embodiments, the
expression inhibitors encompass RNA molecules capable of inhibiting
receptor production when introduced into a receptor-expressing cell
(termed RNAi), including short hairpin double-stranded RNA (shRNA).
In some instances, the expression inhibitors are small interfering
RNA (siRNA). In some instances, the expression inhibitors are small
interfering microRNA. It will be understood that any sequence
capable of reducing the cell surface expression of a receptor, or
reducing the expression of a receptor ligand, can be used in
practicing the methods of the present disclosure. Examples of
agents that inhibit expression of an endogenous gene (e.g., as
described herein) include but are not limited to: (a) an RNAi agent
such as an shRNA or siRNA that specifically targets mRNA encoded by
the endogenous gene; (b) a genome editing agent (e.g., a Zinc
finger nuclease, a TALEN, a CRISPR/Cas genome editing agent such as
Cas9, Cpf1, CasX, CasY, and the like) that cleaves the target
cell's genomic DNA at a locus encoding the endogenous gene (e.g.,
SLC19A1)--thus inducing a genome editing event (e.g., null allele,
partial loss of function allele) at the locus of the endogenous
gene; (c) a modified genome editing agent such as a nuclease dead
zinc finger, TALE, or CRISPR/Cas nuclease fused to a
transcriptional repressor protein that modulates (e.g. reduces)
transcription at the locus encoding the endogenous gene (e.g.,
SLC19A 1) (see, e.g., Qi et al., Cell. Feb. 28, 2013;
152(5):1173-83'; Gilbert et al, Cell. Oct. 23, 2014; 159(3):647-61;
Larson et al., Nat Protoc. 2013 November; 8(11):2180-96). Examples
of agents that increase or activate expression of an endogenous
gene (e.g., as described herein) include, but are not limited to,
CRISPR activation (CRISPRa) agents. When the agent is a CRISPR/Cas
editing agent, the agent can include both the protein and guide RNA
component. The guide nucleic acid (e.g., guide RNA) can be
introduced into the cell as an RNA or as a DNA encoding the RNA
(e.g., encoded by a DNA vector--on a plasmid, virus, and the like).
The CRISPR/Cas protein can be introduced into the cell as a protein
or as a nucleic acid (mRNA or DNA) encoding the protein.
Programmable gene editing agents and their guide nucleic acids
include, but are not limited to, CRISPR/Cas RNa-guided proteins
such as Cas9, CasX, CasY, and Cpf1, Zinc finger proteins such as
Zinc finger nucleases, TALE proteins such as TALENs, CRISPR/Cas
guide RNAs, and the like. Antisense molecules can be used to
down-regulate expression of a target gene in the cell. The
anti-sense reagent may be antisense oligodeoxynucleotides (ODN),
particularly synthetic ODN having chemical modifications from
native nucleic acids, or nucleic acid constructs that express such
anti-sense molecules as RNA. The antisense sequence is
complementary to the mRNA of the targeted protein, and inhibits
expression of the targeted protein. Antisense molecules inhibit
gene expression through various mechanisms, e.g., by reducing the
amount of mRNA available for translation, through activation of
RNAse H, or steric hindrance. One or a combination of antisense
molecules may be administered, where a combination may include
multiple different sequences. Antisense oligonucleotides may be
chemically synthesized by methods known in the art (see Wagner et
al. (1993), supra, and Milligan et al., supra.) Oligonucleotides
may be chemically modified from the native phosphodiester
structure, in order to increase their intracellular stability and
binding affinity. A number of such modifications have been
described in the literature, which alter the chemistry of the
backbone, sugars or heterocyclic bases.
[0313] As an alternative to anti-sense inhibitors, catalytic
nucleic acid compounds, e.g. ribozymes, anti-sense conjugates, etc.
may be used to inhibit gene expression. Ribozymes may be
synthesized in vitro and administered to the patient, or may be
encoded on an expression vector, from which the ribozyme is
synthesized in the targeted cell (for example, see International
patent application WO 9523225, and Beigelman et al. (1995), Nucl.
Acids Res. 23:4434-42). In addition, the transcription level of a
protein can be regulated by gene silencing using RNAi agents, e.g.,
double-strand RNA (Sharp (1999) Genes and Development 13: 139-141).
RNAi, such as double-stranded RNA interference (dsRNAi) or small
interfering RNA (siRNA), has been extensively documented in the
nematode C. elegans (Fire, A., et al, Nature, 391, 806-811, 1998)
and routinely used to "knock down" genes in various systems. RNAi
agents may be dsRNA or a transcriptional template of the
interfering ribonucleic acid that can be used to produce dsRNA in a
cell. A number of options can be utilized to deliver the dsRNA into
a cell or population of cells such as in a cell culture, tissue,
organ or embryo. For instance, RNA can be directly introduced
intracellularly. Various physical methods are generally utilized in
such instances, such as administration by microinjection (see,
e.g., Zernicka-Goetz, et al. (1997) Development 124:1133-1137; and
Wianny, et al. (1998) Chromosoma 107: 430-439). Other options for
cellular delivery include permeabilizing the cell membrane and
electroporation in the presence of the dsRNA, liposome-mediated
transfection, or transfection using chemicals such as calcium
phosphate. A number of established gene therapy techniques can also
be utilized to introduce the dsRNA into a cell. By introducing a
viral construct within a viral particle, for instance, one can
achieve efficient introduction of an expression construct into the
cell and transcription of the RNA encoded by the construct. As
such, other embodiments of the LTA4H modulatory agents include
siRNA or other agents which reduce the translation of LTA4H mRNA
into active protein enzyme form. Additional embodiments of the
invention include small molecule antagonists, antibodies, and mRNA
reducing agents (e.g. siRNA) against the LTB.sub.4 receptor(s).
[0314] The LTA4H enzyme protein level may be reduced using any
convenient protocol. In some instances, the LTA4H level is reduced
by removing systemic LTA4H from a subject, e.g., by removing LTA4H
from the circulatory system of the subject. In such instances, any
convenient protocol for removing circulatory LTA4H may be employed.
For example, blood may be obtained from the subject and
extra-corporeally processed to remove LTA4H from the blood to
produce LTA4H-depleted blood. The resultant LTA4H-depleted blood
may then be returned to the subject. Such protocols may employ a
variety of different techniques in order to remove LTA4H from the
obtained blood. For example, the obtained blood may be contacted
with a filtering component, e.g., a membrane, etc., which allows
passage of LTA4H but inhibits passage of other blood components,
e.g. cells, etc. In some instances, the obtained blood may be
contacted with a LTA4H absorptive component, e.g., porous bead or
particulate composition, which absorbs LTA4H from the blood. In yet
other instances, the obtained blood may be contacted with a LTA4H
binding member stably associated with a solid support, such that
LTA4H binds to the binding member and is thereby immobilized on the
solid support, thereby providing for separation of LTA4H from other
blood constituents. The protocol employed may or may not be
configured to selectively remove LTA4H from the obtained blood, as
desired. A number of different technologies are known for removing
specific proteins from blood, and may be employed in embodiments of
the invention, where such technologies include those described in
U.S. Pat. Nos. 5,240,614; 6,416,487; 6,419,830; 6,423,024;
6,855,121; 7,066,900; 8,211,310; 8,349,550; as well as published
PCT Application Publication No.: WO/2003/020403; the disclosures of
which applications are herein incorporated by reference.
D. Administration
[0315] Aspects of the methods of the inventions described herein
include treatment of a subject with an LTA4H modulatory agent,
e.g., as described above. One of skill in the art would recognize
that methods of treatment of subjects with an LTA4H modulatory
agent are recognized in the art.
[0316] An embodiment of the invention includes treating a subject
diagnosed with a cognitive or motor impairment, or
neuroinflammation by administering to the subject an effective
amount of an LTA4H modulatory agent. Another embodiment of the
invention includes administering the effective amount of an LTA4H
modulatory agent and subsequently monitoring the subject for
improved cognitive or motor function, or a reduction in
neuroinflammation or increase in neurogenesis.
[0317] Biochemically, by an "effective amount" or "effective dose"
of active agent is meant an amount of active agent that will
inhibit, antagonize, decrease, reduce, or suppress by about 20% or
more, e.g., by 30% or more, by 40% or more, or by 50% or more, in
some instances by 60% or more, by 70% or more, by 80% or more, or
by 90% or more, in some cases by about 100%, i.e., to negligible
amounts, and in some instances, reverse the progression of the
cognitive impairment, age-associated dementia, motor disfunction,
or neuroinflammation.
E. Indications
[0318] The subject methods and LTA4H modulatory agent(s) find use
in treating, including preventing, aging-associated conditions,
such as impairments in the cognitive ability of individuals, e.g.,
cognitive disorders, including (but not limited to) age-associated
dementia, immunological conditions, cancer, and physical and
functional decline. Individuals suffering from or at risk of
developing an aging-associated cognitive impairment that will
benefit from treatment with the subject LTA4H modulatory agent(s),
e.g., by the methods disclosed herein, include individuals that are
about 50 years old or older, e.g., 60 years old or older, 70 years
old or older, 80 years old or older, 90 years old or older, and 100
years old or older, i.e., between the age of about 50 and 100,
e.g., 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or about 100 years
old, and are suffering from cognitive impairment associated with
natural aging process, e.g., mild cognitive impairment (M.C.I.);
and individuals that are about 50 years old or older, e.g., 60
years old or older, 70 years old or older, 80 years old or older,
90 years old or older, and usually no older than 100 years old,
i.e., between the ages of about 50 and 90, e.g., 50, 55, 60, 65,
70, 75, 80, 85, 90, 95 or about 100 years old, that have not yet
begun to show symptoms of cognitive impairment. Examples of
cognitive impairments that are due to natural aging include the
following:
[0319] 1. Mild Cognitive Impairment (M.C.I.)
[0320] Mild cognitive impairment is a modest disruption of
cognition that manifests as problems with memory or other mental
functions such as planning, following instructions, or making
decisions that have worsened over time while overall mental
function and daily activities are not impaired. Thus, although
significant neuronal death does not typically occur, neurons in the
aging brain are vulnerable to sub-lethal age-related alterations in
structure, synaptic integrity, and molecular processing at the
synapse, all of which impair cognitive function. Individuals
suffering from or at risk of developing an aging-associated
cognitive impairment that will benefit from treatment with the
subject LTA4H modulatory agents, e.g., by the methods disclosed
herein, also include individuals of any age that are suffering from
a cognitive impairment due to an aging-associated disorder; and
individuals of any age that have been diagnosed with an
aging-associated disorder that is typically accompanied by
cognitive impairment, where the individual has not yet begun to
present with symptoms of cognitive impairment. Examples of such
aging-associated disorders include the following:
[0321] 2. Alzheimer's Disease
[0322] Alzheimer's disease is a progressive, inexorable loss of
cognitive function associated with an excessive number of senile
plaques in the cerebral cortex and subcortical gray matter, which
also contains b-amyloid and neurofibrillary tangles consisting of
tau protein. The common form affects persons>60 yr old, and its
incidence increases as age advances. It accounts for more than 65%
of the dementias in the elderly.
[0323] The cause of Alzheimer's disease is not known. The disease
runs in families in about 15 to 20% of cases. The remaining,
so-called sporadic cases have some genetic determinants. The
disease has an autosomal dominant genetic pattern in most
early-onset and some late-onset cases but a variable late-life
penetrance. Environmental factors are the focus of active
investigation.
[0324] In the course of the disease, synapses, and ultimately
neurons are lost within the cerebral cortex, hippocampus, and
subcortical structures (including selective cell loss in the
nucleus basalis of Meynert), locus coeruleus, and nucleus raphae
dorsalis. Cerebral glucose use and perfusion is reduced in some
areas of the brain (parietal lobe and temporal cortices in
early-stage disease, prefrontal cortex in late-stage disease).
Neuritic or senile plaques (composed of neurites, astrocytes, and
glial cells around an amyloid core) and neurofibrillary tangles
(composed of paired helical filaments) play a role in the
pathogenesis of Alzheimer's disease. Senile plaques and
neurofibrillary tangles occur with normal aging, but they are much
more prevalent in persons with Alzheimer's disease.
[0325] 3. Parkinson's Disease
[0326] Parkinson's Disease (PD) is an idiopathic, slowly
progressive, degenerative CNS disorder characterized by slow and
decreased movement (bradykinesia), muscular rigidity, resting
tremor (dystonia), muscle freezing, and postural instability.
Originally considered primarily a motor disorder, PD is now
recognized to also cause depression and emotional changes. PD also
can affect cognition, behavior, sleep, autonomic function, and
sensory function. The most common cognitive impairments include an
impairment in attention and concentration, working memory,
executive function, producing language, and visuospatial function.
A characteristic of PD is symptoms related to reduced motor
function usually precede those related to cognitive impairment,
which aids in diagnosis of the disease.
[0327] In primary Parkinson's disease, the pigmented neurons of the
substantia nigra, locus coeruleus, and other brain stem
dopaminergic cell groups degenerate. The cause is not known. The
loss of substantia nigra neurons, which project to the caudate
nucleus and putamen, results in depletion of the neurotransmitter
dopamine in these areas. Onset is generally after age 40, with
increasing incidence in older age groups.
[0328] Parkinson's disease is newly diagnosed in about 60,000
Americans each year and currently affects approximately one million
Americans. Even though PD is not fatal in itself, its complications
are the fourteenth leading cause of death in the United States. At
present, PD cannot be cured, and treatment is generally prescribed
to control symptoms, with surgery prescribed in later, severe
cases.
[0329] Treatment options for PD include administration of
pharmaceuticals to help manage motor deficits. These options
increase or substitute for the neurotransmitter, dopamine, of which
PD patients have low brain concentrations. Such medications
include: carbidopa/levodopa (which create more dopamine in the
brain); apomorphine, pramipexolole, ropinirole, and rotingotine
(dopamine agonists); selegiline and rasagiline (MAO-B inhibitors
which prevent breakdown of dopamine); entacapone and tolcapone
(Catechol-O-methyltransferase [COMT]inhibitors which make more
levodopa available in the brain); benztropine and trihexyphenidyl
(anticholinergics); and amantadine (controls tremor and stiffness).
Exercise/physical therapy is also commonly prescribed to help
maintain physical and mental function.
[0330] Current treatment options, however treat the symptoms of PD,
are not curative, and fail to prevent disease progression.
Additionally, current medications tend to lose efficacy in late
stage PD. The most prescribed drug, levodopa, commonly results in
adverse effects within 5 to 10 years after commencing the
medication. These adverse effects can be severe and can result in
motor fluctuations and unpredictable swings in motor control
between doses as well as jerking/twitching (dyskinesia) which are
difficult to manage and are even as disabling as PD's own symptoms.
Thus, there remains a need for new therapies with new mechanisms of
action which can either be administrated along or in combination
with current PD medications.
[0331] 4. Parkinsonism
[0332] Secondary parkinsonism (also referred to as atypical
Parkinson's disease or Parkinson's plus) results from loss of or
interference with the action of dopamine in the basal ganglia due
to other idiopathic degenerative diseases, drugs, or exogenous
toxins. The most common cause of secondary parkinsonism is
ingestion of antipsychotic drugs or reserpine, which produce
parkinsonism by blocking dopamine receptors. Less common causes
include carbon monoxide or manganese poisoning, hydrocephalus,
structural lesions (tumors, infarcts affecting the midbrain or
basal ganglia), subdural hematoma, and degenerative disorders,
including nigrostriatal degeneration. Certain disorders like
Progressive Supranuclear Palsy (PSP), Multiple System Atrophy
(MSA), Corticobasal degeneration (CBD) and Dementia with Lewy
Bodies (DLB) can exhibit Parkinsonism symptoms before the cardinal
symptoms necessary to the specific diagnosis can be made, and thus
may be labeled as "Parkinsonism."
[0333] 5. Frontotemporal Dementia
[0334] Frontotemporal dementia (FTD) is a condition resulting from
the progressive deterioration of the frontal lobe of the brain.
Over time, the degeneration may advance to the temporal lobe.
Second only to Alzheimer's disease (AD) in prevalence, FTD accounts
for 20% of pre-senile dementia cases. Symptoms are classified into
three groups based on the functions of the frontal and temporal
lobes affected:
[0335] Behavioral variant FTD (bvFTD), with symptoms include
lethargy and aspontaneity on the one hand, and disinhibition on the
other; progressive nonfluent aphasia (PNFA), in which a breakdown
in speech fluency due to articulation difficulty, phonological
and/or syntactic errors is observed but word comprehension is
preserved; and semantic dementia (SD), in which patients remain
fluent with normal phonology and syntax but have increasing
difficulty with naming and word comprehension. Other cognitive
symptoms common to all FTD patients include an impairment in
executive function and ability to focus. Other cognitive abilities,
including perception, spatial skills, memory and praxis typically
remain intact. FTD can be diagnosed by observation of reveal
frontal lobe and/or anterior temporal lobe atrophy in structural
MRI scans.
[0336] A number of forms of FTD exist, any of which may be treated
or prevented using the subject methods and compositions. For
example, one form of frontotemporal dementia is Semantic Dementia
(SD). SD is characterized by a loss of semantic memory in both the
verbal and non-verbal domains. SD patients often present with the
complaint of word-finding difficulties. Clinical signs include
fluent aphasia, anomia, impaired comprehension of word meaning, and
associative visual agnosia (the inability to match semantically
related pictures or objects). As the disease progresses, behavioral
and personality changes are often seen similar to those seen in
frontotemporal dementia although cases have been described of
`pure` semantic dementia with few late behavioral symptoms.
Structural MRI imaging shows a characteristic pattern of atrophy in
the temporal lobes (predominantly on the left), with inferior
greater than superior involvement and anterior temporal lobe
atrophy greater than posterior.
[0337] As another example, another form of frontotemporal dementia
is Pick's disease (PiD, also PcD). A defining characteristic of the
disease is build-up of tau proteins in neurons, accumulating into
silver-staining, spherical aggregations known as "Pick bodies."
Symptoms include loss of speech (aphasia) and dementia. Patients
with orbitofrontal dysfunction can become aggressive and socially
inappropriate. They may steal or demonstrate obsessive or
repetitive stereotyped behaviors. Patients with dorsomedial or
dorsolateral frontal dysfunction may demonstrate a lack of concern,
apathy, or decreased spontaneity. Patients can demonstrate an
absence of self-monitoring, abnormal self-awareness, and an
inability to appreciate meaning. Patients with gray matter loss in
the bilateral posterolateral orbitofrontal cortex and right
anterior insula may demonstrate changes in eating behaviors, such
as a pathologic sweet tooth. Patients with more focal gray matter
loss in the anterolateral orbitofrontal cortex may develop
hyperphagia. While some of the symptoms can initially be
alleviated, the disease progresses, and patients often die within
two to ten years.
[0338] 6. Huntington's Disease
[0339] Huntington's disease (HD) is a hereditary progressive
neurodegenerative disorder characterized by the development of
emotional, behavioral, and psychiatric abnormalities; loss of
intellectual or cognitive functioning; and movement abnormalities
(motor disturbances). The classic signs of HD include the
development of chorea--involuntary, rapid, irregular, jerky
movements that may affect the face, arms, legs, or trunk--as well
as cognitive decline including the gradual loss of thought
processing and acquired intellectual abilities. There may be
impairment of memory, abstract thinking, and judgment; improper
perceptions of time, place, or identity (disorientation); increased
agitation; and personality changes (personality disintegration).
Although symptoms typically become evident during the fourth or
fifth decades of life, the age at onset is variable and ranges from
early childhood to late adulthood (e.g., 70s or 80s).
[0340] HD is transmitted within families as an autosomal dominant
trait. The disorder occurs as the result of abnormally long
sequences or "repeats" of coded instructions within a gene on
chromosome 4 (4p16.3). The progressive loss of nervous system
function associated with HD results from loss of neurons in certain
areas of the brain, including the basal ganglia and cerebral
cortex.
[0341] 7. Amyotrophic Lateral Sclerosis
[0342] Amyotrophic lateral sclerosis (ALS) is a rapidly
progressive, invariably fatal, neurological disease that attacks
motor neurons. Muscular weakness and atrophy and signs of anterior
horn cell dysfunction are initially noted most often in the hands
and less often in the feet. The site of onset is random, and
progression is asymmetric. Cramps are common and may precede
weakness. Rarely, a patient survives 30 years; 50% die within 3
years of onset, 20% live 5 years, and 10% live 10 years.
[0343] Diagnostic features include onset during middle or late
adult life and progressive, generalized motor involvement without
sensory abnormalities. Nerve conduction velocities are normal until
late in the disease. Recent studies have documented the
presentation of cognitive impairments as well, particularly a
reduction in immediate verbal memory, visual memory, language, and
executive function.
[0344] A decrease in cell body area, number of synapses and total
synaptic length has been reported in even normal-appearing neurons
of the ALS patients. It has been suggested that when the plasticity
of the active zone reaches its limit, a continuing loss of synapses
can lead to functional impairment. Promoting the formation or new
synapses or preventing synapse loss may maintain neuron function in
these patients.
[0345] 8. Multiple Sclerosis
[0346] Multiple Sclerosis (MS) is characterized by various symptoms
and signs of CNS dysfunction, with remissions and recurring
exacerbations. The most common presenting symptoms are paresthesias
in one or more extremities, in the trunk, or on one side of the
face; weakness or clumsiness of a leg or hand; or visual
disturbances, e.g., partial blindness and pain in one eye
(retrobulbar optic neuritis), dimness of vision, or scotomas.
Common cognitive impairments include impairments in memory
(acquiring, retaining, and retrieving new information), attention
and concentration (particularly divided attention), information
processing, executive functions, visuospatial functions, and verbal
fluency. Common early symptoms are ocular palsy resulting in double
vision (diplopia), transient weakness of one or more extremities,
slight stiffness or unusual fatigability of a limb, minor gait
disturbances, difficulty with bladder control, vertigo, and mild
emotional disturbances; all indicate scattered CNS involvement and
often occur months or years before the disease is recognized.
Excess heat may accentuate symptoms and signs.
[0347] The course is highly varied, unpredictable, and, in most
patients, remittent. At first, months or years of remission may
separate episodes, especially when the disease begins with
retrobulbar optic neuritis. However, some patients have frequent
attacks and are rapidly incapacitated; for a few the course can be
rapidly progressive.
[0348] 9. Glaucoma
[0349] Glaucoma is a common neurodegenerative disease that affects
retinal ganglion cells (RGCs). Evidence supports the existence of
compartmentalized degeneration programs in synapses and dendrites,
including in RGCs. Recent evidence also indicates a correlation
between cognitive impairment in older adults and glaucoma (Yochim B
P, et al. Prevalence of cognitive impairment, depression, and
anxiety symptoms among older adults with glaucoma. J Glaucoma.
2012; 21(4):250-254).
[0350] 10. Myotonic Dystrophy
[0351] Myotonic dystrophy (DM) is an autosomal dominant multisystem
disorder characterized by dystrophic muscle weakness and myotonia.
The molecular defect is an expanded trinucleotide (CTG) repeat in
the 3' untranslated region of the myotonin protein kinase gene on
chromosome 19q. Symptoms can occur at any age, and the range of
clinical severity is broad. Myotonia is prominent in the hand
muscles, and ptosis is common even in mild cases. In severe cases,
marked peripheral muscular weakness occurs, often with cataracts,
premature balding, hatchet facies, cardiac arrhythmias, testicular
atrophy, and endocrine abnormalities (e.g., diabetes mellitus).
Mental retardation is common in severe congenital forms, while an
aging-related decline of frontal and temporal cognitive functions,
particularly language and executive functions, is observed in
milder adult forms of the disorder. Severely affected persons die
by their early 50s.
[0352] 11. Dementia
[0353] Dementia describes a class of disorders having symptoms
affecting thinking and social abilities severely enough to
interfere with daily functioning. Other instances of dementia in
addition to the dementia observed in later stages of the
aging-associated disorders discussed above include vascular
dementia, and dementia with Lewy bodies, described below.
[0354] In vascular dementia, or "multi-infarct dementia", cognitive
impairment is caused by problems in supply of blood to the brain,
typically by a series of minor strokes, or sometimes, one large
stroke preceded or followed by other smaller strokes. Vascular
lesions can be the result of diffuse cerebrovascular disease, such
as small vessel disease, or focal lesions, or both. Patients
suffering from vascular dementia present with cognitive impairment,
acutely or subacutely, after an acute cerebrovascular event, after
which progressive cognitive decline is observed. Cognitive
impairments are similar to those observed in Alzheimer's disease,
including impairments in language, memory, complex visual
processing, or executive function, although the related changes in
the brain are not due to AD pathology but to chronic reduced blood
flow in the brain, eventually resulting in dementia. Single photon
emission computed tomography (SPECT) and positron emission
tomography (PET) neuroimaging may be used to confirm a diagnosis of
multi-infarct dementia in conjunction with evaluations involving
mental status examination.
[0355] Dementia with Lewy bodies (DLB, also known under a variety
of other names including Lewy body dementia, diffuse Lewy body
disease, cortical Lewy body disease, and senile dementia of Lewy
type) is a type of dementia characterized anatomically by the
presence of Lewy bodies (clumps of alpha-synuclein and ubiquitin
protein) in neurons, detectable in post mortem brain histology. Its
primary feature is cognitive decline, particularly of executive
functioning. Alertness and short-term memory will rise and
fall.
[0356] Persistent or recurring visual hallucinations with vivid and
detailed pictures are often an early diagnostic symptom. DLB it is
often confused in its early stages with Alzheimer's disease and/or
vascular dementia, although, where Alzheimer's disease usually
begins quite gradually, DLB often has a rapid or acute onset. DLB
symptoms also include motor symptoms similar to those of
Parkinson's. DLB is distinguished from the dementia that sometimes
occurs in Parkinson's disease by the time frame in which dementia
symptoms appear relative to Parkinson symptoms. Parkinson's disease
with dementia (POD) would be the diagnosis when dementia onset is
more than a year after the onset of Parkinson's. DLB is diagnosed
when cognitive symptoms begin at the same time or within a year of
Parkinson symptoms.
[0357] 12. Progressive Supranuclear Palsy
[0358] Progressive supranuclear palsy (PSP) is a brain disorder
that causes serious and progressive problems with control of gait
and balance, along with complex eye movement and thinking problems.
One of the classic signs of the disease is an inability to aim the
eyes properly, which occurs because of lesions in the area of the
brain that coordinates eye movements. Some individuals describe
this effect as a blurring. Affected individuals often show
alterations of mood and behavior, including depression and apathy
as well as progressive mild dementia. The disorder's long name
indicates that the disease begins slowly and continues to get worse
(progressive), and causes weakness (palsy) by damaging certain
parts of the brain above pea-sized structures called nuclei that
control eye movements (supranuclear). PSP was first described as a
distinct disorder in 1964, when three scientists published a paper
that distinguished the condition from Parkinson's disease. It is
sometimes referred to as Steele-Richardson-Olszewski syndrome,
reflecting the combined names of the scientists who defined the
disorder. Although PSP gets progressively worse, no one dies from
PSP itself.
[0359] 13. Ataxia
[0360] People with ataxia have problems with coordination because
parts of the nervous system that control movement and balance are
affected. Ataxia may affect the fingers, hands, arms, legs, body,
speech, and eye movements. The word ataxia is often used to
describe a symptom of incoordination which can be associated with
infections, injuries, other diseases, or degenerative changes in
the central nervous system. Ataxia is also used to denote a group
of specific degenerative diseases of the nervous system called the
hereditary and sporadic ataxias which are the National Ataxia
Foundation's primary emphases.
[0361] 14. Multiple-System Atrophy
[0362] Multiple-system atrophy (MSA) is a degenerative neurological
disorder. MSA is associated with the degeneration of nerve cells in
specific areas of the brain. This cell degeneration causes problems
with movement, balance, and other autonomic functions of the body
such as bladder control or blood-pressure regulation.
[0363] The cause of MSA is unknown and no specific risk factors
have been identified. Around 55% of cases occur in men, with
typical age of onset in the late 50s to early 60s. MSA often
presents with some of the same symptoms as Parkinson's disease.
However, MSA patients generally show minimal if any response to the
dopamine medications used for Parkinson's.
[0364] 15. Frailty
[0365] Frailty Syndrome ("Frailty") is a geriatric syndrome
characterized by functional and physical decline including
decreased mobility, muscle weakness, physical slowness, poor
endurance, low physical activity, malnourishment, and involuntary
weight loss. Such decline is often accompanied and a consequence of
diseases such as cognitive dysfunction and cancer. However, Frailty
can occur even without disease. Individuals suffering from Frailty
have an increased risk of negative prognosis from fractures,
accidental falls, disability, comorbidity, and premature mortality.
(C. Buigues, et al. Effect of a Prebiotic Formulation on Frailty
Syndrome: A Randomized, Double-Blind Clinical Trial, Int. J. Mol.
Sci. 2016, 17, 932). Additionally, individuals suffering from
Frailty have an increased incidence of higher health care
expenditure. (Id.)
[0366] Common symptoms of Frailty can be determined by certain
types of tests. For example, unintentional weight loss involves a
loss of at least 10 lbs. or greater than 5% of body weight in the
preceding year; muscle weakness can be determined by reduced grip
strength in the lowest 20% at baseline (adjusted for gender and
BMI); physical slowness can be based on the time needed to walk a
distance of 15 feet; poor endurance can be determined by the
individual's self-reporting of exhaustion; and low physical
activity can be measured using a standardized questionnaire. (Z.
Palace et al., The Frailty Syndrome, Today's Geriatric Medicine
7(1), at 18 (2014)).
[0367] In some embodiments, the subject methods and compositions
find use in slowing the progression of aging-associated cognitive,
motor, neuroinflammatory, neurodegenerative, or other age-related
impairment or condition. In other words, cognitive, motor,
neuroinflammatory, neurodegenerative, or other abilities or
conditions in the individual will decline more slowly following
treatment by the disclosed methods than prior to or in the absence
of treatment by the disclosed methods. In some such instances, the
subject methods of treatment include measuring the progression of
cognitive, motor, neuroinflammation, or other age-related ability
or symptom decline after treatment, and determining that the
progression of decline is reduced. In some such instances, the
determination is made by comparing to a reference, e.g., the rate
of decline in the individual prior to treatment, e.g., as
determined by measuring cognitive, motor, neuroinflammatory, or
other age-related abilities or conditions prior at two or more time
points prior to administration of the subject blood product.
[0368] The subject methods and compositions also find use in
stabilizing the cognitive, motor, neuroinflammatory, or other
abilities or conditions of an individual, e.g., an individual
suffering from aging-associated cognitive decline or an individual
at risk of suffering from aging-associated cognitive decline. For
example, the individual may demonstrate some aging-associated
cognitive impairment, and progression of cognitive impairment
observed prior to treatment with the disclosed methods will be
halted following treatment by the disclosed methods. As another
example, the individual may be at risk for developing an
aging-associated cognitive decline (e.g., the individual may be
aged 50 years old or older or may have been diagnosed with an
aging-associated disorder), and the cognitive abilities of the
individual are substantially unchanged, i.e., no cognitive decline
can be detected, following treatment by the disclosed methods as
compared to prior to treatment with the disclosed methods.
[0369] The subject methods and compositions also find use in
reducing cognitive, motor, neuroinflammatory, or other age-related
impairment in an individual suffering from an aging-associated
impairment. In other words, the affected ability is improved in the
individual following treatment by the subject methods. For example,
the cognitive or motor ability in the individual is increased,
e.g., by 2-fold or more, 5-fold or more, 10-fold or more, 15-fold
or more, 20-fold or more, 30-fold or more, or 40-fold or more,
including 50-fold or more, 60-fold or more, 70-fold or more,
80-fold or more, 90-fold or more, or 100-old or more, following
treatment by the subject methods relative to the cognitive or motor
ability that is observed in the individual prior to treatment by
the subject methods.
[0370] In some instances, treatment by the subject methods and
compositions restores the cognitive, motor, or other ability in the
individual suffering from aging-associated cognitive or motor
decline, e.g., to their level when the individual was about 40
years old or less. In other words, cognitive or motor impairment is
abrogated.
[0371] 16. Neuromyelitis Optica Spectrum Disorder
[0372] Neuromyelitis Optica Spectrum Disorder (NMOSD), also known
as Devic disease, is a rare, inflammatory disease of the central
nervous system. It is characterized by optic neuritis (optic nerve
inflammation) and myelitis (spinal cord inflammation). Typically,
patients experience reoccurring bouts of inflammation separated by
periods of remission. The disease is thought to be caused by
auto-antibodies that often target myelin oligodendrocyte
glycoprotein (MOG-IgG) or aquaporin 4 (AQP4-IgG), which leads to
demyelination and axonal damage in the optic nerve and spinal
cord.
[0373] 17. Post-Operative Cognitive Dysfunction
[0374] Post-operative cognitive decline occurs following anesthesia
and a surgical procedure. It is common in patients older than 60
and is diagnosed by pre- and post-surgery cognitive testing.
Patients typically present with memory impairment, delirium, and
impairment in performance on intellectual tasks.
[0375] 18. Chronic Traumatic Encephalopathy
[0376] Chronic traumatic encephalopathy (CTE) is a
neurodegenerative brain disorder most commonly found in athletes,
veterans, or others with a history of repeated head trauma. It is
one of many tauopathies that is characterized by the overabundance
of Tau protein in the brain of patients that leads to neuron loss.
Symptoms include memory loss, changes in mood or personality,
confusion, impaired judgement, impulse control, aggression, and
depression.
[0377] 19. Traumatic Brain Injury
[0378] Traumatic brain injury (TBI) is caused by a violent hit to
the head or body. It can also be caused by an object penetrating
brain tissue during an injury. It results in bleeding, torn tissue,
and physical damage to brain cells and cell death. The physical
symptoms are varied, but include loss of consciousness, headaches,
nausea, extreme fatigue, impaired speech, trouble sleeping,
dizziness, blurred vision, sensitivity to light or sound, memory
loss, and concentration problems.
F. Methods of Diagnosing and Monitoring for Improvement
[0379] In some instances, among the variety of methods to diagnose
and monitor disease progression and improvement in cognitive
disease, motor impairment, neuroinflammatory, or neurodegenerative
disease the following types of assessments are used alone or in
combination with subjects suffering from neurodegenerative disease,
as desired. The following types of methods are presented as
examples and are not limited to the recited methods. Any convenient
methods to monitor disease may be used in practicing the invention,
as desired. Those methods are also contemplated by the methods of
the invention.
[0380] 1. General Cognition
[0381] Embodiments of the methods of the invention further comprise
methods of monitoring the effect of a medication or treatment on a
subject for treating cognitive impairment and/or age-related
dementia, the method comprising comparing cognitive function before
and after treatment. Those having ordinary skill in the art
recognize that there are well-known methods of evaluating cognitive
function. For example, and not by way of limitation, the method may
comprise evaluation of cognitive function based on medical history,
family history, physical and neurological examinations by
clinicians who specialize dementia and cognitive function,
laboratory tests, and neuropsychological assessment. Additional
embodiments which are contemplated by the invention include: the
assessment of consciousness, such as using the Glasgow Coma Scale
(EMV); mental status examination, including the abbreviated mental
test score (AMTS) or mini-mental state examination (MMSE) (Folstein
et al., J. Psychiatr. Res 1975; 12:1289-198); global assessment of
higher functions; estimation of intracranial pressure such as by
fundoscopy. In one embodiment, monitoring the effect on cognitive
impairment and/or age-related dementia includes a 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, 11, or 12-point improvement using the Alzheimer's
Disease Assessment Scale-Cognitive Subscale (ADAS-COG).
[0382] In one embodiment, examinations of the peripheral nervous
system may be used to evaluate cognitive function, including any
one of the followings: sense of smell, visual fields and acuity,
eye movements and pupils (sympathetic and parasympathetic), sensory
function of face, strength of facial and shoulder girdle muscles,
hearing, taste, pharyngeal movement and reflex, tongue movements,
which can be tested individually (e.g. the visual acuity can be
tested by a Snellen chart; a reflex hammer used testing reflexes
including masseter, biceps and triceps tendon, knee tendon, ankle
jerk and plantar (i.e. Babinski sign); Muscle strength often on the
MRC scale 1 to 5; Muscle tone and signs of rigidity.
[0383] 2. Parkinson's Disease
[0384] Embodiments of the methods of the invention further comprise
methods of monitoring the effect of a medication or treatment on a
subject for treating motor impairment, the method comprising
comparing motor function before and after treatment. Those having
ordinary skill in the art recognize that there are well-known
methods of evaluating motor function. For example, and not by way
of limitation, the method may comprise evaluation of motor function
based on medical history, family history, physical and neurological
examinations by clinicians who specialize neurodegeneration and
motor impairment, laboratory tests, and neurodegenerative
assessment. Additional embodiments which are contemplated by the
invention include employment of the rating scales discussed
below.
[0385] Several rating scales have been utilized for evaluating the
progression of PD. The most widely-used scales include the Unified
Parkinson's Disease Rating Scale (UPDRS, which was introduced in
1987) (J. Rehabil Res. Dev., 2012 49(8): 1269-76), and the Hoehn
and Yahr scale (Neruology, 1967 17(5): 427-42). Additional scales
include the Movement Disorder Society (MDS)'s updated UPDRS scale
(MDS-UPDRS) as well as the Schwab and England Activities of Daily
Living (ADL) Scale.
[0386] The UPDRS scale evaluates 31 items that contributed to three
subscales: (1) mentation, behavior, and mood; (2) activities of
daily living; and (3) motor examination. The Hoehn and Yahr scale
classifies PD into five stages with discreet substages: 0--no signs
of disease; 1--symptoms on one side only; 1.5--symptoms on one side
but also involving neck and spine; 2--symptoms on both sides with
no balance impairment; 2.5--mild symptoms on both sides, with
recovery when the `pull` test is given; 3--balance impairment with
mild to moderate disease; 4--severe disability, but ability to walk
or stand unassisted; and 5--need a wheelchair or bedridden without
assistance. The Schwab and England scale classifies PD into several
percentages (from 100%--complete independent to 10%--total
dependent).
[0387] General motor function can be evaluated using widely-used
scales including the General Motor Function Scale (GMF). This tests
three components: dependence, pain, and insecurity. (Aberg A. C.,
et al. (2003) Disabil. Rehabil. May 6, 2003; 25(9):462-72). Motor
function can also be assessed using home-monitoring or wearable
sensors. For example: gait (speed of locomotion, variability, leg
rigidity) can be sensed with an accelerometer; posture (trunk
inclination) by a gyroscope; leg movement by an accelerometer; hand
movement by an accelerometer and gyroscope; tremor (amplitude,
frequency, duration, asymmetry) by an accelerometer; falling by an
accelerometer; gait freezing by an accelerometer, dyskinesia by an
accelerometer, gyroscope, and inertial sensors; bradykinesia
(duration and frequency) by an accelerometer plus gyroscope, and
aphasia (pitch) using a microphone. (Pastorino M, et al., Journal
of Physics: Conference Series 450 (2013) 012055).
[0388] 3. Multiple Sclerosis
[0389] In addition to monitoring improvement for symptoms
associated with cognition, the progression or improvement of
neurodegeneration associated with multiple sclerosis (MS) can be
monitored using techniques well-known to those having ordinary
skill in the art. By way of example, and not limitation, monitoring
can be performed through techniques such as: cerebrospinal fluid
(CSF) monitoring; magnetic resonance imaging (MRI) to detect
lesions and development of demyelinating plaques; evoked potential
studies; and gait monitoring.
[0390] CSF analysis may be performed, for example, through lumbar
puncture to obtain pressure, appearance, and CSF content. Normal
values typically range as follows: pressure (70-180 mm H.sub.2O);
appearance is clear and colorless; total protein (15-60 mg/100 mL);
IgG is 3-12% of the total protein; glucose is 50-80 mg/100 mL; cell
count is 0-5 white blood cells and no red blood cells; chloride
(110-125 mEq/L). Abnormal results may indicate the presence or
progression of MS.
[0391] MRI is another technique that may be performed to monitor
disease progression and improvement. Typical criteria for
monitoring MS with MRI include the appearance of patchy areas of
abnormal white matter in cerebral hemisphere and in paraventricular
areas, lesions present in the cerebellum and/or brain stem as well
as in the cervical or thoracic regions of the spinal cord.
[0392] Evoked potentials may be used to monitor the progression and
improvement of MS in subjects. Evoked potentials measure slowing of
electrical impulses such as in Visual Evoked Response (VER), Brain
Stem Auditory Evoked Responses (BAER), and Somatosensory Evoked
Responses (SSER). Abnormal responses help to indicate that there is
a decrease in the speed of conduction in central sensory
pathways.
[0393] Gait monitoring can also be used to monitor disease
progression and improvement in MS subjects. MS is often accompanied
by an impairment in mobility and an abnormal gait due in part to
fatigue. Monitoring may be performed, for example, with the use of
mobile monitoring devices worn by subjects. (Moon, Y., et al.,
Monitoring gait in multiple sclerosis with novel wearable motion
sensors, PLOS One, 12(2):e0171346 (2017)).
[0394] 4. Huntington's Disease
[0395] In addition to monitoring improvement for symptoms
associated with cognition, the progression or improvement of
neurodegeneration associated with Huntington's Disease (HD) can be
monitored using techniques well-known to those having ordinary
skill in the art. By way of example, and not limitation, monitoring
can be performed through techniques such as: motor function;
behavior; functional assessment; and imaging.
[0396] Examples of motor function that may be monitored as an
indication of disease progression or improvement include chorea and
dystonia, rigidity, bradykinesia, oculomotor dysfunction, and
gait/balance changes. Techniques for performing the monitoring of
these metrics are well-known to those having ordinary skill in the
art. (See Tang C, et al., Monitoring Huntington's disease
progression through preclinical and early stages, Neurodegener Dis
Manag 2(4):421-35 (2012)).
[0397] The psychiatric effects of HD present opportunities to
monitor disease progression and improvement. For example,
psychiatric diagnoses may be performed in order to determine
whether the subject suffers from depression, irritability,
agitation, anxiety, apathy and psychosis with paranoia. (Id.)
[0398] Functional assessment may also be employed to monitor
disease progression or improvement. Total functional score
techniques have been reported (Id.), and often declines by one
point per year in some HD groups.
[0399] MRI or PET may be employed also to monitor disease
progression or improvement. For example, there is a loss of
striatal projection neurons in HD and change in number of these
neurons may be monitored in subjects. Techniques to determine
neuronal change in HD subjects include imaging Dopamine D2 receptor
binding. (Id.)
[0400] 5. ALS
[0401] In addition to monitoring improvement for symptoms
associated with cognition, the progression or improvement of
neurodegeneration associated with Amyotrophic Lateral Sclerosis
(ALS) can be monitored using techniques well-known to those having
ordinary skill in the art. By way of example, and not limitation,
monitoring can be performed through techniques such as: functional
assessment; determining muscle strength; measuring respiratory
function; measuring lower motor neuron (LMN) loss; and measuring
upper motor neuron (UMN) dysfunction.
[0402] Functional assessment can be performed using a functional
scale well-known to those having ordinary skill in the art, such as
the ALS Functional Rating Scale (ALSFRS-R), which evaluates
symptoms related to bulbar, limb, and respiratory function. The
rate of change is useful in predicting survival as well as disease
progression or improvement. Another measure includes the Combined
Assessment of Function and Survival (CAFS), ranking subjects'
clinical outcomes by combining survival time with change in
ALSFRS-R. (Simon N G, et al., Quantifying Disease Progression in
Amyotrophic Lateral Sclerosis, Ann Neurol 76:643-57 (2014)).
[0403] Muscle strength may be tested and quantified through use of
composite Manual Muscle Testing (MMT) scoring. This entails
averaging measures acquired from several muscle groups using the
Medical Research Council (MRC) muscle strength grading scale. (Id.)
Hand-held dynamometry (HHD) may also be used, among other
techniques. (Id.)
[0404] Respiratory function can be performed using portable
spirometry units, used to obtain Forced Vital Capacity (FVC) at
baseline to predict the progression or improvement of the disease.
Additionally, maximal inspiratory pressure, sniff nasal inspiratory
pressure (SNIP), and supping FVC may be determined and used to
monitor disease progression/improvement. (Id.)
[0405] Loss in lower motor neurons is another metric which can be
utilized to monitor disease progression or improvement in ALS. The
Neurophysiological Index may be determined by measuring compound
muscle action potentials (CMAPs) on motor nerve conduction studies,
of which parameters include CMAP amplitude and F-wave frequency.
(Id. and de Carvalho M, et al., Nerve conduction studies in
amyotrophic lateral sclerosis. Muscle Nerve 23:344-352, (2000)).
Lower motor neuron unit numbers (MUNE) may be estimated as well. In
MUNE, the number of residual motor axons supplying a muscle through
estimation of the contribution of individual motor units to the
maximal CMAP response is estimated and used to determine disease
progression or improvement. (Simon N G, et al., supra). Additional
techniques for determining loss of LMN include testing nerve
excitability, electrical impedance myography, and using muscle
ultrasound to detect changes in thickness in muscles. (Id.)
[0406] Dysfunction of upper motor neurons is another metric which
can be utilized to monitor disease progression or improvement in
ALS. Techniques for determining dysfunction include performing MRI
or PET scans on the brain and spinal cord, transcranial magnetic
stimulation; and determining levels of biomarkers in the
cerebrospinal fluid (CSF).
[0407] 6. Glaucoma
[0408] In addition to monitoring improvement for symptoms
associated with cognition, the progression or improvement of
neurodegeneration associated with glaucoma can be monitored using
techniques well-known to those having ordinary skill in the art. By
way of example, and not limitation, monitoring can be performed
through techniques such as: determining intraocular pressure;
assessment of the optic disc or optic nerve head for damage; visual
field testing for peripheral vision loss; and imaging of the optic
disc and retina for topographic analysis.
[0409] 7. Progressive Supranuclear Palsy (PSP)
[0410] In addition to monitoring improvement for symptoms
associated with cognition, the progression or improvement of
neurodegeneration associated with Progressive Supranuclear Palsy
(PSP) can be monitored using techniques well-known to those having
ordinary skill in the art. By way of example, and not limitation,
monitoring can be performed through techniques such as: functional
assessment (activities of daily living, or ADL); motor assessment;
determination of psychiatric symptoms; and volumetric and
functional magnetic resonance imaging (MRI).
[0411] The level of function of a subject in terms of independence,
partial dependence upon others, or complete dependence can be
useful for determining the progression or improvement in the
disease. (See Duff, K, et al., Functional impairment in progressive
supranuclear palsy, Neurology 80:380-84, (2013)). The Progressive
Supranuclear Palsy Rating Scale (PSPRS) is a rating scale that
comprises twenty-eight metrics in six categories: daily activities
(by history); behavior; bulbar, ocular motor, limb motor and
gait/midline. The result is a score ranging from 0-100. Six items
are graded 0-2 and twenty-two items graded 0-4 for a possible total
of 100. The PSPRS scores are practical measures, and robust
predictors of patient survival. They are also sensitive to disease
progression and useful in monitoring disease progression or
improvement. (Golbe L I, et al., A clinical rating scale for
progressive supranuclear palsy, Brain 130:1552-65, (2007)).
[0412] The ADL section from the UPDRS (Unified Parkinson's Disease
Rating Scale) can also be used to quantify functional activity in
subjects with PSP. (Duff K, et al., supra). Similarly, the Schwab
& England Activities Daily Living Score (SE-ADL) can be used
for evaluating independence. (Id.) Additionally, the motor function
sections of the UPDRS are useful as a reliable measure for
assessing disease progression in PSP patients. The motor section
may contain, for example, 27 different measures for quantifying
motor function in PSP patients. Examples of these include resting
tremor, rigidity, finger tapping, posture, and gait). A subject's
disease progression or improvement may also be assessed by
performing a baseline neuropsychological evaluation completed by
trained medical personnel, the assessment using the
Neuropsychiatric Inventory (NPI) to determine the frequency and
severity of behavior abnormalities (e.g. delusions, hallucinations,
agitation, depression, anxiety, euphoria, apathy, disinhibition,
irritability, and aberrant motor behavior). (Id.)
[0413] Functional MRI (fMRI) can be employed to monitor disease
progression and improvement as well. fMRI is a technique using MRI
to measure changes in brain activity in certain regions of the
brain, usually based on blood flow to those regions. Blood flow is
considered to correlate with brain region activation. Patients with
neurodegenerative disorders like PSP can be subjected to physical
or mental tests before or during being scanned in an MRI scanner.
By way of example, and not limitation, tests can be a
well-established force control paradigm where patients as asked to
produce force with the hand most affected by PSP and maximum
voluntary contraction (MVC) is measured by fMRI immediately after
the test takes place. Burciu, R G, et al., Distinct patterns of
brain activity in progressive supranuclear palsy and Parkinson's
disease, Mov. Disord. 30(9):1248-58 (2015)).
[0414] Volumetric MRI is a technique where MRI scanners determine
volume differences in regional brain volume. This may be done, for
example, by contrasting different disorders, or by determining
differences in volume of a brain region in a patient over time.
Volumetric MRI may be employed to determine disease progression or
improvement in neurodegenerative disorders like PSP. The technique
is well-known to those having ordinary skill in the art. (Messina
D, et al., Patterns of brain atrophy in Parkinson's disease,
progressive supranuclear palsy and multiple system atrophy,
Parkinsonism and Related Disorders, 17(3):172-76 (2011)). Examples
of cerebral regions which may be measured include, but are not
limited to, intracranial volume, cerebral cortex, cerebellar
cortex, thalamus, caudate, putamen, pallidum, hippocampus,
amygdala, lateral ventricles, third ventricle, fourth ventricle,
and brain stem.
[0415] 8. Neurogenesis
[0416] The invention also contemplates treating or improving
neurogenesis in a subject with declining or impaired neurogenesis,
which may manifest itself, for example, through reduced cognitive
or motor function, or through association with neuroinflammation.
An embodiment of the invention includes administering, by way of
example and not limitation, an LTA4H modulatory agent to the
subject with reduced or impaired neurogenesis using a Pulsed Dosing
treatment regimen.
[0417] An embodiment of the invention also contemplates determining
the level of neurogenesis before, during, and/or after
administration of the LTA4H modulatory agent. Noninvasive
techniques for evaluating neurogenesis have been reported. (Tamura
Y. et al., J. Neurosci. (2016) 36(31):8123-31). Positron emission
tomography (PET) used with the tracer, [18F]FLT, in combinations
with the BBB transporter inhibitor probenecid, allows for
accumulation of the tracer in neurogenic regions of the brain. Such
imaging allows for an evaluation of neurogenesis in patients being
treated for neurodegenerative disease.
[0418] 9. Neuromyelitis Optica Spectrum Disorder
[0419] Neuromyelitis Optica Spectrum Disorder (NMOSD) can be
diagnosed with a blood test to detect AQP4-IgG or MOG-IgG
antibodies. Disease monitoring uses blood tests, cerebrospinal
fluid tests, spinal taps, and magnetic resonance imaging (MRI) or
computed tomography (CT) scans.
G. Reagents, Devices, and Kits
[0420] Also provided are reagents, devices, and kits thereof for
practicing one or more of the above-described methods. The subject
reagents, devices, and kits thereof may vary greatly. Reagents and
devices of interest include those mentioned above with respect to
the methods of administering the compositions described herein
(e.g., LTA4H modulatory agents) to the subject.
[0421] In addition to the above components, the subject kits will
further include instructions for practicing the subject methods.
These instructions may be present in the subject kits in a variety
of forms, one or more of which may be present in the kit. One form
in which these instructions may be present is as printed
information on a suitable medium or substrate, e.g., a piece or
pieces of paper on which the information is printed, in the
packaging of the kit, in a package insert, etc. Yet another means
would be a computer readable medium, e.g. diskette, CD, portable
flash drive, etc., on which the information has been recorded. Yet
another means that may be present is a website address which may be
used via the internet to access the information at a remote site.
Any convenient means may be present in the kits.
H. Exercise
[0422] Exercise can be characterized by aerobic or anaerobic
activity and can involve high calorie-burning activity and moderate
calorie-burning activity. Exercise may involve strength training
(e.g. weight training or isometric exercise). Exercise may also
involve, for example, running, bicycling, walking, dancing,
marching, swimming, yoga, Tai Chi, balance exercises, leg bends,
jumping rope, surfing, rowing, rotating or flexing the arms or
legs, gardening, cleaning, active games such as bowling, aerobics,
Pilates, and martial arts.
[0423] An exercise regimen may include performing a single exercise
at a certain frequency, or a combination of exercises at a certain
frequency. The frequency may be one, two, three, four, five, six,
or seven times per week. The frequency may vary from week-to-week.
The exercise regimen may be at the same level of intensity and/or
frequency as the subject practiced before administration of the
compositions of the invention. The exercise regimen may also be at
a higher level of intensity and/or frequency compared to the levels
the subject practiced before administration of the compositions of
the invention. The exercise regimen may have been suggested or
prescribed by a health or fitness professional, or the exercise
regimen may have been initiated by the subject himself or
herself.
VII. EXPERIMENTAL EXAMPLES
[0424] The following examples are provided by way of illustration
and not by way of limitation.
A. Experimental Procedures
[0425] 1. Open Field/Novel Object Recognition
[0426] The open field test was used to evaluate general locomotor
activity and exploratory behavior in a novel environment. It
consisted of a square arena (50 cm.times.50 cm). Mice were brought
to the experimental room for at least 30 min of acclimation to the
experimental room conditions (dim lighting) prior to testing. Mice
were placed in the center of the arena and tracked using automated
software (CleverSys or San Diego Instruments) for 15 min. Total
distance traveled, average velocity, and time spent in the
peripheral and center zones were analyzed.
[0427] 2. Y-Maze
[0428] A large Y-maze test assessed short-term memory of the
familiarity of a specific context. Mice were brought to the
experimental room for at least 30 min of acclimation to the
experimental room conditions (dim lighting) prior to testing. For
the initial training trial, the mouse was placed at the end of one
arm of a large Y-maze designated "start arm" (arm length: 15
inches). The third arm of the maze was blocked off, allowing the
mouse to explore two of the three arms freely ("start arm" and
"familiar arm") for 5 min. Each arm contained spatial cues. Three
hours later, the mouse was placed back into the maze in the "start
arm," and allowed to explore all three arms with the third arm
unblocked ("novel arm"). Movements in and out of each arm were
tracked using automated tracking software (CleverSys or San Diego
Instruments). Testing was performed under dim lighting, and the
apparatus was cleaned with 70% ethanol between trials. The time
spent and number of entireties into the "novel arm" and "familiar
arm" were analyzed, as well as total distance travelled and
velocity as measures of general locomotor activity.
[0429] 3. Radial Arm Water Maze (RAWM)
[0430] The water maze (see, e.g. Alamed J, et al., Two-day
radial-arm water maze learning and memory tasks; robust resolution
of amyloid-related memory deficits in transgenic mice, Nat.
Protoc., 1(4):1671-79 (2006)), was filled with water at least 24
hours prior to the test to equilibrate to 25.degree. C. The water
was dyed with white latex paint to make the animals visible for
tracking and to allow for the use of a hidden platform. Eight
distinct visual cues were placed at the end of each of eight arms
of the RAWM inserts. On day 1 animals were subjected to 5 trials
each with a visible platform and a 30-minute inter-trial interval.
Animals had 60 seconds to reach the platform. If they did not reach
the platform in that time they were guided to it and allowed to
remain for 15 seconds before being removed from the tank. The goal
arm remained constant and a different start arm was randomly
assigned for each of the 5 trials so that mouse started in every
arm once except for the two arms directly across from the platform.
The goal arm was switched after every two mice and balanced between
all treatment groups. After each trial the mice were placed in an
empty cage with blue pads and allowed to dry off under a heat lamp
before being placed back into their home cage. Testing day was 48
hours after training, when animals were subjected to the same test
of 5 trials each and a 30-minute inter-trial interval, but with a
hidden platform. Animals were scored for the number of errors
(entry into a non-goal arm) and for latency to reach the platform.
All trials were recorded using TopScan software (CleverSys, Inc.,
Reston, Va.).
[0431] 4. Contextual Fear Conditioning (CFC)
[0432] Mice were brought into the testing room immediately before
their trial to avoid exposure to sounds and scents from testing.
Day 1: For training, mice were placed in the chambers, bright house
light and fan on, for 2 minutes. Then an auditory cue (2000 Hz, 70
dB, conditioned stimulus (CS)) was presented for 30 seconds. A 2
second foot shock (0.6 mA; unconditioned stimulus (US)) was
administered for the final 2 seconds of the CS. This procedure was
repeated once, each after a 2 minute interval, and the mouse was
removed from the chamber 30 seconds after the second shock. The
pans, chamber walls and grid floors were cleaned with 70% ethanol
between trials. Day 2: Seventy-two hours after the training, the
mouse was returned to the same chamber in which the training
occurred (memory for context), and freezing behavior was recorded
for 3 min. The mouse was returned to its home cage. The pans,
chamber walls, and grid floors were cleaned with 70% ethanol
between trials. Day 3: 24 hours after context testing, the mouse
was returned to the same chamber and freezing was recorded in a
novel environment (altered context) and in response to the cue
(memory for cue). The novel environment included different odors
(Peppermint water), sounds, a chamber divider, and different floor
material. The mouse was placed in the novel environment and
freezing was recorded for 2 minutes. The auditory cue (2000 Hz, 70
dB, CS) was then presented for 30 seconds, and freezing was again
recorded for 2 minutes. Mice were returned to their home cages, and
the pans, chamber walls, and floors were cleaned with Ethanol and
with Peppermint water between trials.
[0433] 5. Tissue Collection and Histology/Biochemistry
[0434] On the final day of dosing, mice were deeply anesthetized
with Avertin (250 mg/kg IP). The mice are subjected to cardiac
puncture and blood samples were collected using syringes pre-filled
with EDTA or heparin. Blood was either subjected to calcimycin
stimulation assay or separated into plasma by centrifugation.
Plasma from each mouse was aliquoted and stored at -80.degree.
C.
[0435] Brains were collected following saline perfusion and
separated by mid-sagittal slice with one-half drop fixed in freshly
prepared 4% PFA. PFA was changed to 30% sucrose 24-48 hours later.
A second change to 30% sucrose occurred 24 hours later. The second
half was dissected into hippocampus and cortex and then snap frozen
on dry ice.
[0436] Brain tissue was sectioned or lysed and analyzed for markers
of neurogenesis and aging by standard histological and biochemical
methods, including qRT-PCR, Western blot, ELISA, and
immunohistochemistry.
[0437] 6. Experimental Reagents and Study Blinding
[0438] Recombinant human LTA4H (Bio-techne, 4008-SN) was
buffer-exchanged into sterile PBS and dosed at 4.6 ug/150 uL by
tail vein i.v. injection. SC-57461A (Cayman Chemical, 423169-68)
stock solution was prepared at 10 mg/mL in DMSO. Stock solution was
diluted into sterile PBS immediately prior to p.o. dosing to a
final concentration of 10% DMSO and 1 mg/mL SC-57461A. Mice were
p.o. dosed at 5 mg/kg. CP-105,696 (Sigma, PZ0363), Pinostilbene
hydrate (Sigma, SML0098), and Montelukast (Cayman Chemical,
10008318) stock solutions were prepared at 30 mg/mL in
EtOH/Solutol. Stock solutions were diluted into sterile PBS
immediately prior to p.o. dosing to a final concentration of 10%
EtOH and 3.3 mg/mL inhibitor. Administration to mice was performed
p.o. at a dose of 10 mg/kg. Vehicle was 10% EtOH/Solutol and was
dosed p.o. at a volume of 150 uL.
[0439] SC-57461A ("SC") is an LTA4H dual inhibitors, inhibiting
both the hydrolase and peptidase activity of the enzyme.
Pinostilbene hydrate ("PH") is an inhibitor of the hydrolase
activity of the enzyme. CP-105,696 ("CP") is an LTB4 receptor
antagonist, and Montelukast ("M") is a cysteinyl receptor
antagonist.
B. Example 1
[0440] The concentration of LTA4H protein or LTB4 lipid in young
and old human plasma was measured using a commercially-available
LTA4H enzyme-linked immunosorbent assay (ELISA) (Quantikine ELISA,
R&D Systems) or LTB4 Parameter Kit (Enzo). Plasma samples were
collected by plasmapheresis at Grifols and frozen within 30 min of
collection. Per age group five individual plasma samples were
combined per pool and 7-9 pools were measured for the young and old
plasma group representing 35-45 individual donors.
[0441] FIG. 1A reports that quantification by ELISA shows a
significant increase in LTA4H with age between young and old human
plasma samples. Young plasma from 20-year-old donors had an average
concentration of 690 ng/mL LTA4H while old plasma from 65-year-old
donors had an average concentration of 1140 ng/mL LTA4H. All data
shown are mean.+-.s.e.m; ****p<0.0001, Unpaired t test.
n=8-9
[0442] FIG. 1B reports that quantification by ELISA shows an
increase in LTB4 levels with age between young and old human plasma
samples. Young plasma from 20-year-old donors had an average
concentration of 491 pg/mL LTB4 while old plasma from 65-year-old
donors had an average concentration of 700 pg/mL LTB4. All data
shown are mean.+-.s.e.m; Unpaired t test. n=7.
C. Example 2
[0443] The concentration of mouse LTB4, the product of LTA4H enzyme
hydrolysis activity, was measured using commercially-available LTB4
parameter assay kits (R&D Systems and Enzo). Blood samples were
collected by cardiac puncture into pre-filled syringes with EDTA
and injected into a microcentrifuge tube. The plasma was separated
by centrifugation at 1000 g for 15 minutes at 4.degree. C.
Alternatively, blood was subjected to a calcimycin stimulation
assay to increase the production of LTB4 prior to plasma
collection. All plasma was stored at -80.degree. C. until
measurement of LTB4 levels. LTB4 levels were measured from the
plasma from 4-15 individual young (3 month, 3M) or aged (22.5
month, 22.5M) wild-type mice (WT; C.sub.57BL/6).
[0444] FIG. 2A reports that quantification by ELISA shows a
significant increase in LTB4 levels with age between young and old
mouse plasma samples. Young plasma from 3-month-old mice had an
average concentration of 1000 pg/mL LTB4 while old plasma from
22.5-month-old mice had an average concentration of 1191 pg/mL
LTB4. All data shown are mean.+-.s.e.m; **p<0.01, Unpaired t
test. n=11-15.
[0445] FIG. 2B reports that quantification by ELISA shows a
significant increase in LTB4 levels with age between young and old
mouse plasma samples from both unstimulated and calcimycin
stimulated blood. Young plasma from 3-month-old mice had an average
concentration of 708 pg/mL LTB4 while old plasma from
22.5-month-old mice had an average concentration of 946 pg/mL LTB4.
Stimulated young plasma from 3-month-old mice had an average
concentration of 1739 pg/mL LTB4 while stimulated old plasma from
22.5-month-old mice had an average concentration of 3686 pg/mL
LTB4. All data shown are mean.+-.s.e.m; *p<0.05, **p<0.01,
****p<0.0001. Unpaired t test. n=4-8.
D. Example 3
[0446] Young, 8-week old wild-type (WT; C.sub.57BL/6) mice were
homogenized between groups by body weight. Following group
determination, mice were injected intraperitoneally (IP) with BrdU
(5-bromo-2'-deoxyuridine) formulated in PBS (phosphate buffered
saline) at a final concentration of 10 mg/mL dosed at 150 mg/kg for
5 days. Immediately following the BrdU dosing, group 1 was injected
intravenously (IV) with PBS control and group 2 with recombinant
human LTA4H protein daily for 7 consecutive days. One week after
the completion of LTA4H administration, in week 3, mice in both
treatment groups were injected IP with EdU
(5-ethynyl-2'-deoxyuridine) formulated in PBS at a final
concentration of 10 mg/mL and dosed at 50 mg/kg for 5 days.
Behavioral assays were executed in week 5 and 6, and animals were
sacrificed, and tissues collected immediately after completion of
behavior testing in week 6. FIG. 3 depicts the treatment paradigm
and injection timing for the study.
[0447] Behavior: FIG. 4 reports the results of the open field
testing in mice treated with either PBS control or human
recombinant LTA4H protein. FIGS. 4A and 4B report no change in
total distance travelled or average velocity between treatment
groups. FIG. 4C reports the percent time spent in the periphery or
center of the open field in both treatment groups. All mice spend
significantly more time in the periphery than in the center of the
open field. Taken together the data indicates that general
locomotion as measured by total distance travelled and average
velocity, and anxiety as measured by percent time spent in
periphery or center of the open field are not affected by treatment
with LTA4H. All data shown are mean.+-.s.e.m; ****p<0.0001,
Paired t test, n=14.
[0448] FIG. 5 depicts the results of fear conditioning testing in
mice treated with either PBS control or human recombinant LTA4H
protein. In the training paradigm, mice were placed in the fear
conditioning chamber and allowed to explore for 2 min. Then an
auditory cue (2000 Hz, 70 dB, conditioned stimulus) was presented
for 30 sec, terminating in a 2 sec foot shock (0.6 mA,
unconditioned stimulus). This procedure was repeated once after a 2
min interval and the mouse was removed from the chamber 30 sec
after the second shock. 72 hours after training the mouse was
returned to the same chamber in which the training occurred (memory
for context) and freezing was recorded for 3 min (Context). 24
hours after context testing the mouse was returned to the same
chamber with a novel environment (novel context) and freezing was
recorded for 2 min (Pre-cue). The auditory cue (2000 Hz, 70 dB, CS)
was then presented for 30 sec, and freezing was again recorded for
2 min (Post-cue). FIGS. 5A and 5B show the percent time freezing
during the contextual testing, with LTA4H treated mice showing
significantly decreased freezing compared to PBS treated control
mice. FIG. 5C shows the percent time freezing during the cued
testing, with both treatment groups showing significantly increased
freezing after the cue tone, but no significant difference between
treatment groups. The contextual testing measures hippocampal
dependent spatial memory and shows that LTA4H treatment
significantly impairs the recall of the negative context. Cued
testing is administered to determine whether there is a lack of
ability to perform the fear conditioning task. Animals in both
treatment groups show significantly increased freezing after the
cue tone, showing that they are able to complete the task and show
normal fear behavior. All data shown are mean.+-.s.e.m; *p<0.05,
***p<0.001, 5B Unpaired t test, SC paired t test, n=14.
[0449] Histology: FIG. 6 reports the number of EdU-labeled cells
within the granule cell layer of the dentate gyrus in mice treated
with either PBS control or human recombinant LTA4H protein. There
is a significant decrease in the number of EdU-labeled cells in the
LTA4H treated animals. This data indicates that there is a decrease
in the number of proliferating cells that incorporate the EdU label
in week 3 of the treatment paradigm. All data shown are
mean.+-.s.e.m; *p<0.05, unpaired t test, n=14.
[0450] FIG. 7 depicts representative images of cell nuclei labeled
with Hoechst 33342 (Trihydrochloride trihydrate) and Ki67 antibody
labeled proliferating cells in the hippocampus of PBS or
recombinant LTA4H treated mice. There are fewer Ki67 labeled cells
in the hippocampus of LTA4H treated mice than in the PBS treated
mice.
[0451] FIG. 8 reports the number of Ki67-labeled cells within the
granule cell layer of the dentate gyrus in mice treated with either
PBS control or human recombinant LTA4H protein. There is a
significant decrease in the number of Ki67-labeled cells in the
LTA4H treated animals. This data indicates that there is a decrease
in the number of proliferating cells that express Ki67 in study
week 6. All data shown are mean.+-.s.e.m; *p<0.05, unpaired t
test, n=14.
[0452] FIG. 9 reports the results of quantitative polymerase chain
reaction (qPCR) quantifying mRNA levels of vesicular glutamate
receptor (vglut1), synapsin 1 (syn1), synaptophysin (syp), early
growth response 1 (egr1), doublecortin (dcx), beta III tubulin
(tuj1), glial acidic fibrillary protein (gfap), SRY-Box 2 (sox2),
oligodendrocyte transcription factor 2 in 3 months old (young)
wild-type (C57BL/6) mice treated with recombinant human LTA4H
protein or phosphate buffered saline (PBS) control. There is a
significant decrease in egr1 and tuj1 expression. Egr1 is an
immediate early gene and a reduction in expression is indicative of
a depression of neuronal activity. Tuj1 is a neuronal marker and
the reduction in expression points to detrimental effects on
neurons. Furthermore, there is a trend towards a decrease in olig
2, a marker of oligodendrocytes suggesting detrimental effects on
this cell type as well. Overall the decreases in neuronal markers
and trends towards decreases in oligodendrocyte markers indicate a
detrimental effect on neuronal activity and integrity in LTA4H
treated animals. All data shown are mean.+-.s.e.m; **p<0.01,
unpaired t test, n=14.
[0453] These results show that there is significant detrimental
effect of peripherally administered human recombinant LTA4H protein
on hippocampus-dependent cognition in the contextual fear
conditioning test as well as significant detrimental effects on
proliferation of neural stem and progenitor cells in the dentate
gyrus of the hippocampus of 3 months old wild-type (C57BL/6) mice.
Furthermore, there is also a detrimental effect on the expression
of the neuronal activity marker egr1 and the mature neuron marker
tuj1 indicated additional negative effects of peripherally
administered LTA4H protein.
[0454] The initial study in young, 8-week old wild-type (WT;
C57BL/6) mice was repeated in a second cohort of mice with
additional timepoints and readouts. Mice were homogenized between 3
treatment groups by body weight. Group 1 (Vehicle) was injected
intravenously (IV) with PBS control 3 times per week for 6 weeks,
group 2 (LTA4H Pulse) with recombinant human LTA4H protein daily
for 7 consecutive days, and group 3 (LTA4H Continuous) with
recombinant human LTA4H protein 3 times per week for 6 weeks. In
week 4 after the initiation of dosing, mice in all treatment groups
were injected IP with BrdU (5-bromo-2'-deoxyuridine) formulated in
PBS (phosphate buffered saline) at a final concentration of 10
mg/mL dosed at 150 mg/kg for 5 days. Behavioral assays were
executed in week 5 and 6, and animals were sacrificed, and tissues
collected immediately after completion of behavior testing in week
6. FIG. 10 depicts the treatment paradigm and injection timing for
the study.
[0455] Behavior: FIG. 11 reports the results of the open field
testing in mice treated with PBS control, human recombinant LTA4H
protein pulse dosing, or human recombinant LTA4H protein continuous
dosing. FIGS. 11A and 11B report a significant reduction in
distance traveled and average velocity with LTA4H continuous
dosing. FIG. 11C reports the percent time spent in the periphery or
center of the open field in both treatment groups. All mice spend
significantly more time in the periphery than in the center of the
open field. The data indicates that general locomotion as measured
by total distance travelled and average velocity is impaired with
continuous dosing of LTA4H, but not with pulse dosing of LTA4H.
Additionally, the data indicate that anxiety as measured by percent
time spent in periphery or center of the open field are not
affected by treatment with LTA4H with either dosing paradigm. All
data shown are mean.+-.s.e.m; Distance and Velocity: One-way ANOVA
with multiple comparisons **p<0.01. Percent time in center vs.
periphery, Two-way ANOVA with paired t tests ****p<0.0001.
n=14.
[0456] FIG. 12 reports the results of the Y-maze behavioral task in
mice treated with PBS control, human recombinant LTA4H protein
pulse dosing, or human recombinant LTA4H protein continuous dosing.
The Y-maze task tests hippocampus-dependent spatial memory and is
designed to have unique cues in the form of black shapes adhered to
walls at the ends of two of the arms, while the third is un-cued
and designated as the starting point for the mice. First, mice were
individually placed in the starting arm and allowed to explore only
one of the other two arms for 5 minutes of training. FIG. 12A
reports that there were no differences in number of entries into
the familiar arm between treatment groups during training. During
testing, a significant increase in entries into the novel over the
familiar arm signifies contextual memory of the familiar arm. FIG.
12B reports that PBS vehicle treated mice had intact memory of the
familiar arm, while mice treated with LTA4H by pulse or continuous
dosing had impaired memory. All data shown are mean.+-.s.e.m;
Two-way ANOVA with paired t tests *p<0.05. n=14.
[0457] Histology: FIG. 13 reports the number of BrdU and DCX
co-labeled cells within the granule cell layer of the dentate gyrus
in mice treated with PBS control or human recombinant LTA4H protein
either by pulse or continuous dosing. There is a significant
decrease in the number of BrdU/DCX-labeled cells in the
continuously dosed LTA4H treated animals and a statistical trend
towards a decrease in BrdU/DCX-labeled in mice pulse dosed with
LTA4H. This data indicates that there is a decrease in the number
of proliferating neuronal cells that incorporate the BrdU label in
week 4 of the treatment paradigm. All data shown are mean.+-.s.e.m;
*p<0.05, unpaired t test, n=14.
[0458] FIG. 14 reports the average number of Iba1-labeled cells in
the hippocampus of mice treated with PBS control or human
recombinant LTA4H protein either by pulse or continuous dosing.
There is a significant increase in the number of Iba1-labeled cells
in mice that are pulsed dosed with LTA4H relative to mice dosed
with vehicle PBS control. This data indicates that there is an
increase in the number of microglia cells, marking an increase in
inflammation, upon LTA4H pulse treatment. All data shown are
mean.+-.s.e.m; One-way ANOVA with multiple comparisons *p<0.05,
n=14.
[0459] To test if dosing with recombinant human LTA4H had
short-term effects on histological markers of inflammation, a third
cohort of 8-week old wild-type (WT; C57BL/6) mice was tested 10
days following pulse dosing. Mice were homogenized between 2
treatment groups by body weight. Group 1 (Vehicle) was injected
intravenously (IV) with PBS control for 7 consecutive days and
group 2 (LTA4H) with recombinant human LTA4H protein daily for 7
consecutive days. BrdU (5-bromo-2'-deoxyuridine) formulated in PBS
(phosphate buffered saline) at a final concentration of 10 mg/mL
dosed at 150 mg/kg for 5 days immediately following PBS or LTA4H
dosing in week 2. Animals were sacrificed and tissues collected 10
days following PBS or LTA4H dosing in week 4. FIG. 15 depicts the
treatment paradigm and injection timing for the study.
[0460] Histology: FIG. 16 reports the average number of
CD68-labeled cells in the hippocampus of mice treated with PBS
control or human recombinant LTA4H protein. There is a significant
increase in the number of CD68-labeled cells in mice that are
pulsed dosed with LTA4H relative to mice dosed with vehicle PBS
control 10 days following dosing. This data indicates that there is
an increase in the number of activated microglia cells, marking an
increase in inflammation, upon LTA4H pulse. All data shown are
mean.+-.s.e.m; Unpaired t test *p<0.05, n=14.
E. Example 4
[0461] FIG. 17A depicts the signaling pathway of LTA4H enzyme and
FIG. 17B depicts the key to the diagram in panel A.
[0462] Nineteen-month-old (19 mo) wild type (WT; C57BL/6) mice were
homogenized into five (5) groups by body weight, total distance
travelled in the open field test, and average velocity in the open
field test. Group 1 was administered 10% EtOH control PO daily for
4 weeks, Group 2 was administered 5 mg/kg of SC-57461A LTA4H dual
inhibitor PO daily for 4 weeks; Group 3 was administered 10 mg/kg
of CP-105,696 LTB4 receptor (BLTR) antagonist PO daily for 4 weeks,
Group 4 was administered 10 mg/kg of Montelukast cysteinyl receptor
(CysLTR) antagonist daily for 4 weeks, and Group 5 was administered
10 mg/kg of pinostilbene hydrate daily for 4 weeks. During Week 4
of treatment all groups were tested using open field, radial arm
water maze, and Y-maze. During Week 5 animals were sacrificed, and
tissues collected for histological and biochemical analysis.
[0463] Behavior: FIG. 18 reports the results of the open field
testing. FIGS. 18A and 18B report no change in total distance
travelled or average velocity between treatment groups. FIG. 18C
reports the percent time spent in the periphery or center of the
open field in all treatment groups. All mice spend significantly
more time in the periphery than in the center of the open field.
Taken together the data indicates that general locomotion as
measured by total distance travelled and average velocity, and
anxiety as measured by percent time spent in periphery or center of
the open field are not affected by treatment with inhibitors to
LTA4H or LTA4H downstream effectors. All data shown are
mean.+-.s.e.m; ****p<0.0001, Paired t test, n=13-15.
[0464] FIG. 19A reports the mean latency for the mice to locate the
target platform in the radial arm water maze over the course of
training and testing. FIG. 19B reports the mean number of errors
made by the mice in locating the target platform in the radial arm
water maze over the course of training and testing. FIG. 19C
reports the mean latency for the mice to locate the target platform
for last two training trials depicted in FIG. 19A. FIG. 19D reports
the mean latency for the mice to locate the target platform for
last two testing trials depicted in FIG. 19A. FIG. 19E reports the
mean number of errors made by the mice in locating the target
platform for last two training trials depicted in FIG. 19B. FIG.
19F reports the mean number of errors for the mice to locate the
target platform for last two testing trials depicted in FIG. 19B.
All data shown are mean.+-.s.e.m; *p<0.05, **p<0.01 Unpaired
t test, n=13-15. Taken together, FIG. 19 reports that there are no
differences in learning between treatment groups and that mice
treated with the LTA4H inhibitor SC 57461A or the cysteinyl
leukotriene receptor inhibitor Montelukast have an improvement in
hippocampus-dependent spatial memory.
[0465] FIG. 20A reports the percentage of entries into the novel
and familiar arms of the Y-maze. The Y-maze task tests
hippocampus-dependent memory and is designed to have unique cues in
the form of black shapes adhered to walls at the ends of two of the
arms, while the third is un-cued and designated as the starting
point for the mice. First, mice were individually placed in the
starting arm and allowed to explore only one of the other two arms
for 5 minutes of training. Then mice are tested with the novel arm
open for exploration. During testing, a significant increase in
entries into the novel over the familiar arm signifies contextual
memory of the familiar arm. Aged mice treated with vehicle control
are impaired in the Y-maze and do not have any preference for the
novel versus the familiar arms. Mice treated with the LTA4H
inhibitor SC 57461A have a trend towards preference for the novel
arm and mice treated with the LTB4 receptor BLTR inhibitor CP
105,696 have a statistically significant preference for the novel
arm in this task. FIG. 20B reports the total distance traveled in
the Y-maze and there are no differences between treatment groups.
Taken together FIG. 20 shows that inhibition of LTA4H or the LTB4
receptor leads to an improvement in the hippocampus
spatial-dependent memory Y-maze task. All data shown are
mean.+-.s.e.m; *p<0.05, Paired t test, n=13-15.
[0466] Histology: FIG. 21A reports the integrated optical density
of aquaporin 4 (AQP4) in the hippocampus. There is a significant
decrease in integrated optical density of AQP4 in mice that were
treated with the inhibitors Montelukast and a trend towards a
decrease with mice treated with the inhibitor pinostilbene hydrate.
This data indicates that there is a reduction of aquaporin 4,
marking astrocyte end feet, upon LTA4H or downstream effector
inhibition. All data shown are mean.+-.s.e.m; Unpaired t test
*p<0.05, n=13-15. FIG. 21B reports the fluorescence intensity of
aquaporin 4 (AQP4) in the hippocampus in the perivascular space.
There are no changes with any treatment groups. All data shown are
mean.+-.s.e.m; n=13-15. FIG. 21C reports the fluorescence intensity
of aquaporin 4 (AQP4) in the hippocampus in the space immediately
surrounding blood vessels (vascular). There is a trend towards a
decrease in the fluorescence intensity AQP4 in mice that were
treated with the inhibitors Montelukast and pinostilbene hydrate.
All data shown are mean.+-.s.e.m; Unpaired t tests, n=13-15.
Together these data indicate that there is a reduction of aquaporin
4 surrounding blood vessels in the hippocampus upon LTA4H or
downstream effector inhibition.
[0467] ELISA: FIG. 22 reports plasma concentration of LTB4 in pg/mL
measured by ELISA. Inhibition of LTA4H with SC 57461A reduces the
plasma levels of LTB4. All data shown are mean.+-.s.e.m;
*p<0.05, **p<0.01 Unpaired t test, n=13-15.
[0468] Gene Expression: FIG. 23 reports the results of quantitative
polymerase chain reaction (qPCR) quantifying the hippocampal mRNA
levels of ionized calcium-binding adapter molecule 1 (Iba-1),
interleukin 6 (IL-6), interleukin 1-beta (IL-1.beta.), Eotaxin,
nuclear factor kappa-light-chain-enhancer of activated B cells
(NF-.kappa.B), and tumor necrosis factor alpha (TNF.alpha.) in aged
wild-type (C.sub.57BL/6) mice treated with inhibitors to LTA4H or
downstream effectors. FIG. 23B reports a significant decrease in
IL-6 expression in mice treated with the LTA4H inhibitor SC-5761A.
FIG. 23C reports a significant decrease in IL-1.beta. expression in
mice treated with the LTA4H inhibitor SC-5761A and the inhibitor
Montelukast. FIG. 23F reports a significant decrease in TNF.alpha.
expression in mice treated with the LTA4H inhibitors SC-5761A and
pinostilbene hydrate and the inhibitor Montelukast. All data shown
are mean.+-.s.e.m; *p<0.05, **p<0.01, Unpaired t test,
n=13-15.
[0469] FIG. 24A reports the results of quantitative polymerase
chain reaction (qPCR) quantifying the hippocampal mRNA levels of
the neuronal genes beta III tubulin (tuj1), synapsin 1 (syn1),
post-synaptic density protein 95 (dlg4), and brain derived
neurotrophic factor (bdnf) in aged wild-type (C.sub.57BL/6) mice
treated with vehicle or the LTA4H inhibitor SC 57461A. All data
shown are mean.+-.s.e.m; Unpaired t test, n=13-15.
[0470] FIG. 24B reports the results of quantitative polymerase
chain reaction (qPCR) quantifying the hippocampal mRNA levels of
the microglia genes (total, M1-type, M2-type) cluster of
differentiation molecule 11b (CD11b), interleukin 18 (IL-18),
cluster of differentiation (CD68), interleukin 1.alpha.
(IL-1.alpha.), interleukin 4 (IL-4), insulin-like growth factor 1
(IGF-1), and transforming growth factor .beta. (TGF.beta.) in aged
wild-type (C.sub.57BL/6) mice treated with vehicle or the LTA4H
inhibitor SC 57461A. All data shown are mean.+-.s.e.m; Unpaired t
test, n=13-15.
[0471] FIG. 24C reports the results of quantitative polymerase
chain reaction (qPCR) quantifying the hippocampal mRNA levels of
the astrocytic genes (total, A1-type, A2-type) aquaporin 4 (aqp4),
glial acidic fibrillary protein (gfap), six transmembrane
epithelial antigen of prostate 4 (steap4), sphingosine-1-phosphate
receptor 1 (s1pr3), tissue inhibitor of metalloproteinases (timp1),
H2 class I histocompatibility antigen (h2d1), guanylate-binding
protein 2 (gbp2), N-acetyllactosaminide alpha-1
3-galactosyltransferase (ggta1), H2T23 protein (h2t23), and
cardiotrophin-like cytokine factor 1 (clcf1) in aged wild-type
(C.sub.57BL/6) mice treated with vehicle or the LTA4H inhibitor SC
57461A. FIG. 24C reports a significant decrease in aqp4 and h2d1
expression in mice treated with the LTA4H inhibitor SC-5761A and a
trend towards a decrease in expression of timp1. All data shown are
mean.+-.s.e.m; *p<0.05, Unpaired t test, n=13-15.
[0472] FIG. 24D reports the results of quantitative polymerase
chain reaction (qPCR) quantifying the hippocampal mRNA levels of
the immediate early genes FBJ osteosarcoma oncogene (cfos), early
growth response 1 (egr1), and CAMP responsive element binding
protein 1 (creb1) in aged wild-type (C.sub.57BL/6) mice treated
with vehicle or the inhibitors to LTA4H and downstream effectors.
There is a significant increase in cfos expression with mice
treated with the inhibitor to cysteinyl leukotriene receptors
Montelukast. Cfos is an immediate early gene and increased gene
expression is indicative of increased neuronal activity. All data
shown are mean.+-.s.e.m; **p<0.01, Unpaired t test, n=13-15.
[0473] In summary, this example investigated the hypothesis that
inhibition of the specific detrimental factor LTA4H upregulated in
age can improve cognitive deficits in old animals. Specifically, we
tested the LTA4H pathway with the following inhibitors: SC-57461A
(LTA4H dual inhibitor), pinostilbene hydrate (LTA4H hydrolase
inhibitor), CP-105, 696 (LTB4 Receptor1 inhibitor), and Montelukast
(cysteinyl leukotriene receptor inhibitor). Montelukast was used as
a positive control because it has previously been reported to
improve cognition and reduce inflammation in aged mice.
(Marschallinger J, supra). The results from this study suggest that
there are beneficial effects of LTA4H inhibition on cognitive
performance in aged mice, possibly due to a reduction in
proinflammatory cytokines in the hippocampus.
[0474] Treatment with the LTA4H dual inhibitor SC-57461A resulted
in improvements in the Radial Arm Water Maze test. Treated mice had
significantly shorter latency and made fewer errors when compared
to vehicle mice during the hidden platform testing phase (FIG.
19D). Our positive control Montelukast also showed improvements in
this behavior, replicating what has been reported in the literature
(Marschallinger, et al. Nature Communications 9 Dec. 2014). To
determine the potential mechanisms for improvements in cognition,
we analyzed numerous histological and biochemical markers in the
hippocampus of these mice. There was a significant reduction in the
mRNA levels of a number of proinflammatory cytokines and astrocyte
markers, including IL6 IL1b, tnfa, aqp4, and h2d1 (FIG. 21, FIG. 23
and FIG. 24). The gene expression data suggests that there may be
more subtle changes occurring with microglia or astrocytes, which
secrete the proinflammatory cytokines. Our positive control
Montelukast, showed reductions in many of the same inflammatory
readouts as SC-57461A, as well as, an increase in the mRNA
immediate early gene cfos (FIG. 23 and FIG. 24). Taken together,
these data suggest that Montelukast may be acting via slightly
different mechanisms to improve cognition.
[0475] A secondary question we wanted to answer with this study was
regarding the importance of inhibiting the dual enzymatic
activities of LTA4H in aged mice. LTA4H has a hydrolase activity
that metabolizes LTA4 to LTB4 and it also has a peptidase activity
where it digests PGP. (Snelgrove R J (2010), supra). Previous
publications have shown that the hydrolase activity of LTA4H
produces as a proinflammatory signal, while the peptidase activity
of LTA4H produces an anti-inflammatory signal. (Y. Michael Shim M
P, supra; and Snelgrove, R J. Leukotriene A4 hydrolase: an
anti-inflammatory role for a proinflammatory enzyme. Thorax, 66(6):
p. 550-51 (2011)). In order to test if the inhibition of the
hydrolase activity alone was sufficient to see improvements in
cognition in aged mice, we included a treatment group with
pinostilbene hydrate, which has been reported to only inhibit the
hydrolase activity and not the peptidase activity of LTA4H in
vitro. (Low C. M., et al., The development of novel LTA4H
modulators to selectively target LTB4 generation. Sci Rep, 7: p.
44449 (2017)). However, in contrast to the dual inhibitor
SC-57461A, we did not detect a reduction in LTB4 levels in the
terminal plasma from mice treated with pinostilbene hydrate
relative to vehicle treated mice (FIG. 22), suggesting that our
dosing concentration, frequency, or route of administration was
insufficient to inhibit LTA4H in vivo. Therefore, those studies
were inconclusive, and it is still unclear the importance of the
dual enzyme activities of LTA4H. Despite not observing a reduction
in terminal plasma LTB4, we found that pinostilbene hydrate did
cause a significant reduction in AQP4 levels measured by
immunofluorescence (FIG. 21) and in mRNA levels of tnfa measured by
qPCR (FIG. 23F). Therefore, it is possible the pinostilbene hydrate
does have some effect on neuroinflammation.
[0476] Taken together these data show that inhibition of LTA4H,
which is upregulated in human aging, can significantly improve
cognitive deficits and neuroinflammation in aged mice and strongly
support the hypothesis that inhibiting LTA4H in age-related
cognitive disease would be beneficial and effective at improving
cognitive function and neuroinflammation.
[0477] Although the foregoing invention has been described in some
detail by way of illustration and example for purposes of clarity
of understanding, it is readily apparent to those of ordinary skill
in the art in light of the teachings of this invention that certain
changes and modifications may be made thereto without departing
from the spirit or scope of the appended claims.
[0478] Accordingly, the preceding merely illustrates the principles
of the invention. It will be appreciated that those skilled in the
art will be able to devise various arrangements which, although not
explicitly described or shown herein, embody the principles of the
invention and are included within its spirit and scope.
Furthermore, all examples and conditional language recited herein
are principally intended to aid the reader in understanding the
principles of the invention and the concepts contributed by the
inventors to furthering the art, and are to be construed as being
without limitation to such specifically recited examples and
conditions. Moreover, all statements herein reciting principles,
aspects, and embodiments of the invention as well as specific
examples thereof, are intended to encompass both structural and
functional equivalents thereof. Additionally, it is intended that
such equivalents include both currently known equivalents and
equivalents developed in the future, i.e., any elements developed
that perform the same function, regardless of structure. Moreover,
nothing disclosed herein is intended to be dedicated to the public
regardless of whether such disclosure is explicitly recited in the
claims.
[0479] The scope of the present invention, therefore, is not
intended to be limited to the exemplary embodiments shown and
described herein. Rather, the scope and spirit of present invention
is embodied by the appended claims. In the claims, 35 U.S.C. .sctn.
112(f) or 35 U.S.C. .sctn. 112(6) is expressly defined as being
invoked for a limitation in the claim only when the exact phrase
"means for" or the exact phrase "step for" is recited at the
beginning of such limitation in the claim; if such exact phrase is
not used in a limitation in the claim, then 35 U.S.C. .sctn. 112
(f) or 35 U.S.C. .sctn. 112(6) is not invoked.
* * * * *