U.S. patent application number 13/714051 was filed with the patent office on 2013-07-25 for autoimmune disorder treatment using rxr agonists.
This patent application is currently assigned to Dartmouth College. The applicant listed for this patent is Dartmouth College, IO Therapeutics, Inc.. Invention is credited to Roshantha A. Chandraratna, Ethan Dmitrovsky, Randolph Noelle, Elizabeth Nowak.
Application Number | 20130190395 13/714051 |
Document ID | / |
Family ID | 48613185 |
Filed Date | 2013-07-25 |
United States Patent
Application |
20130190395 |
Kind Code |
A1 |
Chandraratna; Roshantha A. ;
et al. |
July 25, 2013 |
AUTOIMMUNE DISORDER TREATMENT USING RXR AGONISTS
Abstract
The present specification provides RXR agonist compounds,
compositions comprising such RXR agonists, and methods using such
compounds and compositions to treat an autoimmune disorder,
inflammation associated with an autoimmune disorder and/or a
transplant rejection as well as use of such RXR agonists to
manufacture a medicament and use of such compounds and compositions
to treat an autoimmune disorder, inflammation associated with an
autoimmune disorder and/or a transplant rejection.
Inventors: |
Chandraratna; Roshantha A.;
(Laguna Hills, CA) ; Dmitrovsky; Ethan; (Hanover,
NH) ; Nowak; Elizabeth; (West Lebanon, NH) ;
Noelle; Randolph; (Plainfield, NH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
IO Therapeutics, Inc.;
Dartmouth College; |
Laguna Hills
Hanover |
CA
NH |
US
US |
|
|
Assignee: |
Dartmouth College
Hanover
NH
IO Therapeutics, Inc.
Laguna Hills
CA
|
Family ID: |
48613185 |
Appl. No.: |
13/714051 |
Filed: |
December 13, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61570182 |
Dec 13, 2011 |
|
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|
Current U.S.
Class: |
514/510 ;
514/569 |
Current CPC
Class: |
A61K 9/0073 20130101;
A61K 31/192 20130101; A61P 37/00 20180101; A61P 25/28 20180101;
A61K 31/216 20130101; A61K 31/4704 20130101; A61K 31/47 20130101;
A61K 31/353 20130101; Y02A 50/30 20180101; Y02A 50/414 20180101;
A61K 31/343 20130101; A61P 25/00 20180101; A61K 31/201
20130101 |
Class at
Publication: |
514/510 ;
514/569 |
International
Class: |
A61K 31/192 20060101
A61K031/192 |
Goverment Interests
[0002] This invention was made with government support under
R01-CA062275 and R01-AT005382 awarded by National Institutes of
Health (NIH). The government has certain rights in the invention.
Claims
1-72. (canceled)
73. A method of treating an autoimmune disorder, the method
comprising the step of administering to an individual in need
thereof a therapeutically effective amount of a RXR agonist,
wherein administration of the RXR agonist reduces a symptom
associated with the autoimmune disorder, thereby treating the
individual.
74. The method according to claim 73, wherein the RXR agonist is a
compound having the structure of formula I: ##STR00070## wherein Z
is a radical shown in Formula II: ##STR00071## Y is cycloalkyl or
cycloalkenyl of 3 to 8 carbons optionally substituted with one or
two R.sup.4 groups, or Y is selected from phenyl, pyridyl, thienyl,
furyl, pyrrolyl, pyridazinyl, pyrimidiyl, pyrazinyl, thiazolyl,
oxazolyl, and imidazolyl, the groups being optionally substituted
with one or two R.sup.4 groups, the divalent Y radical being
substituted by the Z and
--(CR.sup.1.dbd.CR.sup.1.dbd.CR.sup.1.dbd.CR.sup.1)-- groups on
adjacent carbons; R.sup.1 and R.sup.2 independently are H, lower
alkyl or fluoroalkyl; R.sup.3 is hydrogen, lower alkyl, Cl or Br;
R.sup.4 is lower alkyl, fluoroalkyl or halogen, and B is hydrogen,
--COOH or a pharmaceutically acceptable salt thereof, --COOR.sup.8,
--CONR.sup.9R.sup.10, --CH.sub.2OH, --CH.sub.2OR.sup.11,
--CH.sub.2OCOR.sup.11, --CHO, --CH(OR.sup.12).sub.2,
--CHOR.sup.13O, --OCOR.sup.7, --CR.sup.7(OR.sup.12).sub.2,
--CR.sup.7OR.sup.13O, or tri-lower alkylsilyl, where R.sup.7 is an
alkyl, cycloalkyl or alkenyl group, containing 1 to 5 carbons,
R.sup.8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of
5 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1
to 10 carbons, or R.sup.8 is phenyl or lower alkylphenyl, R.sup.9
and R.sup.10 independently are hydrogen, an alkyl group of 1 to 10
carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower
alkylphenyl, R.sup.11 is lower alkyl, phenyl or lower alkylphenyl,
R.sup.12 is lower alkyl, and R.sup.13 is divalent alkyl radical of
2-5 carbons; and n is 1 or 2.
75. The method according to claim 74, wherein the RXR agonist is a
compound having the structure of formula V: ##STR00072## where
R.sup.4 is lower alkyl of 1 to 6 carbons; B is --COOH or
--COOR.sup.8 where R.sup.8 is lower alkyl of 1 to 6 carbons, and
the configuration about the cyclopropane ring is cis, and the
configuration about the double bonds in the pentadienoic acid or
ester chain attached to the cyclopropane ring is trans in each of
the double bonds, or a pharmaceutically acceptable salt of the
compound.
76. The method according to claim 75, wherein the RXR agonist is a
compound having the structure of formula XII: ##STR00073## wherein
R is H, lower alkyl or 1 to 6 carbons, or a pharmaceutically
acceptable salt of the compound.
77. The method according to claim 76, wherein the RXR agonist is
3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydron-
aphth-7-yl]2(E),4(E) heptadienoic acid, and has the structure of
formula XXIX: ##STR00074##
78. The method according to claim 73, wherein the autoimmune
disorder is systemic autoimmune disorder or organ-specific
autoimmune disorder.
79. The method according to claim 73, wherein the therapeutically
effective amount is about 0.01 mg/kg/day to about 100
mg/kg/day.
80. The method according to claim 73, wherein the therapeutically
effective amount is about 0.1 mg/m.sup.2/day to about 100
mg/m.sup.2/day.
81. The method according to claim 73, wherein the symptom reduced
is inflammation, fatigue, dizziness, malaise, elevated fever and
high body temperature, extreme sensitivity to cold in the hands and
feet, weakness and stiffness in muscles and joints, weight changes,
digestive or gastrointestinal problems, low or high blood pressure,
irritability, anxiety, or depression, infertility or reduced sex
drive (low libido), blood sugar changes, and depending on the type
of autoimmune disorder, an increase in the size of an organ or
tissue, or the destruction of an organ or tissue.
82. A method of treating a transplant rejection, the method
comprising the step of administering to an individual in need
thereof a therapeutically effective amount of a RXR agonist,
wherein administration of the RXR agonist reduces a symptom
associated with the transplant rejection, thereby treating the
individual.
83. The method according to claim 82, wherein the RXR agonist is a
compound having the structure of formula I: ##STR00075## wherein Z
is a radical shown in Formula II: ##STR00076## Y is cycloalkyl or
cycloalkenyl of 3 to 8 carbons optionally substituted with one or
two R.sup.4 groups, or Y is selected from phenyl, pyridyl, thienyl,
furyl, pyrrolyl, pyridazinyl, pyrimidiyl, pyrazinyl, thiazolyl,
oxazolyl, and imidazolyl, the groups being optionally substituted
with one or two R.sup.4 groups, the divalent Y radical being
substituted by the Z and
--(CR.sup.1.dbd.CR.sup.1.dbd.CR.sup.1.dbd.CR.sup.1)-- groups on
adjacent carbons; R.sup.1 and R.sup.2 independently are H, lower
alkyl or fluoroalkyl; R.sup.3 is hydrogen, lower alkyl, Cl or Br;
R.sup.4 is lower alkyl, fluoroalkyl or halogen, and B is hydrogen,
--COOH or a pharmaceutically acceptable salt thereof, --COOR.sup.8,
--CONR.sup.9R.sup.10, --CH.sub.2OH, --CH.sub.2OR.sup.11,
--CH.sub.2OCOR.sup.11, --CHO, --CH(OR.sup.12).sub.2,
--CHOR.sup.13O, --OCOR.sup.7, --CR.sup.7(OR.sup.12).sub.2,
--CR.sup.7OR.sup.13O, or tri-lower alkylsilyl, where R.sup.7 is an
alkyl, cycloalkyl or alkenyl group, containing 1 to 5 carbons,
R.sup.8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of
5 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1
to 10 carbons, or R.sup.8 is phenyl or lower alkylphenyl, R.sup.9
and R.sup.10 independently are hydrogen, an alkyl group of 1 to 10
carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower
alkylphenyl, R.sup.11 is lower alkyl, phenyl or lower alkylphenyl,
R.sup.12 is lower alkyl, and R.sup.13 is divalent alkyl radical of
2-5 carbons; and n is 1 or 2.
84. The method according to claim 83, wherein the RXR agonist is a
compound having the structure of formula V: ##STR00077## where
R.sup.4 is lower alkyl of 1 to 6 carbons; B is --COOH or
--COOR.sup.8 where R.sup.8 is lower alkyl of 1 to 6 carbons, and
the configuration about the cyclopropane ring is cis, and the
configuration about the double bonds in the pentadienoic acid or
ester chain attached to the cyclopropane ring is trans in each of
the double bonds, or a pharmaceutically acceptable salt of the
compound.
85. The method according to claim 84, wherein the RXR agonist is a
compound having the structure of formula XII: ##STR00078## wherein
R is H, lower alkyl or 1 to 6 carbons, or a pharmaceutically
acceptable salt of the compound.
86. The method according to claim 85, wherein the RXR agonist is
3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydron-
aphth-7-yl]2(E),4(E) heptadienoic acid, and has the structure of
formula XXIX: ##STR00079##
87. The method according to claim 82, wherein the transplant
rejection is a hyperacute rejection, an acute rejection, or a
chronic rejection.
88. The method according to claim 82, wherein the transplant
rejection is a graft-versus-host-disease.
89. The method according to claim 82, wherein the therapeutically
effective amount is about 0.01 mg/kg/day to about 100
mg/kg/day.
90. The method according to claim 82, wherein the therapeutically
effective amount is about 0.1 mg/m.sup.2/day to about 100
mg/m.sup.2/day.
91. The method according to claim 82, wherein the symptom reduced
is inflammation, fatigue, dizziness, malaise, elevated fever and
high body temperature, extreme sensitivity to cold in the hands and
feet, weakness and stiffness in muscles and joints, weight changes,
digestive or gastrointestinal problems, low or high blood pressure,
irritability, anxiety, or depression, infertility or reduced sex
drive (low libido), blood sugar changes, and depending on the type
of transplant rejection, an increase in the size of an organ or
tissue, or the destruction of an organ or tissue.
92. A method of treating an autoimmune disorder, the method
comprising the step of administering to an individual in need
thereof a therapeutically effective amount of a RXR agonist,
wherein the RXR agonist is
3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydron-
aphth-7-yl]2(E),4(E) heptadienoic acid; and wherein administration
of the RXR agonist reduces a symptom associated with the autoimmune
disorder, thereby treating the individual.
Description
[0001] This patent application claims priority pursuant to 35
U.S.C. .sctn.119(e) to U.S. Provisional Patent Application Ser. No.
61/570,182, filed Dec. 13, 2011, which is hereby incorporated by
reference in its entirety.
[0003] Attempts to treat autoimmune disorders have met with limited
success. This is due, in part, to the fact that the etiology of
autoimmune disorders is a complex response based in part on a
combination of factors, including, without limitation, genetic
make-up of individual, gender or hormonal status, bacterial or
viral infection, metal or chemical toxin exposure, vaccinations or
immunizations, stress, trauma, smoking and/or nutritional
deficiencies. Therefore, compounds, compositions, and methods that
can reduce a symptom associated with an autoimmune disorder,
inflammation associated with an autoimmune disorder, and/or a
transplant rejection would be highly desirable.
[0004] Naive CD4.sup.+ T cells play a central role in immune
protection. They do so through their capacity to help B cells make
antibodies, to induce macrophages to develop enhanced microbicidal
activity, to recruit neutrophils, eosinophils, and basophils to
sites of infection and inflammation, and, through their production
of cytokines and chemokines, to orchestrate the full panoply of
immune responses. Naive CD4.sup.+ T cells are multipotential
precursors that differentiate into various T cell subsets, such as,
e.g., T helper (Th) cells (also called T effector cells) and T
regulatory (Treg) cells. T helper cells are characterized by their
distinct functions and include Th1, Th2, and Th17. Th1 cells aid in
the clearance of intracellular bacteria and viruses, secrete
IFN-.gamma. in response to the cytokine interleukin-12 (IL-12), and
require the transcription factors T-box21 (T-bet) and signal
transducer and activator of transcription 1 (Stat1) and (Stat4).
Th2 cells help control extracellular pathogens, secrete the
cytokines IL-4, IL-5 and IL-13, and require transcription factors
GATA-binding protein 3 (GATA-3) and Stat6. Th17 cells provide
protection against fungi and various other extracellular bacteria,
secrete the pro-inflammatory cytokine IL-17A, and express the
transcription factor retinoic acid orphan receptor gamma
(ROR.gamma.t). Treg cells play a critical role in maintaining
self-tolerance as well as in regulating immune responses and
express the transcription factor forkhead box P3 (FoxP3). Tregs
normally develop in the thymus, but can also differentiate from
naive CD4.sup.+ cells stimulated with TGF-.beta. and IL-2.
Development and differentiation of Treg cells, as well as
expression of FoxP3, require the transcription factor Stat5.
[0005] Although several cytokines participate in Th17 cell
differentiation, IL-6 and TGF-8 are key factors for the generation
of Th17 cells from naive T CD4.sup.+ cells. On the other hand, IL-6
inhibits TGF-8-induced Treg cells which suppress adaptive T cell
responses and prevent autoimmunity, and are thus important in the
maintenance of immune homeostasis. The two T-cell subsets play
prominent roles in immune functions: Th17 plays a key role in the
pathogenesis of autoimmune diseases and protection against
bacterial infections, while Treg functions to restrain excessive
helper T-cell responses. Essentially immunosuppressive Tregs cells
and pro-inflammatory Th17 cells functionally antagonize each
other.
[0006] As such, a fine balance between Th17 and Treg cells may be
crucial for the stability of immune homeostasis. Once the
equilibrium is broken, the destabilization may lead to chronic
inflammation and autoimmunity. For example, dysregulation or
overproduction of IL-6 leads to autoimmune diseases such as
multiple sclerosis (MS) and rheumatoid arthritis (RA), in which
Th17 cells are considered to be the primary cause of pathology.
Clinical evidence indicates that both defects in Treg function or
reduced numbers, as well as Th17 activity are important in several
autoimmune diseases, including seronegative arthritis in adults,
and childhood arthritis (juvenile idiopathic arthritis). Therefore,
an effective approach in the treatment of various autoimmune and
inflammatory diseases will be to normalize the balance between Treg
and Th17 cell development.
[0007] There are two main types of receptors that mediate the
effects of derivatives of vitamin A in mammals (and other
organisms), the Retinoic Acid Receptors (RARs) and the Retinoid X
Receptors (RXRs). Within each type there are three subtypes
designated RAR alpha, RAR beta, and RAR gamma for the RAR family
and RXR alpha, RXR beta, and RXR gamma for the RXR family. These
receptor types are evolutionarily related but are functionally
distinct. The ligands that activate the RARs, referred to as
retinoids, and the ligands that activate the RXRs, referred to as
rexinoids, elicit quite different biological effects. Retinoic acid
(RA), the physiological hormone of all three RARs, has been shown
to enhance the in vitro differentiation of Treg cells that suppress
immunity. RA can also inhibit the differentiation of
pro-inflammatory Th17 cells that have been casually implicated in
the development of many human autoimmune diseases. Based on this
ability to restore a normal Th17/Treg cell ratio by decreasing Th17
cells while simultaneously increasing Treg cells, RAR agonists have
been proposed as effective therapeutic compounds for the treatment
of inflammatory and autoimmune disorders. However, recent findings
have identified retinoid signaling through RARs as being required
for the initial development of Th17 cell mediated immune responses
and inflammation. These counteracting effects of RAR pan agonists
on Th17 cell development bring into question the value of such
compounds as anti-inflammatory and immunosuppressive agents.
[0008] Although RAR agonists like RA have been used to treat
autoimmune disorders associated with inflammation, their usefulness
in clinical practice has been limited due to unwanted side effects
and counter-therapeutic inflammatory effects. Thus, what are needed
are compounds and compositions that maintain the ability to inhibit
Th17 cell formation and function and to promote Treg cell
formation, but not possess any pro-inflammatory activities and
other unwanted side effects associated with RAR pan agonists like
RA. Such compounds will be of considerable therapeutic value as
immunomodulatory agents.
[0009] The present specification discloses compounds, compositions,
and methods for treating an individual suffering from an autoimmune
disorder. This is accomplished by administering a therapeutically
effective amount of a RXR agonist or composition comprising such
agonist to an individual suffering from an autoimmune disorder. As
disclosed herein, the disclosed RXR agonists can control the
Th17/Treg cell number ratio by elevating Treg cell numbers and
suppressing Th17 cell numbers. As such, the disclosed RXR agonists
would be useful in treating an autoimmune disorder.
SUMMARY
[0010] Thus, aspects of the present specification disclose a RXR
agonist. Non-limiting examples of a RXR agonist include a compound
having the structure of formula I,
##STR00001##
wherein Z is a radical having the structure of Formula II:
##STR00002##
Y is cycloalkyl or cycloalkenyl of 3 to 8 carbons optionally
substituted with one or two R.sup.4 groups, or Y is selected from
phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyridazinyl, pyrimidiyl,
pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, the groups being
optionally substituted with one or two R.sup.4 groups, the divalent
Y radical being substituted by the Z and
--(CR.sup.1.dbd.CR.sup.1.dbd.CR.sup.1.dbd.CR.sup.1)-- groups on
adjacent carbons; R.sup.1 and R.sup.2 independently are H, lower
alkyl or fluoroalkyl; R.sup.3 is hydrogen, lower alkyl, Cl or Br;
R.sup.4 is lower alkyl, fluoroalkyl or halogen, and B is hydrogen,
--COOH or a pharmaceutically acceptable salt thereof, --COOR.sup.8,
--CONR.sup.9R.sup.10, --CH.sub.2OH, --CH.sub.2OR.sup.11,
--CH.sub.2OCOR.sup.11, --CHO, --CH(OR.sup.12).sub.2,
--CHOR.sup.13O, --OCOR.sup.7, --CR.sup.7(OR.sup.12).sub.2,
--CR.sup.7OR.sup.13O, or tri-lower alkylsilyl, where R.sup.7 is an
alkyl, cycloalkyl or alkenyl group, containing 1 to 5 carbons,
R.sup.9 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of
5 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1
to 10 carbons, or R.sup.9 is phenyl or lower alkylphenyl, R.sup.9
and R.sup.10 independently are hydrogen, an alkyl group of 1 to 10
carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower
alkylphenyl, R.sup.11 is lower alkyl, phenyl or lower alkylphenyl,
R.sup.12 is lower alkyl, R.sup.13 is divalent alkyl radical of 2-5
carbons; and n is 1 or 2.
[0011] Other aspects of the present specification disclose a method
of treating an autoimmune disorder, the method comprising the step
of administering to an individual in need thereof a therapeutically
effective amount of a RXR agonist, wherein administration of the
compound or composition reduces a symptom associated with the
autoimmune disorder, thereby treating the individual. Aspects of
the present specification also disclose a use of a RXR agonist to
treat an autoimmune disorder, wherein administration of the
compound or composition reduces a symptom associated with the
autoimmune disorder, thereby treating the individual. Non-limiting
examples of a RXR agonist include a compound or a composition
disclosed herein. The autoimmune disorder can be a systemic
autoimmune disorder or an organ-specific autoimmune disorder.
Non-limiting examples of an autoimmune disorder that can be treated
using a compound or a composition disclosed herein include an acute
disseminated encephalomyelitis (ADEM), an Addison's disease, an
allergy, allergic rhinitis, an Alzheimer's disease, an
anti-phospholipid antibody syndrome (APS), an arthritis such as,
e.g., a monoarthritis, an oligoarthritis, or a polyarthritis like
an osteoarthritis, a rheumatoid arthritis, a juvenile idiopathic
arthritis, a septic arthritis, a spondyloarthropathy, a gout, a
pseudogout, or Still's disease, an asthma, an autoimmune deficiency
syndrome (AIDS), an autoimmune hemolytic anemia, an autoimmune
hepatitis, an autoimmune inner ear disease, a bullous pemphigoid, a
celiac disease, a Chagas disease, a chronic obstructive pulmonary
disease (COPD), a diabetes mellitus type 1 (IDDM), an
endometriosis, a gastrointestinal disorder such as, e.g., an
irritable bowel disease or an inflammatory bowel disease like
Crohn's disease or an ulcerative colitis, a Goodpasture's syndrome,
a Graves' disease, a Guillain-Barre syndrome (GBS), a Hashimoto's
thyroiditis, a hidradenitis suppurativa, an idiopathic
thrombocytopenic purpura, an interstitial cystitis, a lupus, such
as, e.g., a discoid lupus erythematosus, a drug-induced lupus
erythematosus. a lupus nephritis, a neonatal lupus, a subacute
cutaneous lupus erythematosus, or a systemic lupus erythematosus, a
morphea, a multiple sclerosis (MS), a myasthenia gravis, a myopathy
such as, e.g., a dermatomyositis, an inclusion body myositis, or a
polymyositis, a myositis, a narcolepsy, a neuromyotonia, a
Parkinson's disease, a pemphigus vulgaris, a pernicious anaemia, a
primary biliary cirrhosis, a psoriasis, a recurrent disseminated
encephalomyelitis, a rheumatic fever, a schizophrenia, a
scleroderma, a Sjogren's syndrome, a skin disorder such as, e.g.,
dermatitis, an eczema, a statis dermatitis, a hidradenitis
suppurativa, a psoriasis, a rosacea or a scleroderma, a
tenosynovitis, a uveitis, vasculitis such as, e.g., a Buerger's
disease, a cerebral vasculitis, a Churg-Strauss arteritis, a
cryoglobulinemia, an essential cryoglobulinemic vasculitis, a giant
cell arteritis, a Golfers vasculitis, a Henoch-Schonlein purpura, a
hypersensitivity vasculitis, a Kawasaki disease, a microscopic
polyarteritis/polyangiitis, a polyarteritis nodosa, a polymyalgia
rheumatica (PMR), a rheumatoid vasculitis, a Takayasu arteritis, or
a Wegener's granulomatosis, or a vitiligo. Non-limiting examples of
a symptom reduced by a method of treating an autoimmune disorder
disclosed herein include inflammation, fatigue, dizziness, malaise,
elevated fever and high body temperature, extreme sensitivity to
cold in the hands and feet, weakness and stiffness in muscles and
joints, weight changes, digestive or gastrointestinal problems, low
or high blood pressure, irritability, anxiety, or depression,
infertility or reduced sex drive (low libido), blood sugar changes,
and depending on the type of autoimmune disease, an increase in the
size of an organ or tissue, or the destruction of an organ or
tissue. Non-limiting examples of an inflammation symptom reduced by
a method of treating an autoimmune disorder disclosed herein
include edema, hyperemia, erythema, bruising, tenderness,
stiffness, swollenness, fever, a chill, congestion of the
respiratory tract including nose, and bronchi, congestion of a
sinus, a breathing problem, fluid retention, a blood clot, a loss
of appetite, an increased heart rate, a formation of granulomas,
fibrinous, pus, or non-viscous serous fluid, a formation of an
ulcer, or pain.
[0012] Yet other aspects of the present specification disclose a
method of treating inflammation as a result of an autoimmune
disorder, the method comprising the step of administering to an
individual in need thereof a therapeutically effective amount of a
RXR agonist, wherein administration of the compound or composition
reduces a symptom associated with inflammation, thereby treating
the individual. Aspects of the present specification also disclose
a use of a RXR agonist to treat inflammation as a result of an
autoimmune disorder, wherein administration of the compound or
composition reduces a symptom associated with inflammation, thereby
treating the individual. Non-limiting examples of a RXR agonist
include a compound or a composition disclosed herein. Non-limiting
examples of a symptom reduced by a method of treating inflammation
disclosed herein include edema, hyperemia, erythema, bruising,
tenderness, stiffness, swollenness, fever, a chill, congestion of
the respiratory tract including nose, and bronchi, congestion of a
sinus, a breathing problem, fluid retention, a blood clot, a loss
of appetite, an increased heart rate, a formation of granulomas,
fibrinous, pus, or non-viscous serous fluid, a formation of an
ulcer, or pain.
[0013] Still aspects of the present specification disclose a method
of treating a transplant rejection, the method comprising the step
of administering to an individual in need thereof a therapeutically
effective amount of a RXR agonist, wherein administration of the
RXR agonist reduces a symptom associated with the transplant
rejection, thereby treating the individual. Aspects of the present
specification also disclose a use of a RXR agonist to treat a
transplant rejection, wherein administration of the compound or
composition reduces a symptom associated with the transplant
rejection, thereby treating the individual. Non-limiting examples
of a RXR agonist include a compound or a composition disclosed
herein. Non-limiting examples of a transplant rejection include a
hyperacute rejection, an acute rejection, or a chronic rejection,
as well as, a graft-versus-host-disease. Non-limiting examples of a
symptom reduced by a method of treating a transplant rejection
disclosed herein include inflammation, fatigue, dizziness, malaise,
elevated fever and high body temperature, extreme sensitivity to
cold in the hands and feet, weakness and stiffness in muscles and
joints, weight changes, digestive or gastrointestinal problems, low
or high blood pressure, irritability, anxiety, or depression,
infertility or reduced sex drive (low libido), blood sugar changes,
and depending on the type of autoimmune disease, an increase in the
size of an organ or tissue, or the destruction of an organ or
tissue. Non-limiting examples of an inflammation symptom reduced by
a method of treating a transplant rejection include edema,
hyperemia, erythema, bruising, tenderness, stiffness, swollenness,
fever, a chill, congestion of the respiratory tract including nose,
and bronchi, congestion of a sinus, a breathing problem, fluid
retention, a blood clot, a loss of appetite, an increased heart
rate, a formation of granulomas, fibrinous, pus, or non-viscous
serous fluid, a formation of an ulcer, or pain.
[0014] Further aspects of the present specification disclose a
method of promoting Treg cell differentiation in an individual, the
method comprising the step of administering to the individual in
need thereof a therapeutically effective amount of a RXR agonist,
wherein administration of the RXR agonist promotes Treg cell
differentiation. Aspects of the present specification also disclose
a use of a RXR agonist to promote Treg cell differentiation in an
individual, wherein administration of the RXR agonist to the
individual promotes Treg cell differentiation. Administration of
the RXR agonist to the individual can also inhibit Th17 cell
differentiation.
[0015] Further aspects of the present specification disclose a
method of inhibiting Th17 cell differentiation in an individual,
the method comprising the step of administering to the individual
in need thereof a therapeutically effective amount of a RXR
agonist, wherein administration of the RXR agonist inhibits Th17
cell differentiation. Aspects of the present specification also
disclose a use of a RXR agonist to inhibit Th17 cell
differentiation in an individual, wherein administration of the RXR
agonist to the individual inhibits Th17 cell differentiation.
Administration of the RXR agonist to the individual can also
promote Treg cell differentiation.
[0016] Other aspects of the present specification disclose a method
of concurrently promoting Treg cell differentiation as well as
inhibiting Th17 cell differentiation in an individual, the method
comprising the step of administering to the individual in need
thereof a therapeutically effective amount of a RXR agonist,
wherein administration of the RXR agonist promotes Treg cell
differentiation and inhibits Th17 cell differentiation. Aspects of
the present specification also disclose a use of a RXR agonist to
concurrently promote Treg cell differentiation as well as inhibit
Th17 cell differentiation in an individual, wherein administration
of the RXR agonist to the individual promotes Treg cell
differentiation and inhibits Th17 cell differentiation.
BRIEF DESCRIPTION OF DRAWINGS
[0017] FIG. 1 shows RXR agonist effects on gene expression. FIG. 1A
shows that RXR agonists regulate Foxp3 expression; and FIG. 1B
shows that RXR agonists regulate .alpha.4.beta.7 (B)
expression.
[0018] FIG. 2 shows RXR agonist effects on differentiation. FIG. 2A
shows that RXR agonists increase Treg differentiation under Th17
conditions; and FIG. 2B shows that RXR agonists inhibit Th17
differentiation under Th17 conditions.
[0019] FIG. 3 shows the effects of RAR signaling inhibition on RXR
agonist inducement of Treg differentiation.
[0020] FIG. 4 shows RXR agonist activation of transcription from
RXR.alpha., RXR.beta., RXR.gamma., RAR.alpha., RAR.beta., and
RAR.gamma. using transactivation assays.
[0021] FIG. 5 shows that RXR agonists attenuate experimental
autoimmune encephalomyelitis (EAE) in C57BL/6 mice.
[0022] FIG. 6 shows that RXR agonists reduce leukocyte infiltration
into the central nervous system. FIG. 6A shows that RXR agonists
reduce CD4+ T cell infiltration into the central nervous system;
and FIG. 6B shows that RXR agonists reduce myeloid dendritic cell
infiltration into the central nervous system.
[0023] FIG. 7 shows RXR agonists attenuate EAE in SJL mice.
DESCRIPTION
[0024] The RARs and RXRs and their cognate ligands function by
distinct mechanisms. The RARs always form heterodimers with RXRs
and these RAR/RXR heterodimers bind to specific response elements
in the promoter regions of target genes. The binding of RAR
agonists to the RAR receptor of the heterodimer results in
activation of transcription of target genes leading to retinoid
effects. On the other hand, RXR agonists do not activate RAR/RXR
heterodimers. RXR heterodimer complexes like RAR/RXR, can be
referred to as non-permissive RXR heterodimers as activation of
transcription due to ligand-binding occurs only at the non-RXR
protein (e.g., RAR); activation of transcription due to ligand
binding does not occur at the RXR. RXRs also interact with nuclear
receptors other than RARs and RXR agonists may elicit some of its
biological effects by binding to such RXR/receptor complexes. These
RXR/receptor complexes can be referred to as permissive RXR
heterodimers as activation of transcription due to ligand-binding
could occur at the RXR, the other receptor, or both receptors.
Examples of RXR permissive heterodimers include, without
limitation, peroxisome proliferator activated
receptor/RXR(PPAR/RXR), farnesyl X receptor/RXR (FXR/RXR), or liver
X receptor/RXR (LXR/RXR). Alternately, RXRs may form RXR/RXR
homodimers which can be activated by RXR agonists leading to
rexinoid effects. Also, RXRs interact with proteins other than
nuclear receptors and ligand binding to an RXR within such protein
complexes can also lead to rexinoid effects. Due to these
differences in mechanisms of action, RXR agonists and RAR agonists
elicit distinct biological outcomes and even in the instances where
they mediate similar biological effects, they do so by different
mechanisms. Moreover, the unwanted side effects of retinoids, such
as pro-inflammatory responses or mucocutaneous toxicity, are
mediated by activation of one or more of the RAR receptor subtypes.
Stated another way, biological effects mediated via RXR pathways
would not induce pro-inflammatory responses, and thus, would not
result in unwanted side effects.
[0025] As disclosed herein, RXR agonists inhibit Th17 cell
formation and promote Treg cell formation by mechanisms that do not
involve their function as RAR agonists. As such, a selective RXR
agonist that does not activate RARs would be a more effective agent
in the treatment of an autoimmune disorder, inflammation associated
with an autoimmune disorder, or a transplant rejection. In support
of this, the present specification discloses that RXR agonists have
cell differentiating effects in that they can regulate the
Th17/Treg cell number ratio by elevating Treg cell numbers and
suppressing Th17 cell numbers. In this manner, a normal balance of
both these cell types can be achieved and immune homeostatis
restored. Furthermore, since selective RXR agonists achieve these
therapeutic effects without activation of RARs, they would be
optimally effective and beneficial in treating an autoimmune
disorder, inflammation associated with an autoimmune disorder, or a
transplant rejection.
[0026] Thus, aspects of the present specification provide, in part,
a RXR agonist. As used herein, the term "RXR agonist", is
synonymous with "RXR selective agonist" and refers to a compound
that selectively binds to one or more RXR receptors like a
RXR.alpha., a RXR.beta., or a RXR.gamma. in a manner that elicits
gene transcription via an RXR response element. As used herein, the
term "selectively binds," when made in reference to a RXR agonist,
refers to the discriminatory binding of a RXR agonist to the
indicated target receptor like a RXR.alpha., a RXR.beta., or a
RXR.gamma. such that the RXR agonist does not substantially bind
with non-target receptors like a RAR.alpha., a RAR.beta. or a
RAR.gamma..
[0027] A RXR agonist may be a pure RXR agonist. A pure RXR agonist
is one which does not activate to any appreciable degree a
permissive heterodimer such as, e.g., PPAR/RXR, FXR/RXR, and
LXR/RXR. One example of a pure RXR agonist is
3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4
tetrahydronaphth-7-yl]2(E),4(E) heptadienoic acid (RXR agonist
194204) disclosed herein, the structure of which is shown in
Formula XXIX. In an aspect of this embodiment, a pure RXR agonist
shows no ability to activate a permissive heterodimer. In another
aspect of this embodiment, a pure RXR agonist shows no ability to
activate PPAR/RXR, FXR/RXR, and/or LXR/RXR. In other aspects of
this embodiment, a pure RXR agonist activates a permissive
heterodimer by 1% or less, 2% or less, 3% or less, 4% or less, 5%
or less, 6% or less, 7% or less, 8% or less, 9% or less, or 10% or
less relative to the ability of a non-pure RXR agonist to activate
the same permissive heterodimer. A non-pure RXR agonist is one that
can activate a permissive heterodimer like PPAR/RXR, FXR/RXR, or
LXR/RXR. Example of a non-pure RXR agonist include, e.g., LGD1069
(bexarotene) and LGD268.
[0028] Selective binding of a RXR agonist to a RXR receptor
includes binding properties such as, e.g., binding affinity and
binding specificity. Binding affinity refers to the length of time
a RXR agonist resides at its RXR receptor binding site, and can be
viewed as the strength with which a RXR agonist binds its a RXR
receptor. Binding affinity can be described as a RXR agonist's
equilibrium dissociation constant (KD), which is defined as the
ratio Kd/Ka at equilibrium, where Ka is a RXR agonist's association
rate constant and kd is a RXR agonist's dissociation rate constant.
Binding affinity is determined by both the association and the
dissociation and alone neither high association nor low
dissociation can ensure high affinity. The association rate
constant (Ka), or on-rate constant (Kon), measures the number of
binding events per unit time, or the propensity of a RXR agonist
and its RXR receptor to associate reversibly into its
agonist-receptor complex. The association rate constant is
expressed in M.sup.-1 s.sup.-1, and is symbolized as follows:
[Ag].times.[Rc].times.Kon. The larger the association rate
constant, the more rapidly a RXR agonist binds to its RXR receptor,
or the higher the binding affinity between agonist and receptor.
The dissociation rate constant (Kd), or off-rate constant (Koff),
measures the number of dissociation events per unit time propensity
of an agonist-receptor complex to separate (dissociate) reversibly
into its component molecules, namely the RXR agonist and the RXR
receptor. The dissociation rate constant is expressed in s.sup.-1,
and is symbolized as follows: [Ag+Rc].times.Koff. The smaller the
dissociation rate constant, the more tightly bound a RXR agonist is
to its RXR receptor, or the higher the binding affinity between
agonsit and receptor. The equilibrium dissociation constant (KD)
measures the rate at which new agonist-receptor complexes formed
equals the rate at which agonist-receptor complexes dissociate at
equilibrium. The equilibrium dissociation constant is expressed in
M, and is defined as Koff/Kon=[Ag].times.[Rc]/[Ag+Rc], where [Ag]
is the molar concentration of a RXR agonist, [Rc] is the molar
concentration of the RXR receptor, and [Ag+Rc] is the of molar
concentration of the agonist-receptor complex, where all
concentrations are of such components when the system is at
equilibrium. The smaller the equilibrium dissociation constant, the
more tightly bound a RXR agonist is to its RXR receptor, or the
higher the binding affinity between agonist and receptor.
[0029] In aspects of this embodiment, the binding affinity of a RXR
agonist that selectively binds to a RXR receptor can have an
association rate constant of, e.g., less than 1.times.10.sup.5
M.sup.-1 s.sup.-1, less than 1.times.10.sup.6 M.sup.-1 s.sup.-1,
less than 1.times.10.sup.7 M.sup.-1 s.sup.-1, or less than
1.times.10.sup.8 M.sup.-1 s.sup.-1. In another embodiment, the
binding affinity of a RXR agonist that selectively binds to a RXR
receptor can have an association rate constant of, e.g., more than
1.times.10.sup.5 M.sup.-1 s.sup.-1, more than 1.times.10.sup.6
M.sup.-1 s.sup.-1, more than 1.times.10.sup.7 M.sup.-1 s.sup.-1, or
more than 1.times.10.sup.8 M.sup.-1 s.sup.-1. In other aspects, the
binding affinity of a RXR agonist that selectively binds to a RXR
receptor can have an association rate constant between, e.g.,
1.times.10.sup.5 M.sup.-1 s.sup.-1 to 1.times.10.sup.8 M.sup.-1
s.sup.-1, 1.times.10.sup.6 M.sup.-1 s.sup.-1 to 1.times.10.sup.8
M.sup.-1 s.sup.-1, 1.times.10.sup.5 M.sup.-1 s.sup.-1 to
1.times.10.sup.7 M.sup.-1 s.sup.-1, or 1.times.10.sup.6 M.sup.-1
s.sup.-1 to 1.times.10.sup.7 M.sup.-1 s.sup.-1.
[0030] In other aspects of this embodiment, the binding affinity of
a RXR agonist that selectively binds to a RXR receptor can have a
disassociation rate constant of, e.g., less than 1.times.10.sup.-3
s.sup.-1, less than 1.times.10.sup.-4 s.sup.-1, or less than
1.times.10.sup.-5 s.sup.-1. In another embodiment, the binding
affinity of a RXR agonist that selectively binds to a RXR receptor
can have a disassociation rate constant of, e.g., more than
1.times.10.sup.-3 s.sup.-1, more than 1.times.10.sup.-4 s.sup.-1,
or more than 1.times.10.sup.-5 s.sup.-1. In other aspects, the
binding affinity of a RXR agonist that selectively binds to a RXR
receptor can have a disassociation rate constant between, e.g.,
1.times.10.sup.-3 s.sup.-1 to 1.times.10.sup.-5 s.sup.-1,
1.times.10.sup.-3 s.sup.-1 to 1.times.10.sup.-4 s.sup.-1, or
1.times.10.sup.-4 s.sup.-1 to 1.times.10.sup.-5 s.sup.-1.
[0031] In yet other aspects of this embodiment, the binding
affinity of a RXR agonist that selectively binds to a RXR receptor
can have an equilibrium disassociation constant of less than 100
nM. In aspects of this embodiment, the binding affinity of a RXR
agonist that selectively binds to a RXR receptor can have an
equilibrium disassociation constant of, e.g., less than 100 nM,
less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM,
less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM,
or less than 10 nM. In aspects of this embodiment, the binding
affinity of a RXR agonist that selectively binds to a RXR receptor
can have an equilibrium disassociation between, e.g., 0.1 nM to 10
nM, 0.1 nM to 50 nM, 0.1 nM to 100 nM, 0.5 nM to 10 nM, 0.5 nM to
50 nM, 0.5 nM to 100 nM, 1 nM to 10 nM, 1 nM to 50 nM, or 1 nM to
100 nM.
[0032] In still other aspects of this embodiment, the binding
affinity of a RXR agonist that selectively binds to a RXR can have
an association rate constant for a RAR receptor of, e.g., less than
1.times.10.sup.0 M.sup.-1 s.sup.-1, less than 1.times.10.sup.1
M.sup.-1 s.sup.-1, less than 1.times.10.sup.2 M.sup.-1 s.sup.-1,
less than 1.times.10.sup.3 M.sup.-1 s.sup.-1, or less than
1.times.10.sup.4 M.sup.-1 s.sup.-1. In another embodiment, the
binding affinity of a RXR agonist that selectively binds to a RXR
receptor can have an association rate constant of a RAR receptor
of, e.g., at most 1.times.10.sup.0 M.sup.-1 s.sup.-1, at most
1.times.10.sup.1 M.sup.-1 s.sup.-1, at most 1.times.10.sup.2
M.sup.-1 s.sup.-1, at most 1.times.10.sup.3 M.sup.-1 s.sup.-1, or
at most 1.times.10.sup.4 M.sup.-1 s.sup.-1.
[0033] In further aspects of this embodiment, the binding affinity
of a RXR agonist that selectively binds to a RXR receptor can have
an equilibrium disassociation constant for a RAR receptor of, e.g.,
more than 500 nM, for than 1,000 nM, more than 5,000 nm, or more
than 10,000 nM. In another embodiment, the binding affinity of a
RXR agonist that selectively binds to a RXR receptor can have an
equilibrium disassociation constant for a RAR receptor between,
e.g., 500 nM to 10,000 nM, 1,000 nM to 10,000 nM, or 5,000 nM to
10,000 nM.
[0034] Binding specificity is the ability of a RXR agonist to
discriminate between a RXR receptor and a receptor that does not
contain its binding site, such as, e.g., a RAR receptor. One way to
measure binding specificity is to compare the Kon association rate
of a RXR agonist for its RXR relative to the Kon association rate
of a RXR agonist for a receptor that does not contain its binding
site. For example, comparing the association rate constant (Ka) of
a RXR agonist for its RXR receptor relative to a RAR receptor
[0035] In aspects of this embodiment, a RXR agonist that
selectively binds to a RXR receptor can have an association rate
constant (Ka) for a receptor not comprising its binding site of,
e.g., less than 1.times.10.sup.0 M.sup.-1 s.sup.-1, less than
1.times.10.sup.1 M.sup.-1 s.sup.-1, less than 1.times.10.sup.2
M.sup.-1 s.sup.-1, less than 1.times.10.sup.3 M.sup.-1 s.sup.-1 or
less than 1.times.10.sup.4 M.sup.-1 s.sup.-1. In other aspects of
this embodiment, a RXR agonist that selectively binds to a RXR
receptor can have an association rate constant (Ka) for a receptor
not comprising its binding site of, e.g., at most 1.times.10.sup.0
M.sup.-1 s.sup.-1, at most 1.times.10.sup.1 M.sup.-1 s.sup.-1, at
most 1.times.10.sup.2 M.sup.-1 s.sup.-1, at most 1.times.10.sup.3
M.sup.-1 s.sup.-1 or at most 1.times.10.sup.4 M.sup.-1
s.sup.-1.
[0036] In other aspects of this embodiment, a RXR agonist that
selectively binds to a RXR receptor can have an association rate
constant (Ka) for a receptor not comprising its binding site of,
e.g., at least 2-fold more, at least 3-fold more, at least 4-fold
more, at least 5-fold more, at least 6-fold more, at least 7-fold
more, at least 8-fold more, or at least 9-fold more. In further
aspects of this embodiment, a RXR agonist that selectively binds to
a RXR receptor can have an association rate constant (Ka) for a
receptor not comprising its binding site of, e.g., at least 10-fold
more, at least 100-fold more, at least 1,000-fold more or at least
10,000-fold more. In yet other aspects of this embodiment, a RXR
agonist that selectively binds to a RXR receptor can have an
association rate constant (Ka) for a receptor not comprising its
binding site of, e.g., at most 1-fold more, at most 2-fold more, at
most 3-fold more, at most 4-fold more, at most 5-fold more, at most
6-fold more, at most 7-fold more, at most 8-fold more, or at most
9-fold more. In yet other aspects of this embodiment, a RXR agonist
that selectively binds to a RXR receptor can have an association
rate constant (Ka) for a receptor not comprising its binding site
of, e.g., at most 10-fold more, at most 100-fold more, at most
1,000-fold more or at most 10,000-fold more.
[0037] The binding specificity of a RXR agonist that selectively
binds to a RXR receptor can also be characterized as a binding
ratio that such a RXR agonist can discriminate its RXR receptor
relative to a receptor not comprising its binding site, such as,
e.g., a RAR receptor. In aspects of this embodiment, a RXR agonist
that selectively binds to a RXR receptor has a binding ratio for
its RXR receptor relative to a receptor not comprising its binding
site of, e.g., at least 2:1, at least 3:1, at least 4:1, at least
5:1, at least 64:1, at least 7:1, at least 8:1, at least 9:1, at
least 10:1, at least 15:1, at least 20:1, at least 25:1, at least
30:1, at least 35:1, or at least 40:1. In other aspects of this
embodiment, a RXR agonist that selectively binds to a RXR receptor
has a binding ratio for its RXR receptor relative to a RAR receptor
of, e.g., at least 2:1, at least 3:1, at least 4:1, at least 5:1,
at least 64:1, at least 7:1, at least 8:1, at least 9:1, at least
10:1, at least 15:1, at least 20:1, at least 25:1, at least 30:1,
at least 35:1, or at least 40:1.
[0038] In aspects of this embodiment, a RXR agonist will have a
ratio of activity at a RXR receptor relative to a RAR receptor of,
e.g., at least 5 greater, at least 10 greater, at least 15, or at
least 20 greater.
[0039] The binding specificity of a RXR agonist that selectively
binds to a RXR receptor can also be characterized as an activity
ratio that such a RXR agonist can exert activity through binding to
its RXR receptor relative to a receptor not comprising its binding
site, such as, e.g., a RAR receptor. In aspects of this embodiment,
a RXR agonist that selectively binds to a RXR receptor has an
activity ratio through its RXR receptor relative to a receptor not
comprising its binding site of, e.g., at least 2:1, at least 3:1,
at least 4:1, at least 5:1, at least 64:1, at least 7:1, at least
8:1, at least 9:1, at least 10:1, at least 15:1, at least 20:1, at
least 25:1, at least 30:1, at least 35:1, or at least 40:1. In
other aspects of this embodiment, a RXR agonist that selectively
binds to a RXR receptor has an activity ratio through its RXR
receptor relative to a RAR receptor of, e.g., at least 2:1, at
least 3:1, at least 4:1, at least 5:1, at least 64:1, at least 7:1,
at least 8:1, at least 9:1, at least 10:1, at least 15:1, at least
20:1, at least 25:1, at least 30:1, at least 35:1, or at least
40:1.
[0040] In an aspect of this embodiment, a RXR agonist is a compound
having the structure of formula I:
##STR00003##
wherein Z is a radical having the structure of Formula II:
##STR00004##
Y is cycloalkyl or cycloalkenyl of 3 to 8 carbons optionally
substituted with one or two R.sup.4 groups, or Y is selected from
phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyridazinyl, pyrimidiyl,
pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, the groups being
optionally substituted with one or two R.sup.4 groups, the divalent
Y radical being substituted by the Z and
--(CR.sup.1.dbd.CR.sup.1.dbd.CR.sup.1.dbd.CR.sup.1)-- groups on
adjacent carbons; R.sup.1 and R.sup.2 independently are H, lower
alkyl or fluoroalkyl; R.sup.3 is hydrogen, lower alkyl, Cl or Br;
R.sup.4 is lower alkyl, fluoroalkyl or halogen, and B is hydrogen,
--COOH or a pharmaceutically acceptable salt thereof, --COOR.sup.8,
--CONR.sup.9R.sup.10, --CH.sub.2OH, --CH.sub.2OR.sup.11,
--CH.sub.2OCOR.sup.11, --CHO, --CH(OR.sup.12).sub.2,
--CHOR.sup.13O, --OCOR.sup.7, --CR.sup.7(OR.sup.12).sub.2,
--CR.sup.7OR.sup.13O, or tri-lower alkylsilyl, where R.sup.7 is an
alkyl, cycloalkyl or alkenyl group, containing 1 to 5 carbons,
R.sup.8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of
5 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1
to 10 carbons, or R.sup.8 is phenyl or lower alkylphenyl, R.sup.9
and R.sup.10 independently are hydrogen, an alkyl group of 1 to 10
carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower
alkylphenyl, R.sup.11 is lower alkyl, phenyl or lower alkylphenyl,
R.sup.12 is lower alkyl, R.sup.13 is divalent alkyl radical of 2-5
carbons; and n is 1 or 2.
[0041] In an aspect of this embodiment, a RXR agonist is a compound
having the structure of formula III:
##STR00005##
wherein R.sup.2 is hydrogen or lower alkyl; R.sup.3 is hydrogen or
lower alkyl, and B is hydrogen, COOH or a pharmaceutically
acceptable salt thereof, --COOR.sup.8, --CONR.sup.9R.sup.10,
--CH.sub.2OH, --CH.sub.2OR.sup.11, --CH.sub.2OCOR.sup.11, --CHO,
--CH(OR.sup.12).sub.2, --CHOR.sup.13O, --COR.sup.7,
--CR.sup.7(OR.sup.12).sub.2, --CR.sup.7OR.sup.13O, or tri-lower
alkylsilyl, where R.sup.7 is an alkyl, cycloalkyl or alkenyl group
containing 1 to 5 carbons, R.sup.8 is an alkyl group of 1 to 10
carbons, a cycloalkyl group of 5 to 10 carbons or
trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or
R.sup.8 is phenyl or lower alkylphenyl, R.sup.9 and R.sup.10
independently are hydrogen, an alkyl group of 1 to 10 carbons, or a
cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl,
R.sup.11 is lower alkyl, phenyl or lower alkylphenyl, R.sup.12 is
lower alkyl, and R.sup.13 is divalent alkyl radical of 2-5
carbons.
[0042] In an aspect of this embodiment, a RXR agonist is a compound
having the structure of formula IV:
##STR00006##
wherein n is 1 or 2; R.sup.1 and R.sup.2 independently are H, lower
alkyl or fluoroalkyl; R.sup.3 is hydrogen, lower alkyl, Cl or Br;
R.sup.4 is H, lower alkyl, fluoroalkyl or halogen, and B is
hydrogen, --COOH or a pharmaceutically acceptable salt thereof,
--COOR.sup.8, --CONR.sup.9R.sup.10, --CH.sub.2OH,
--CH.sub.2OR.sup.11, --CH.sub.2OCOR.sup.11, --CHO,
--CH(OR.sup.12).sub.2, --CHOR.sup.13O, --COR.sup.7,
--CR.sup.7(OR.sup.12).sub.2, --CR.sup.7OR.sup.13O, or trilower
alkylsilyl where R.sup.7 is an alkyl, cycloalkyl or alkenyl group
containing 1 to 5 carbons, R.sup.8 is an alkyl group of 1 to 10
carbons, or R.sup.8 is phenyl or lower alkylphenyl, R.sup.9 and
R.sup.10 independently are hydrogen, an alkyl group of 1 to 10
carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower
alkylphenyl, R.sup.11 is lower alkyl, phenyl or lower alkylphenyl,
R.sup.12 is lower alkyl, and R.sup.13 is divalent alkyl radical of
2-5 carbons.
[0043] In an aspect of this embodiment, a RXR agonist is a compound
having the structure of formula V:
##STR00007##
where R.sup.4 is lower alkyl of 1 to 6 carbons; B is --COOH or
--COOR.sup.8 where R.sup.8 is lower alkyl of 1 to 6 carbons, and
the configuration about the cyclopropane ring is cis, and the
configuration about the double bonds in the pentadienoic acid or
ester chain attached to the cyclopropane ring is trans in each of
the double bonds, or a pharmaceutically acceptable salt of the
compound.
[0044] In an aspect of this embodiment, a RXR agonist is a compound
having the structure of formula VI:
##STR00008##
wherein Z is a radical having the structure of Formula VII:
##STR00009##
Y is cycloalkyl or cycloalkenyl of 3 to 8 carbons optionally
substituted with one or two R.sup.4 groups, or Y is selected from
phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyridazinyl, pyrimidiyl,
pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, the groups being
optionally substituted with one or two R.sup.4 groups, the divalent
Y radical being substituted by the Z and
--(CR.sup.1.dbd.CR.sup.1.dbd.CR.sup.1.dbd.CR.sup.1)-- groups on
adjacent carbons; X is S or O; R.sup.1 and R.sup.2 independently
are H, lower alkyl or fluoroalkyl; R.sup.3 is hydrogen, lower
alkyl, Cl or Br; R.sup.4 is lower alkyl, fluoroalkyl or halogen,
and B is hydrogen, --COOH or a pharmaceutically acceptable salt
thereof, --COOR.sup.8, --CONR.sup.9R.sup.10, --CH.sub.2OH,
--CH.sub.2OR.sup.11, --CH.sub.2OCOR.sup.11, --CHO,
--CH(OR.sup.12).sub.2, --CHOR.sup.13O, --OCOR.sup.7,
--CR.sup.7(OR.sup.12).sub.2, --CR.sup.7OR.sup.13O, or tri-lower
alkylsilyl, where R.sup.7 is an alkyl, cycloalkyl or alkenyl group,
containing 1 to 5 carbons, R.sup.8 is an alkyl group of 1 to 10
carbons, a cycloalkyl group of 5 to 10 carbons or
trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or
R.sup.8 is phenyl or lower alkylphenyl, R.sup.9 and R.sup.10
independently are hydrogen, an alkyl group of 1 to 10 carbons, or a
cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl,
R.sup.11 is lower alkyl, phenyl or lower alkylphenyl, R.sup.12 is
lower alkyl, and R.sup.13 is divalent alkyl radical of 2-5
carbons.
[0045] In an aspect of this embodiment, a RXR agonist is a compound
having the structure of formula VIII:
##STR00010##
wherein X is S or O; R.sup.2 is hydrogen or lower alkyl; R.sup.3 is
hydrogen or lower alkyl, and B is hydrogen, --COOH or a
pharmaceutically acceptable salt thereof, --COOR.sup.8,
--CONR.sup.9R.sup.10, --CH.sub.2OH, --CH.sub.2OR.sup.11,
--CH.sub.2OCOR.sup.11, --CHO, --CH(OR.sup.12).sub.2,
--CHOR.sup.13O, .sup.--COR.sup.7, --CR.sup.7(OR.sup.12).sub.2,
--CR.sup.7OR.sup.13O, or trilower alkylsilyl, where R.sup.7 is an
alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons,
R.sup.8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of
5 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1
to 10 carbons, or R.sup.9 is phenyl or lower alkylphenyl, R.sup.9
and R.sup.10 independently are hydrogen, an alkyl group of 1 to 10
carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower
alkylphenyl, R.sup.11 is lower alkyl, phenyl or lower alkylphenyl,
R.sup.12 is lower alkyl, and R.sup.13 is divalent alkyl radical of
2-5 carbons.
[0046] In an aspect of this embodiment, a RXR agonist is a compound
having the structure of formula IX:
##STR00011##
wherein Z is a radical having the structure of Formula X:
##STR00012##
Y is selected from pyridyl, pyrrolyl, pyridazinyl, pyrimidinyl,
pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, the groups being
optionally substituted with one or two R.sup.4 groups, the divalent
Y radical being substituted by the Z and
--(CR.sup.1.dbd.CR.sup.1.dbd.CR.sup.1.dbd.CR.sup.1)-- groups on
adjacent carbons; X is NR.sup.5; n is 1 or 2; R.sup.1 and R.sup.2
independently are H, lower alkyl or fluoroalkyl; R.sup.3 is
hydrogen, lower alkyl, Cl or Br; R.sup.4 is lower alkyl,
fluoroalkyl or halogen; R.sup.5 is H or lower alkyl, and B is
hydrogen, --COOH or a pharmaceutically acceptable salt thereof,
--COOR.sup.8, --CONR.sup.9R.sup.10, --CH.sub.2OH,
--CH.sub.2OR.sup.11, --CH.sub.2OCOR.sup.11, --CHO,
--CH(OR.sup.12).sub.2, --CHOR.sup.13O, --COW,
--CR.sup.7(OR.sup.12).sub.2, --CR.sup.7OR.sup.13O, or trilower
alkylsilyl, where R.sup.7 is an alkyl, cycloalkyl or alkenyl group
containing 1 to 5 carbons, R.sup.9 is an alkyl group of 1 to 10
carbons, a cycloalkyl group of 5 to 10 carbons or
trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or
R.sup.9 is phenyl or lower alkylphenyl, R.sup.9 and R.sup.10
independently are hydrogen, an alkyl group of 1 to 10 carbons, or a
cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl,
R.sup.11 is lower alkyl, phenyl or lower alkylphenyl, R.sup.12 is
lower alkyl, and R.sup.13 is divalent alkyl radical of 2 to 5
carbons.
[0047] In an aspect of this embodiment, a RXR agonist is a compound
having the structure of formula IX:
##STR00013##
wherein Z is a radical having the structure of Formula X:
##STR00014##
Y is selected from pyridyl, pyrrolyl, pyridazinyl, pyrimidinyl,
pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, the groups being
optionally substituted with one or two R.sup.4 groups, the divalent
Y radical being substituted by the Z and
--(CR.sup.1.dbd.CR.sup.1.dbd.CR.sup.1.dbd.CR.sup.1)-- groups on
adjacent carbons; X is NR.sup.5; n is 1 or 2; R.sup.1 and R.sup.2
independently are H, lower alkyl or fluoroalkyl; R.sup.3 is
hydrogen, lower alkyl, Cl or Br; R.sup.4 is lower alkyl,
fluoroalkyl or halogen; R.sup.5 is H or lower alkyl, and B is
hydrogen, --COOH or a pharmaceutically acceptable salt thereof,
--COOR.sup.8, --CONR.sup.9R.sup.10, --CH.sub.2OH,
--CH.sub.2OR.sup.11, --CH.sub.2OCOR.sup.11, --CHO,
--CH(OR.sup.12).sub.2, --CHOR.sup.13O, --COR.sup.7,
--CR.sup.7(OR.sup.12).sub.2, --CR.sup.7OR.sup.13O, or trilower
alkylsilyl, where R.sup.7 is an alkyl, cycloalkyl or alkenyl group
containing 1 to 5 carbons, R.sup.8 is an alkyl group of 1 to 10
carbons, a cycloalkyl group of 5 to 10 carbons or
trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or
R.sup.8 is phenyl or lower alkylphenyl, R.sup.9 and R.sup.10
independently are hydrogen, an alkyl group of 1 to 10 carbons, or a
cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl,
R.sup.11 is lower alkyl, phenyl or lower alkylphenyl, R.sup.12 is
lower alkyl, and R.sup.13 is divalent alkyl radical of 2 to 5
carbons.
[0048] In an aspect of this embodiment, a RXR agonist is a compound
having the structure of formula XII:
##STR00015##
wherein R is H, lower alkyl or 1 to 6 carbons, or a
pharmaceutically acceptable salt of the compound.
[0049] In an aspect of this embodiment, a RXR agonist is a compound
having the structure of formula XII:
##STR00016##
wherein Z is a radical having the structure of Formula XIV:
##STR00017##
Y is cyclopropyl, the Y group being optionally substituted with one
or two R.sup.4 groups, the divalent Y radical being substituted by
the Z and --(CR.sup.1.dbd.CR.sup.1.dbd.CR.sup.1.dbd.CR.sup.1)--
groups on adjacent carbons; X is NR.sup.5; R.sup.1 and R.sup.2
independently are H, lower alkyl or fluoroalyl; R.sup.3 is
hydrogen, lower alkyl, Cl or Br; R.sup.4 is lower alkyl,
fluoroalkyl or hydrogen; R.sup.5 is H or lower alkyl, and B is
hydrogen, --COOH or a pharmaceutically acceptable salt thereof,
--COOR.sup.8, --CONR.sup.9R.sup.10, --CH.sub.2OH,
--CH.sub.2OR.sup.11, --CH.sub.2OCOR.sup.11, --CHO,
--CH(OR.sup.12).sub.2, --CHOR.sup.13O, --COR.sup.7,
--CR.sup.7(OR.sup.12).sub.2, --CR.sup.7OR.sup.13O, or trilower
alkylsilyl, where R.sup.7 is an alkyl, cycloalkyl or alkenyl group
containing 1 to 5 carbons, R.sup.8 is an alkyl group of 1 to 10
carbons, a cycloalkyl group of 5 to 10 carbons or
trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or
R.sup.8 is phenyl or lower alkylphenyl, R.sup.9 and R.sup.10
independently are hydrogen, an alkyl group of 1 to 10 carbons, or a
cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl,
R.sup.11 is lower alkyl, phenyl or lower alkylphenyl, R.sup.12 is
lower alkyl, and R.sup.13 is divalent alkyl radical of 2 to 5
carbons.
[0050] In an aspect of this embodiment, a RXR agonist is a compound
having the structure of formula XV:
##STR00018##
wherein X is NR.sup.5; R.sup.5 is H or lower alkyl; R.sup.2 is H or
lower alkyl; R.sup.3 is H or lower alkyl, and B is hydrogen, --COOH
or a pharmaceutically acceptable salt thereof, --COOR.sup.8,
--CONR.sup.9R.sup.10, --CH.sub.2OH, --CH.sub.2OR.sup.11,
--CH.sub.2OCOR.sup.11, --CHO, --CH(OR.sup.12).sub.2,
--CHOR.sup.13O, --COR.sup.7, --CR.sup.7(OR.sup.12).sub.2,
--CR.sup.7OR.sup.13O, or trilower alkylsilyl, where R.sup.7 is an
alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons,
R.sup.9 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of
5 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1
to 10 carbons, or R.sup.9 is phenyl or lower alkylphenyl, R.sup.9
and R.sup.10 independently are hydrogen, an alkyl group of 1 to 10
carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower
alkylphenyl, R.sup.11 is lower alkyl, phenyl or lower alkylphenyl,
R.sup.12 is lower alkyl, and R.sup.13 is divalent alkyl radical of
2 to 5 carbons.
[0051] In an aspect of this embodiment, a RXR agonist is a compound
having the structure of formula XVI:
##STR00019##
where Y is a bivalent radical having the structure of Formula
XVII:
##STR00020##
the two X.sup.1 groups jointly represent an oxo (.dbd.O) or thione
(.dbd.S) function, or X.sup.1 is independently selected from H or
alkyl of 1 to 6 carbons; the two X.sup.2 groups jointly represent
an oxo (.dbd.O) or a thione (.dbd.S) function, or X.sup.2
independently selected from H or alkyl of 1 to 6 carbons, with the
proviso that one of the joint X.sup.1 grouping or of the joint
X.sup.2 grouping represents an oxo (.dbd.O) or thione (.dbd.S)
function; W is O, C(R.sup.1).sub.2, or W does not exist; R.sup.1 is
independently H, lower alkyl of 1 to 6 carbons, or lower
fluoroalkyl of 1 to 6 carbons; R.sup.2 is independently H, lower
alkyl of 1 to 6 carbons, or lower fluoroalkyl of 1 to 6 carbons;
R.sup.3 is hydrogen, lower alkyl of 1 to 6 carbons, OR.sup.1,
fluoro substituted lower alkyl of 1 to 6 carbons halogen, NO.sub.2,
NH.sub.2, --NHCO(C.sub.1-C.sub.6) alkyl, or --NHCO(C.sub.1-C.sub.6)
alkenyl; A is hydrogen, --COOH or a pharmaceutically acceptable
salt thereof, --COOR.sup.8, --CONR.sup.9R.sup.10, --CH.sub.2OH,
--CH.sub.2OR.sup.11, --CH.sub.2OCOR.sup.11, --CHO,
--CH(OR.sup.12).sub.2, --CH(OR.sup.13O), --COR.sup.7,
--CR.sup.7(OR.sup.12).sub.2, --CR.sup.7(OR.sup.13O), or
--Si(C.sub.1-C.sub.6).sub.3, where R.sup.7 is an alkyl, cycloalkyl
or alkenyl group containing 1 to 5 carbons, R.sup.9 is an alkyl
group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl
group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10
carbons, or R.sup.8 is phenyl or lower alkyphenyl, R.sup.9 and
R.sup.10 independently are hydrogen, an alkyl group of 1 to 10
carbons, or a cycloalkyl group of 5-10 carbons, or phenyl,
hydroxyphenyl or lower alkylphenyl, R.sup.11 is lower alkyl, phenyl
or lower alkylphenyl, R.sup.12 is lower alkyl, and R.sup.13 is
divalent alkyl radical of 2 to 5 carbons, and R.sup.14 is H, alkyl
of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons,
alkenyl of 2 to 10 carbons and having 1 to 3 double bonds.
[0052] In an aspect of this embodiment, a RXR agonist is a compound
having the structure of formula XVIII:
##STR00021##
wherein R.sup.1 is independently H, lower alkyl of 1 to 6 carbons,
or lower fluoroalkyl of 1 to 6 carbons; R.sup.1* is hydrogen or
C.sub.1-6-alkyl; R.sup.2* is independently H, lower alkyl of 1 to 6
carbons, or lower fluoroalkyl of 1 to 6 carbons; R.sup.3* is
hydrogen, lower alkyl of 1 to 6 carbons, fluoro substituted lower
alkyl of 1 to 6 carbons or halogen; X.sup.1* is an oxo (.dbd.O) or
a thione (.dbd.S) group; A* is hydrogen, --COOH or a
pharmaceutically acceptable salt thereof, --COOR.sup.8,
--CONR.sup.9R.sup.10, where R.sup.8 is an alkyl group of 1 to 10
carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10
carbons, or a cycloalkyl group of 5 to 10 carbons, or R.sup.8 is
phenyl or lower alkylphenyl, R.sup.9 and R.sup.10 independently are
hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group
of 5-10 carbons, or phenyl, hydroxyphenyl or lower alkylphenyl, and
the cyclopropyl group is attached to the 6 or 7 position of the
tetrahydroquinoline moiety, and R.sup.14* is alkyl of 1 to 10
carbons or fluoro-substituted alkyl of 1 to 10 carbons.
[0053] In an aspect of this embodiment, a RXR agonist is a compound
having the structure of formulae XIX, XX, or XXI:
##STR00022##
where X is O, S, or (CR.sup.1R.sup.1).sub.n, where n is 0, 1 or 2;
Y is a bivalent radical having the structure of Formulae XXII or
XXIII where o is an integer between 1 through 4
##STR00023##
or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical
having 1 to 3 heteroatoms selected from N, S and O, the aryl or
heteroaryl groups being unsubstituted, or substituted with 1 to 3
C.sub.1-6 alkyl or with 1 to 3 C.sub.1-6fluoroalkyl groups with the
proviso that when the compound is in accordance with Formula II
then Y is not a 5 or 6 membered ring; X.sup.1 is S or NH; R.sup.1
is independently H, lower alkyl of 1 to 6 carbons, or lower
fluoroalkyl of 1 to 6 carbons; R.sup.2 is independently H, lower
alkyl of 1 to 6 carbons, OR.sup.1, adamantly, or lower fluoroalkyl
of 1 to 6 carbons, or the two R.sup.2 groups jointly represent an
oxo (.dbd.O) group with the proviso that when the compound is in
accordance with Formula II then at least one of the R.sup.2
substituents is branched-chain alkyl or adamantly; R.sup.3 is
hydrogen, lower alkyl of 1 to 6 carbons, OR.sup.1, fluoro
substituted lower alkyl of 1 to 6 carbons or halogen, NO.sub.2,
NH.sub.2, --NHCO(C.sub.1-C.sub.6) alkyl, or --NHCO(C.sub.1-C.sub.6)
alkenyl; A is --COOH or a pharmaceutically acceptable salt thereof,
COOR.sup.8, --CONR.sup.9R.sup.10, --CH.sub.2OH,
--CH.sub.2OR.sup.11, --CH.sub.2OCOR.sup.11, --CHO,
--CH(OR.sup.12).sub.2, --CH(OR.sup.13O), --COR.sup.7,
--CR.sup.7(OR.sup.12).sub.2, CR.sup.7(OR.sup.13O), or
--Si(C.sub.1-6alkyl).sub.3, where R.sup.7 is an alkyl, cycloalkyl
or alkenyl group containing 1 to 5 carbons, R.sup.8 is an alkyl
group of 1 to 10 carbons or (trimethylsilyl) alkyl where the alkyl
group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10
carbons, or R.sup.8 is phenyl or lower alkylphenyl, R.sup.9 and
R.sup.10 independently are hydrogen, an alkyl group of 1 to 10
carbons, or a cycloalkyl group of 5-10 carbons, or phenyl,
hydroxyphenyl or lower alkylphenyl, R.sup.12 is lower alkyl, and
R.sup.13 is divalent alkyl radical of 2-5 carbons, and R.sup.14 is
alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10
carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds,
alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic
aryl selected from the group consisting of phenyl,
C.sub.1-C.sub.10-alkylphenyl, naphthyl,
C.sub.1-C.sub.10-alkylnaphthyl, phenyl-C.sub.1-C.sub.10-alkyl,
naphthyl-C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10-alkenylphenyl
having 1 to 3 double bonds, C.sub.1-C.sub.10-alkynylphenyl having 1
to 3 triple bonds, phenyl-C.sub.1-C.sub.10 alkenyl having 1 to 3
double bonds, phenyl-C.sub.1-C.sub.10 alkenyl having 1 to 3 triple
bonds, hydroxyl alkyl of 1 to 10 carbons, hydroxyalkenyl having 2
to 10 carbons and 1 to 3 double bonds, hydroxyalkynyl having 2 to
10 carbons and 1 to 3 triple bonds, acyloxyalkyl of 1 to 10
carbons, acyloxyalkenyl having 2 to 10 carbons and 1 to 3 double
bonds, or acyloxyalkynyl of 2 to 10 carbons and 1 to 3 triple
bonds, acyloxyalkyl of 1 to 10 carbons, acyloxyalkenyl having 2 to
10 carbons and 1 to 3 double bonds, or acyloxyalkynyl of 2 to 10
carbons and 1 to 3 triple bonds where the acyl group is represented
by --COR.sup.8, or R.sup.14 is a 5 or 6 membered heteroaryl group
having 1 to 3 heteroatoms, the heteroatoms being selected from a
group consisting of O, S, and N, the heteroaryl group being
unsubstituted or substituted with a C.sub.1-C.sub.10 alkyl group,
with a C.sub.1-C.sub.10 fluoroalkyl group, or with halogen, and the
dashed line in Formula XXII represents a bond or absence of a
bond.
[0054] In an aspect of this embodiment, a RXR agonist is a compound
having the structure of formula XXIV:
##STR00024##
wherein R is H, lower alkyl of 1 to 6 carbons, or a
pharmaceutically acceptable salt of the compound.
[0055] In an aspect of this embodiment, a RXR agonist is a compound
having the structure of formula XXV:
##STR00025##
wherein R is H, lower alkyl of 1 to 6 carbons, and R.sup.1 is
iso-propyl or tertiary-butyl, or a pharmaceutically acceptable salt
of the compound.
[0056] In an aspect of this embodiment, a RXR agonist is a compound
having the structure of formula XXVI:
##STR00026##
wherein R is H, lower alkyl of 1 to 6 carbons, and R.sup.1 is
iso-propyl, n-butyl or tertiary-butyl, or a pharmaceutically
acceptable salt of the compound.
[0057] In an aspect of this embodiment, a RXR agonist is a compound
having the structure of formula XXVII:
##STR00027##
where X is O or S; Y is a bivalent cycloalkyl or cycloalkenyl
radical optionally substituted with one to four R.sup.4 groups, the
cycloalkenyl radical having 5 to 6 carbons and one double bond, or
Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1
to 3 heteroatoms selected from N, S and O, the aryl or heteroaryl
groups optionally substituted with 1 to 4 R.sup.4 groups with the
proviso that the cycloalkyl or the cycloalkenyl radical is not
substituted on the same carbon with the condensed cyclic moiety and
with the diene containing moiety; R.sup.1 is independently H, alkyl
of 1 to 6 carbons, or fluoroalkyl of 1 to 6 carbons; R.sup.2 is
independently H, alkyl of 1 to 8 carbons, or fluoroalkyl of 1 to 8
carbons; R.sup.12 is independently H, alkyl of 1 to 8 carbons, or
fluoroalyl of 1 to 8 carbons; R.sup.3 is hydrogen, alkyl of 1 to 10
carbons, fluoro substituted alkyl of 1 to 10 carbons, halogen,
alkoxy of 1 to 10 carbons, or alkylthio of 1 to 10 carbons;
NO.sub.2, NH.sub.2, --NHCO(C.sub.1-C.sub.6) alkyl,
--NHCO(C.sub.1-C.sub.6) alkenyl, --NR.sup.1H or N(R.sup.1).sub.2,
benzyloxy, C.sub.1-C.sub.6 alkyl-substituted benzyloxy, or R.sup.3
is selected from the groups shown below:
##STR00028##
R.sup.4 is H, halogen, alkyl of 1 to 10 carbons, fluoro substituted
alkyl of 1 to 6 carbons, alkoxy of 1 to 10 carbons, or alkylthio of
1 to 10 carbons; m is an integer having the values of 0 to 3; r is
an integer having the values of 1 to 10; s is an integer having the
values 1 to 4; t is an integer having the values 1 to 5;
##STR00029##
represents a 5 or 6 membered heteroaryl ring having 1 to 3
heteroatoms selected from the group consisting of N, S and O; B is
hydrogen, COOH or a pharmaceutically acceptable salt thereof,
--COOR.sup.8, --CONR.sup.9R.sup.10, --CH.sub.2OH,
--CH.sub.2OR.sup.11, --CH.sub.2OCOR.sup.11, --CHO,
--CH(OR.sup.12).sub.2, --CHOR.sup.13O, --COR.sup.7,
--CR.sup.7(OR.sup.12).sub.2, --CR.sup.7OR.sup.13O, or trilower
alkylsilyl, where R.sup.7 is an alkyl, cycloalkyl or alkenyl group
containing 1 to 5 carbons, R.sup.9 is an alkyl group of 1 to 10
carbons, a cycloalkyl group of 5 to 10 carbons or
trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or
R.sup.9 is phenyl or lower alkylphenyl, R.sup.9 and R.sup.10
independently are hydrogen, an alkyl group of 1 to 10 carbons, or a
cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl,
R.sup.11 is lower alkyl, phenyl or lower alkylphenyl, R.sup.12 is
lower alkyl, and R.sup.13 is divalent alkyl radical of 2 to 5
carbons.
[0058] In an aspect of this embodiment, a RXR agonist is a compound
having the structure of formula XXVIII:
##STR00030##
wherein R.sup.1 is H or methyl; R.sup.9 is H, alkyl of 1 to 6
carbons, or a pharmaceutically acceptable cation, and R.sup.3 is
hydrogen, alkyl of 1 to 10 carbons, halogen, alkoxy of 1 to 10
carbons, or R.sup.3 is selected from the groups shown below:
##STR00031##
where R.sup.4 is H, halogen, alkyl of 1 to 10 carbons, carbons,
alkoxy of 1 to 10; r is an integer having the values of 1 to 10; s
is an integer having the values 1 to 4;
##STR00032##
represents a 5 or 6 membered heteroaryl ring having 1 to 3
heteroatoms selected from the group consisting of N, S and O, and t
is an integer having the values 1 to 5.
[0059] In an aspect of this embodiment, a RXR agonist is
3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydron-
aphth-7-yl]2(E),4(E) heptadienoic acid, and has the structure of
formula XXIX:
##STR00033##
[0060] Aspects of the present specification provide, in part, a RXR
agonist having activity that promotes Treg cell differentiation. In
aspects of this embodiment, a RXR agonist promotes Treg cell
differentiation by at least 10%, at least 20%, at least 30%, at
least 40%, at least 50%, at least 60%, at least 70%, at least 80%,
at least 90%, at least 100%, at least 200%, at least 300%, at least
400%, or at least 500%. In other aspects of this embodiment, a RXR
agonist promotes Treg cell differentiation by about 10% to about
25%, about 10% to about 50%, about 10% to about 75%, about 10% to
about 100%, about 10% to about 200%, about 10% to about 300%, about
10% to about 400%, about 10% to about 500%, about 25% to about 50%,
about 25% to about 75%, about 25% to about 100%, about 25% to about
200%, about 25% to about 300%, about 25% to about 400%, about 25%
to about 500%, about 50% to about 100%, about 50% to about 200%,
about 50% to about 300%, about 50% to about 400%, or about 50% to
about 500%.
[0061] In an embodiment, a RXR agonist has activity that results in
increased Foxp3 expression in cells exposed to the RXR agonist. In
aspects of this embodiment, a RXR agonist increases Foxp3
expression in cells by at least 10%, at least 20%, at least 30%, at
least 40%, at least 50%, at least 60%, at least 70%, at least 80%,
at least 90%, at least 100%, at least 200%, at least 300%, at least
400%, or at least 500%, relative to cells not exposed to the same
RXR agonist. In other aspects of this embodiment, a RXR agonist
increases Foxp3 expression in cells by about 10% to about 25%,
about 10% to about 50%, about 10% to about 75%, about 10% to about
100%, about 10% to about 200%, about 10% to about 300%, about 10%
to about 400%, about 10% to about 500%, about 25% to about 50%,
about 25% to about 75%, about 25% to about 100%, about 25% to about
200%, about 25% to about 300%, about 25% to about 400%, about 25%
to about 500%, about 50% to about 100%, about 50% to about 200%,
about 50% to about 300%, about 50% to about 400%, or about 50% to
about 500%, relative to cells not exposed to the same RXR
agonist.
[0062] In another aspect of this embodiment, a RXR agonist has
activity that results in increased Foxp3 expression in naive
CD4.sup.+ CD25.sup.- FoxP3.sup.- cells cultured under Treg cell
differentiation conditions. In other aspects of this embodiment, a
RXR agonist increases Foxp3 expression in naive CD4.sup.+
CD25.sup.- FoxP3.sup.- cells cultured under Treg cell
differentiation by at least 10%, at least 20%, at least 30%, at
least 40%, at least 50%, at least 60%, at least 70%, at least 80%,
at least 90%, at least 100%, at least 200%, at least 300%, at least
400%, or at least 500%, relative to naive CD4.sup.+ CD25.sup.-
FoxP3.sup.- cells cultured under Treg cell differentiation not
exposed to the same RXR agonist. In yet other aspects of this
embodiment, a RXR agonist increases Foxp3 expression in naive
CD4.sup.+ CD25.sup.- FoxP3.sup.- cells cultured under Treg cell
differentiation by about 10% to about 25%, about 10% to about 50%,
about 10% to about 75%, about 10% to about 100%, about 10% to about
200%, about 10% to about 300%, about 10% to about 400%, about 10%
to about 500%, about 25% to about 50%, about 25% to about 75%,
about 25% to about 100%, about 25% to about 200%, about 25% to
about 300%, about 25% to about 400%, about 25% to about 500%, about
50% to about 100%, about 50% to about 200%, about 50% to about
300%, about 50% to about 400%, or about 50% to about 500%, relative
to naive CD4.sup.+ CD25.sup.- FoxP3.sup.- cells cultured under Treg
cell differentiation not exposed to the same RXR agonist.
[0063] In an embodiment, a RXR agonist has activity that results in
increased .alpha.4.beta.7 expression in cells exposed to the RXR
agonist. In aspects of this embodiment, a RXR agonist increases
.alpha.4.beta.7 expression in cells by at least 10%, at least 20%,
at least 30%, at least 40%, at least 50%, at least 60%, at least
70%, at least 80%, at least 90%, at least 100%, at least 200%, at
least 300%, at least 400%, or at least 500%, relative to cells not
exposed to the same RXR agonist. In other aspects of this
embodiment, a RXR agonist increases .alpha.4.beta.7 expression in
cells by about 10% to about 25%, about 10% to about 50%, about 10%
to about 75%, about 10% to about 100%, about 10% to about 200%,
about 10% to about 300%, about 10% to about 400%, about 10% to
about 500%, about 25% to about 50%, about 25% to about 75%, about
25% to about 100%, about 25% to about 200%, about 25% to about
300%, about 25% to about 400%, about 25% to about 500%, about 50%
to about 100%, about 50% to about 200%, about 50% to about 300%,
about 50% to about 400%, or about 50% to about 500%, relative to
cells not exposed to the same RXR agonist.
[0064] In another aspect of this embodiment, a RXR agonist has
activity that results in increased .alpha.4.beta.7 expression in
naive CD4.sup.+ CD25.sup.- FoxP3.sup.- cells cultured under Treg
cell differentiation conditions. In other aspects of this
embodiment, a RXR agonist increases .alpha.4.beta.7 expression in
naive CD4.sup.+ CD25.sup.- FoxP3.sup.- cells cultured under Treg
cell differentiation by at least 10%, at least 20%, at least 30%,
at least 40%, at least 50%, at least 60%, at least 70%, at least
80%, at least 90%, at least 100%, at least 200%, at least 300%, at
least 400%, or at least 500%, relative to naive CD4.sup.+
CD25.sup.- FoxP3.sup.- cells cultured under Treg cell
differentiation not exposed to the same RXR agonist. In yet other
aspects of this embodiment, a RXR agonist increases .alpha.4.beta.7
expression in naive CD4.sup.+ CD25.sup.- FoxP3.sup.- cells cultured
under Treg cell differentiation by about 10% to about 25%, about
10% to about 50%, about 10% to about 75%, about 10% to about 100%,
about 10% to about 200%, about 10% to about 300%, about 10% to
about 400%, about 10% to about 500%, about 25% to about 50%, about
25% to about 75%, about 25% to about 100%, about 25% to about 200%,
about 25% to about 300%, about 25% to about 400%, about 25% to
about 500%, about 50% to about 100%, about 50% to about 200%, about
50% to about 300%, about 50% to about 400%, or about 50% to about
500%, relative to naive CD4.sup.+ CD25.sup.- FoxP3.sup.- cells
cultured under Treg cell differentiation not exposed to the same
RXR agonist.
[0065] Aspects of the present specification provide, in part, a RXR
agonist having activity that inhibits Th17 cell differentiation. In
aspects of this embodiment, a RXR agonist inhibits Th17 cell
differentiation by at least 10%, at least 20%, at least 30%, at
least 40%, at least 50%, at least 60%, at least 70%, at least 80%,
at least 90%, at least 100%, at least 200%, at least 300%, at least
400%, or at least 500%. In other aspects of this embodiment, a RXR
agonist inhibits Th17 cell differentiation by about 10% to about
25%, about 10% to about 50%, about 10% to about 75%, about 10% to
about 100%, about 10% to about 200%, about 10% to about 300%, about
10% to about 400%, about 10% to about 500%, about 25% to about 50%,
about 25% to about 75%, about 25% to about 100%, about 25% to about
200%, about 25% to about 300%, about 25% to about 400%, about 25%
to about 500%, about 50% to about 100%, about 50% to about 200%,
about 50% to about 300%, about 50% to about 400%, or about 50% to
about 500%.
[0066] In an embodiment, a RXR agonist has activity that results in
decreased IL-17A expression in cells exposed to the RXR agonist. In
aspects of this embodiment, a RXR agonist decreases IL-17A
expression in cells by at least 10%, at least 20%, at least 30%, at
least 40%, at least 50%, at least 60%, at least 70%, at least 80%,
at least 90%, at least 100%, at least 200%, at least 300%, at least
400%, or at least 500%, relative to cells not exposed to the same
RXR agonist. In other aspects of this embodiment, a RXR agonist
decreases IL-17A expression in cells by about 10% to about 25%,
about 10% to about 50%, about 10% to about 75%, about 10% to about
100%, about 10% to about 200%, about 10% to about 300%, about 10%
to about 400%, about 10% to about 500%, about 25% to about 50%,
about 25% to about 75%, about 25% to about 100%, about 25% to about
200%, about 25% to about 300%, about 25% to about 400%, about 25%
to about 500%, about 50% to about 100%, about 50% to about 200%,
about 50% to about 300%, about 50% to about 400%, or about 50% to
about 500%, relative to cells not exposed to the same RXR
agonist.
[0067] In another aspect of this embodiment, a RXR agonist has
activity that results in decreased IL-17A expression in naive
CD4.sup.+ CD25.sup.- FoxP3.sup.- cells cultured under Th17 cell
differentiation conditions. In other aspects of this embodiment, a
RXR agonist decreases IL-17A expression in naive CD4.sup.+
CD25.sup.- FoxP3.sup.- cells cultured under Th17 cell
differentiation by at least 10%, at least 20%, at least 30%, at
least 40%, at least 50%, at least 60%, at least 70%, at least 80%,
at least 90%, at least 100%, at least 200%, at least 300%, at least
400%, or at least 500%, relative to naive CD4.sup.+ CD25.sup.-
FoxP3.sup.- cells cultured under Th17 cell differentiation not
exposed to the same RXR agonist. In yet other aspects of this
embodiment, a RXR agonist decreases IL-17A expression in naive
CD4.sup.+ CD25.sup.- FoxP3.sup.- cells cultured under Th17 cell
differentiation by about 10% to about 25%, about 10% to about 50%,
about 10% to about 75%, about 10% to about 100%, about 10% to about
200%, about 10% to about 300%, about 10% to about 400%, about 10%
to about 500%, about 25% to about 50%, about 25% to about 75%,
about 25% to about 100%, about 25% to about 200%, about 25% to
about 300%, about 25% to about 400%, about 25% to about 500%, about
50% to about 100%, about 50% to about 200%, about 50% to about
300%, about 50% to about 400%, or about 50% to about 500%, relative
to naive CD4.sup.+ CD25.sup.- FoxP3.sup.- cells cultured under Th17
cell differentiation not exposed to the same RXR agonist.
[0068] Aspects of the present specification provide, in part, a RXR
agonist having activity that both promotes Treg cell
differentiation and inhibits Th17 cell differentiation. In aspects
of this embodiment, a RXR agonist promotes Treg cell
differentiation by at least 10%, at least 20%, at least 30%, at
least 40%, at least 50%, at least 60%, at least 70%, at least 80%,
at least 90%, at least 100%, at least 200%, at least 300%, at least
400%, or at least 500% as well as inhibits Th17 cell
differentiation by at least 10%, at least 20%, at least 30%, at
least 40%, at least 50%, at least 60%, at least 70%, at least 80%,
at least 90%, at least 100%, at least 200%, at least 300%, at least
400%, or at least 500%. In other aspects of this embodiment, a RXR
agonist promotes Treg cell differentiation by about 10% to about
25%, about 10% to about 50%, about 10% to about 75%, about 10% to
about 100%, about 10% to about 200%, about 10% to about 300%, about
10% to about 400%, about 10% to about 500%, about 25% to about 50%,
about 25% to about 75%, about 25% to about 100%, about 25% to about
200%, about 25% to about 300%, about 25% to about 400%, about 25%
to about 500%, about 50% to about 100%, about 50% to about 200%,
about 50% to about 300%, about 50% to about 400%, or about 50% to
about 500%, as well as inhibits Th17 cell differentiation by about
10% to about 25%, about 10% to about 50%, about 10% to about 75%,
about 10% to about 100%, about 10% to about 200%, about 10% to
about 300%, about 10% to about 400%, about 10% to about 500%, about
25% to about 50%, about 25% to about 75%, about 25% to about 100%,
about 25% to about 200%, about 25% to about 300%, about 25% to
about 400%, about 25% to about 500%, about 50% to about 100%, about
50% to about 200%, about 50% to about 300%, about 50% to about
400%, or about 50% to about 500%.
[0069] In an embodiment, a RXR agonist has activity that results in
increased FoxP3 and/or .alpha.4.beta.7 expression as well as
decreases IL-17A expression in cells exposed to the RXR agonist. In
aspects of this embodiment, a RXR agonist increases FoxP3 and/or
.alpha.4.beta.7 expression in cells by at least 10%, at least 20%,
at least 30%, at least 40%, at least 50%, at least 60%, at least
70%, at least 80%, at least 90%, at least 100%, at least 200%, at
least 300%, at least 400%, or at least 500%, as well as decreases
IL-17A expression in cells by at least 10%, at least 20%, at least
30%, at least 40%, at least 50%, at least 60%, at least 70%, at
least 80%, at least 90%, at least 100%, at least 200%, at least
300%, at least 400%, or at least 500%, relative to cells not
exposed to the same RXR agonist. In other aspects of this
embodiment, a RXR agonist increases FoxP3 and/or .alpha.4.beta.7
expression in cells by about 10% to about 25%, about 10% to about
50%, about 10% to about 75%, about 10% to about 100%, about 10% to
about 200%, about 10% to about 300%, about 10% to about 400%, about
10% to about 500%, about 25% to about 50%, about 25% to about 75%,
about 25% to about 100%, about 25% to about 200%, about 25% to
about 300%, about 25% to about 400%, about 25% to about 500%, about
50% to about 100%, about 50% to about 200%, about 50% to about
300%, about 50% to about 400%, or about 50% to about 500%, as well
as decreases IL-17A expression in cells by about 10% to about 25%,
about 10% to about 50%, about 10% to about 75%, about 10% to about
100%, about 10% to about 200%, about 10% to about 300%, about 10%
to about 400%, about 10% to about 500%, about 25% to about 50%,
about 25% to about 75%, about 25% to about 100%, about 25% to about
200%, about 25% to about 300%, about 25% to about 400%, about 25%
to about 500%, about 50% to about 100%, about 50% to about 200%,
about 50% to about 300%, about 50% to about 400%, or about 50% to
about 500%, relative to cells not exposed to the same RXR
agonist.
[0070] In another aspect of this embodiment, a RXR agonist has
activity that results in increased FoxP3 and/or .alpha.4.beta.7
expression in naive CD4.sup.+ CD25.sup.- FoxP3.sup.- cells cultured
under Treg cell differentiation conditions as well as decreases
IL-17A expression in naive CD4.sup.+ CD25.sup.- FoxP3.sup.- cells
cultured under Th17 cell differentiation conditions. In other
aspects of this embodiment, a RXR agonist increases FoxP3 and/or
.alpha.4.beta.7 expression in naive CD4.sup.+ CD25.sup.-
FoxP3.sup.- cells cultured under Treg cell differentiation by at
least 10%, at least 20%, at least 30%, at least 40%, at least 50%,
at least 60%, at least 70%, at least 80%, at least 90%, at least
100%, at least 200%, at least 300%, at least 400%, or at least
500%, relative to naive CD4.sup.+ CD25.sup.- FoxP3.sup.- cells
cultured under Treg cell differentiation not exposed to the same
RXR agonist as well as decreases IL-17A expression in naive
CD4.sup.+ CD25.sup.- FoxP3.sup.- cells cultured under Th17 cell
differentiation by at least 10%, at least 20%, at least 30%, at
least 40%, at least 50%, at least 60%, at least 70%, at least 80%,
at least 90%, at least 100%, at least 200%, at least 300%, at least
400%, or at least 500%, relative to naive CD4.sup.+ CD25.sup.-
FoxP3.sup.- cells cultured under Th17 cell differentiation not
exposed to the same RXR agonist.
[0071] In yet other aspects of this embodiment, a RXR agonist
increases FoxP3 and/or .alpha.4.beta.7 expression in naive
CD4.sup.+ CD25.sup.- FoxP3.sup.- cells cultured under Treg cell
differentiation by about 10% to about 25%, about 10% to about 50%,
about 10% to about 75%, about 10% to about 100%, about 10% to about
200%, about 10% to about 300%, about 10% to about 400%, about 10%
to about 500%, about 25% to about 50%, about 25% to about 75%,
about 25% to about 100%, about 25% to about 200%, about 25% to
about 300%, about 25% to about 400%, about 25% to about 500%, about
50% to about 100%, about 50% to about 200%, about 50% to about
300%, about 50% to about 400%, or about 50% to about 500%, relative
to naive CD4.sup.+ CD25.sup.- FoxP3.sup.- cells cultured under Treg
cell differentiation not exposed to the same RXR agonist as well as
decreases IL-17A expression in naive CD4.sup.+ CD25.sup.-
FoxP3.sup.- cells cultured under Th17 cell differentiation by about
10% to about 25%, about 10% to about 50%, about 10% to about 75%,
about 10% to about 100%, about 10% to about 200%, about 10% to
about 300%, about 10% to about 400%, about 10% to about 500%, about
25% to about 50%, about 25% to about 75%, about 25% to about 100%,
about 25% to about 200%, about 25% to about 300%, about 25% to
about 400%, about 25% to about 500%, about 50% to about 100%, about
50% to about 200%, about 50% to about 300%, about 50% to about
400%, or about 50% to about 500%, relative to naive CD4.sup.+
CD25.sup.- FoxP3.sup.- cells cultured under Th17 cell
differentiation not exposed to the same RXR agonist.
[0072] Aspects of the present specification provide, in part, a
composition comprising a RXR agonist. A RXR agonist includes the
compounds disclosed herein. The compositions disclosed herein may,
or may not, comprise any number and combination of compounds
disclosed herein. For instance, a composition can comprise, e.g.,
two or more compounds disclosed herein, three or more compounds
disclosed herein, four or more compounds disclosed herein, or five
or more compounds disclosed herein.
[0073] A compound disclosed herein, or a composition comprising
such a compound, is generally administered to an individual as a
pharmaceutical composition. Pharmaceutical compositions may be
prepared by combining a therapeutically effective amount of at
least one compound as disclosed herein, or a pharmaceutically
acceptable acid addition salt thereof, as an active ingredient,
with conventional acceptable pharmaceutical excipients, and by
preparation of unit dosage forms suitable for therapeutic use. As
used herein, the term "pharmaceutical composition" and refers to a
therapeutically effective concentration of an active compound, such
as, e.g., any of the compounds disclosed herein. Preferably, the
pharmaceutical composition does not produce an adverse, allergic,
or other untoward or unwanted reaction when administered to an
individual. A pharmaceutical composition disclosed herein is useful
for medical and veterinary applications. A pharmaceutical
composition may be administered to an individual alone, or in
combination with other supplementary active compounds, agents,
drugs or hormones. The pharmaceutical compositions may be
manufactured using any of a variety of processes, including,
without limitation, conventional mixing, dissolving, granulating,
dragee-making, levigating, emulsifying, encapsulating, entrapping,
and lyophilizing. The pharmaceutical composition can take any of a
variety of forms including, without limitation, a sterile solution,
suspension, emulsion, lyophilizate, tablet, pill, pellet, capsule,
powder, syrup, elixir, or any other dosage form suitable for
administration.
[0074] A pharmaceutical composition produced using the methods
disclosed herein may be a liquid formulation, semi-solid
formulation, or a solid formulation. A formulation disclosed herein
can be produced in a manner to form one phase, such as, e.g., an
oil or a solid. Alternatively, a formulation disclosed herein can
be produced in a manner to form two phase, such as, e.g., an
emulsion. A pharmaceutical composition disclosed herein intended
for such administration may be prepared according to any method
known to the art for the manufacture of pharmaceutical
compositions.
[0075] Liquid formulations suitable for parenteral injection may
comprise physiologically acceptable sterile aqueous or nonaqueous
solutions, dispersions, suspensions or emulsions and sterile
powders for reconstitution into sterile injectable solutions or
dispersions. Examples of suitable aqueous and nonaqueous carriers,
diluents, solvents or vehicles include water, ethanol, polyols
(propylene glycol, polyethyleneglycol (PEG), glycerol, and the
like), suitable mixtures thereof, vegetable oils (such as olive
oil) and injectable organic esters such as ethyl oleate. Proper
fluidity can be maintained, for example, by the use of a coating
such as lecithin, by the maintenance of the required particle size
in the case of dispersions and by the use of surfactants.
[0076] Semi-solid formulations suitable for topical administration
include, without limitation, ointments, creams, salves, and gels.
In such solid formulations, the active compound may be admixed with
at least one inert customary excipient (or carrier) such as, a
lipid and/or polyethylene glycol.
[0077] Solid formulations suitable for oral administration include
capsules, tablets, pills, powders and granules. In such solid
formulations, the active compound may be admixed with at least one
inert customary excipient (or carrier) such as sodium citrate or
dicalcium phosphate or (a) fillers or extenders, as for example,
starches, lactose, sucrose, glucose, mannitol and silicic acid, (b)
binders, as for example, carboxymethylcellulose, alignates,
gelatin, polyvinylpyrrolidone, sucrose and acacia, (c) humectants,
as for example, glycerol, (d) disintegrating agents, as for
example, agar-agar, calcium carbonate, potato or tapioca starch,
alginic acid, certain complex silicates and sodium carbonate, (e)
solution retarders, as for example, paraffin, (f) absorption
accelerators, as for example, quaternary ammonium compounds, (g)
wetting agents, as for example, cetyl alcohol and glycerol
monostearate, (h) adsorbents, as for example, kaolin and bentonite,
and (i) lubricants, as for example, talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate or mixtures thereof. In the case of capsules, tablets and
pills, the dosage forms may also comprise buffering agents.
[0078] In liquid and semi-solid formulations, a concentration of a
therapeutic compound disclosed herein typically may be between
about 50 mg/mL to about 1,000 mg/mL. In aspects of this embodiment,
a therapeutically effective amount of a therapeutic compound
disclosed herein may be from, e.g., about 50 mg/mL to about 100
mg/mL, about 50 mg/mL to about 200 mg/mL, about 50 mg/mL to about
300 mg/mL, about 50 mg/mL to about 400 mg/mL, about 50 mg/mL to
about 500 mg/mL, about 50 mg/mL to about 600 mg/mL, about 50 mg/mL
to about 700 mg/mL, about 50 mg/mL to about 800 mg/mL, about 50
mg/mL to about 900 mg/mL, about 50 mg/mL to about 1,000 mg/mL,
about 100 mg/mL to about 200 mg/mL, about 100 mg/mL to about 300
mg/mL, about 100 mg/mL to about 400 mg/mL, about 100 mg/mL to about
500 mg/mL, about 100 mg/mL to about 600 mg/mL, about 100 mg/mL to
about 700 mg/mL, about 100 mg/mL to about 800 mg/mL, about 100
mg/mL to about 900 mg/mL, about 100 mg/mL to about 1,000 mg/mL,
about 200 mg/mL to about 300 mg/mL, about 200 mg/mL to about 400
mg/mL, about 200 mg/mL to about 500 mg/mL, about 200 mg/mL to about
600 mg/mL, about 200 mg/mL to about 700 mg/mL, about 200 mg/mL to
about 800 mg/mL, about 200 mg/mL to about 900 mg/mL, about 200
mg/mL to about 1,000 mg/mL, about 300 mg/mL to about 400 mg/mL,
about 300 mg/mL to about 500 mg/mL, about 300 mg/mL to about 600
mg/mL, about 300 mg/mL to about 700 mg/mL, about 300 mg/mL to about
800 mg/mL, about 300 mg/mL to about 900 mg/mL, about 300 mg/mL to
about 1,000 mg/mL, about 400 mg/mL to about 500 mg/mL, about 400
mg/mL to about 600 mg/mL, about 400 mg/mL to about 700 mg/mL, about
400 mg/mL to about 800 mg/mL, about 400 mg/mL to about 900 mg/mL,
about 400 mg/mL to about 1,000 mg/mL, about 500 mg/mL to about 600
mg/mL, about 500 mg/mL to about 700 mg/mL, about 500 mg/mL to about
800 mg/mL, about 500 mg/mL to about 900 mg/mL, about 500 mg/mL to
about 1,000 mg/mL, about 600 mg/mL to about 700 mg/mL, about 600
mg/mL to about 800 mg/mL, about 600 mg/mL to about 900 mg/mL, or
about 600 mg/mL to about 1,000 mg/mL.
[0079] In semi-solid and solid formulations, an amount of a
therapeutic compound disclosed herein typically may be between
about 0.01% to about 45% by weight. In aspects of this embodiment,
an amount of a therapeutic compound disclosed herein may be from,
e.g., about 0.1% to about 45% by weight, about 0.1% to about 40% by
weight, about 0.1% to about 35% by weight, about 0.1% to about 30%
by weight, about 0.1% to about 25% by weight, about 0.1% to about
20% by weight, about 0.1% to about 15% by weight, about 0.1% to
about 10% by weight, about 0.1% to about 5% by weight, about 1% to
about 45% by weight, about 1% to about 40% by weight, about 1% to
about 35% by weight, about 1% to about 30% by weight, about 1% to
about 25% by weight, about 1% to about 20% by weight, about 1% to
about 15% by weight, about 1% to about 10% by weight, about 1% to
about 5% by weight, about 5% to about 45% by weight, about 5% to
about 40% by weight, about 5% to about 35% by weight, about 5% to
about 30% by weight, about 5% to about 25% by weight, about 5% to
about 20% by weight, about 5% to about 15% by weight, about 5% to
about 10% by weight, about 10% to about 45% by weight, about 10% to
about 40% by weight, about 10% to about 35% by weight, about 10% to
about 30% by weight, about 10% to about 25% by weight, about 10% to
about 20% by weight, about 10% to about 15% by weight, about 15% to
about 45% by weight, about 15% to about 40% by weight, about 15% to
about 35% by weight, about 15% to about 30% by weight, about 15% to
about 25% by weight, about 15% to about 20% by weight, about 20% to
about 45% by weight, about 20% to about 40% by weight, about 20% to
about 35% by weight, about 20% to about 30% by weight, about 20% to
about 25% by weight, about 25% to about 45% by weight, about 25% to
about 40% by weight, about 25% to about 35% by weight, or about 25%
to about 30% by weight.
[0080] A pharmaceutical composition disclosed herein can optionally
include a pharmaceutically acceptable carrier that facilitates
processing of an active compound into pharmaceutically acceptable
compositions. As used herein, the term "pharmaceutically
acceptable" refers to those compounds, materials, compositions,
and/or dosage forms which are, within the scope of sound medical
judgment, suitable for contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem complications commensurate with a reasonable
benefit/risk ratio. As used herein, the term "pharmacologically
acceptable carrier" is synonymous with "pharmacological carrier"
and refers to any carrier that has substantially no long term or
permanent detrimental effect when administered and encompasses
terms such as "pharmacologically acceptable vehicle, stabilizer,
diluent, additive, auxiliary, or excipient." Such a carrier
generally is mixed with an active compound or permitted to dilute
or enclose the active compound and can be a solid, semi-solid, or
liquid agent. It is understood that the active compounds can be
soluble or can be delivered as a suspension in the desired carrier
or diluent. Any of a variety of pharmaceutically acceptable
carriers can be used including, without limitation, aqueous media
such as, e.g., water, saline, glycine, hyaluronic acid and the
like; solid carriers such as, e.g., starch, magnesium stearate,
mannitol, sodium saccharin, talcum, cellulose, glucose, sucrose,
lactose, trehalose, magnesium carbonate, and the like; solvents;
dispersion media; coatings; antibacterial and antifungal agents;
isotonic and absorption delaying agents; or any other inactive
ingredient. Selection of a pharmacologically acceptable carrier can
depend on the mode of administration. Except insofar as any
pharmacologically acceptable carrier is incompatible with the
active compound, its use in pharmaceutically acceptable
compositions is contemplated. Non-limiting examples of specific
uses of such pharmaceutical carriers can be found in Pharmaceutical
Dosage Forms and Drug Delivery Systems (Howard C. Ansel et al.,
eds., Lippincott Williams & Wilkins Publishers, 7.sup.th ed.
1999); Remington: The Science and Practice of Pharmacy (Alfonso R.
Gennaro ed., Lippincott, Williams & Wilkins, 20.sup.th ed.
2000); Goodman & Gilman's The Pharmacological Basis of
Therapeutics (Joel G. Hardman et al., eds., McGraw-Hill
Professional, 10.sup.th ed. 2001); and Handbook of Pharmaceutical
Excipients (Raymond C. Rowe et al., APhA Publications, 4.sup.th
edition 2003). These protocols are routine and any modifications
are well within the scope of one skilled in the art and from the
teaching herein.
[0081] A pharmaceutical composition disclosed herein can optionally
include, without limitation, other pharmaceutically acceptable
components (or pharmaceutical components), including, without
limitation, buffers, preservatives, tonicity adjusters, salts,
antioxidants, osmolality adjusting agents, physiological
substances, pharmacological substances, bulking agents, emulsifying
agents, wetting agents, sweetening or flavoring agents, and the
like. Various buffers and means for adjusting pH can be used to
prepare a pharmaceutical composition disclosed herein, provided
that the resulting preparation is pharmaceutically acceptable. Such
buffers include, without limitation, acetate buffers, borate
buffers, citrate buffers, phosphate buffers, neutral buffered
saline, and phosphate buffered saline. It is understood that acids
or bases can be used to adjust the pH of a composition as needed.
Pharmaceutically acceptable antioxidants include, without
limitation, sodium metabisulfite, sodium thiosulfate,
acetylcysteine, butylated hydroxyanisole, and butylated
hydroxytoluene. Useful preservatives include, without limitation,
benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric
acetate, phenylmercuric nitrate, a stabilized oxy chloro
composition, such as, e.g., sodium chlorite and chelants, such as,
e.g., DTPA or DTPA-bisamide, calcium DTPA, and CaNaDTPA-bisamide.
Tonicity adjustors useful in a pharmaceutical composition include,
without limitation, salts such as, e.g., sodium chloride, potassium
chloride, mannitol or glycerin and other pharmaceutically
acceptable tonicity adjustor. The pharmaceutical composition may be
provided as a salt and can be formed with many acids, including but
not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric,
malic, succinic, etc. Salts tend to be more soluble in aqueous or
other protonic solvents than are the corresponding free base forms.
It is understood that these and other substances known in the art
of pharmacology can be included in a pharmaceutical composition
useful in the invention.
[0082] A compound disclosed herein, or a composition comprising
such a compound, may also be incorporated into a drug delivery
platform in order to achieve a controlled compound release profile
over time. Such a drug delivery platform comprises a compound
disclosed herein dispersed within a polymer matrix, typically a
biodegradable, bioerodible, and/or bioresorbable polymer matrix. As
used herein, the term "polymer" refers to synthetic homo- or
copolymers, naturally occurring homo- or copolymers, as well as
synthetic modifications or derivatives thereof having a linear,
branched or star structure. Copolymers can be arranged in any form,
such as, e.g., random, block, segmented, tapered blocks, graft, or
triblock. Polymers are generally condensation polymers. Polymers
can be further modified to enhance their mechanical or degradation
properties by introducing cross-linking agents or changing the
hydrophobicity of the side residues. If crosslinked, polymers are
usually less than 5% crosslinked, usually less than 1%
crosslinked.
[0083] Suitable polymers include, without limitation, alginates,
aliphatic polyesters, polyalkylene oxalates, polyamides,
polyamidoesters, polyanhydrides, polycarbonates, polyesters,
polyethylene glycol, polyhydroxyaliphatic carboxylic acids,
polyorthoesters, polyoxaesters, polypeptides, polyphosphazenes,
polysaccharides, and polyurethanes. The polymer usually comprises
at least about 10% (w/w), at least about 20% (w/w), at least about
30% (w/w), at least about 40% (w/w), at least about 50% (w/w), at
least about 60% (w/w), at least about 70% (w/w), at least about 80%
(w/w), or at least about 90% (w/w) of the drug delivery platform.
Examples of biodegradable, bioerodible, and/or bioresorbable
polymers and methods useful to make a drug delivery platform are
described in, e.g., Drost, et. al., Controlled Release Formulation,
U.S. Pat. No. 4,756,911; Smith, et. al., Sustained Release Drug
Delivery Devices, U.S. Pat. No. 5,378,475; Wong and Kochinke,
Formulation for Controlled Release of Drugs by Combining Hyrophilic
and Hydrophobic Agents, U.S. Pat. No. 7,048,946; Hughes, et. al.,
Compositions and Methods for Localized Therapy of the Eye, U.S.
Patent Publication 2005/0181017; Hughes, Hypotensive
Lipid-Containing Biodegradable Intraocular Implants and Related
Methods, U.S. Patent Publication 2005/0244464; Altman, et al., Silk
Fibroin Hydrogels and Uses Thereof, U.S. Patent Publication
2011/0008437; each of which is incorporated by reference in its
entirety.
[0084] In aspects of this embodiment, a polymer composing the
matrix is a polypeptide such as, e.g., silk fibroin, keratin, or
collagen. In other aspects of this embodiment, a polymer composing
the matrix is a polysaccharide such as, e.g., cellulose, agarose,
elastin, chitosan, chitin, or a glycosaminoglycan like chondroitin
sulfate, dermatan sulfate, keratan sulfate, or hyaluronic acid. In
yet other aspects of this embodiment, a polymer composing the
matrix is a polyester such as, e.g., D-lactic acid, L-lactic acid,
racemic lactic acid, glycolic acid, caprolactone, and combinations
thereof.
[0085] One of ordinary skill in the art appreciates that the
selection of a suitable polymer for forming a suitable disclosed
drug delivery platform depends on several factors. The more
relevant factors in the selection of the appropriate polymer(s),
include, without limitation, compatibility of polymer with drug,
desired release kinetics of drug, desired biodegradation kinetics
of platform at implantation site, desired bioerodible kinetics of
platform at implantation site, desired bioresorbable kinetics of
platform at implantation site, in vivo mechanical performance of
platform, processing temperatures, biocompatibility of platform,
and patient tolerance. Other relevant factors that, to some extent,
dictate the in vitro and in vivo behavior of the polymer include
the chemical composition, spatial distribution of the constituents,
the molecular weight of the polymer and the degree of
crystallinity.
[0086] A drug delivery platform includes both a sustained release
drug delivery platform and an extended release drug delivery
platform. As used herein, the term "sustained release" refers to
the release of a compound disclosed herein over a period of about
seven days or more. As used herein, the term "extended release"
refers to the release of a compound disclosed herein over a period
of time of less than about seven days.
[0087] In aspects of this embodiment, a sustained release drug
delivery platform releases a compound disclosed herein with
substantially first order release kinetics over a period of, e.g.,
about 7 days after administration, about 15 days after
administration, about 30 days after administration, about 45 days
after administration, about 60 days after administration, about 75
days after administration, or about 90 days after administration.
In other aspects of this embodiment, a sustained release drug
delivery platform releases a compound disclosed herein with
substantially first order release kinetics over a period of, e.g.,
at least 7 days after administration, at least 15 days after
administration, at least 30 days after administration, at least 45
days after administration, at least 60 days after administration,
at least 75 days after administration, or at least 90 days after
administration.
[0088] In aspects of this embodiment, a drug delivery platform
releases a compound disclosed herein with substantially first order
release kinetics over a period of, e.g., about 1 day after
administration, about 2 days after administration, about 3 days
after administration, about 4 days after administration, about 5
days after administration, or about 6 days after administration. In
other aspects of this embodiment, a drug delivery platform releases
a compound disclosed herein with substantially first order release
kinetics over a period of, e.g., at most 1 day after
administration, at most 2 days after administration, at most 3 days
after administration, at most 4 days after administration, at most
5 days after administration, or at most 6 days after
administration.
[0089] Aspects of the present invention provide, in part, an
autoimmune disorder. An autoimmune disorder arises from an
overactive immune response of the body against substances and
tissues normally present in the body resulting in a break in
tolerance toward self-antigens. In other words, the body actually
attacks its own cells because the immune system mistakes some part
of the body as a pathogen and attacks it. Characterized by the
development of pathogenic T cell populations infiltrating the
target organ or tissue, autoimmune disorders may be restricted to
certain organs or involve a particular tissue in different
places.
[0090] Autoimmune diseases can be broadly divided into systemic and
organ-specific autoimmune disorders, depending on the principal
clinico-pathologic features of each disease. Systemic autoimmune
diseases include, without limitation, systemic lupus erythematosus
(SLE), Sjogren's syndrome, Scleroderma, rheumatoid arthritis and
polymyositis. Local autoimmune diseases may be endocrinologic
(Diabetes Mellitus Type 1, Hashimoto's thyroiditis, Addison's
disease etc.), dermatologic (pemphigus vulgaris), hematologic
(autoimmune haemolytic anemia), neural (multiple sclerosis) or can
involve virtually any circumscribed mass of body tissue.
Non-limiting examples of an autoimmune disorder that can be treated
using a compound or a composition disclosed herein include an acute
disseminated encephalomyelitis (ADEM), an Addison's disease, an
allergy, allergic rhinitis, an Alzheimer's disease, an
anti-phospholipid antibody syndrome (APS), an arthritis such as,
e.g., a monoarthritis, an oligoarthritis, or a polyarthritis like
an osteoarthritis, a rheumatoid arthritis, a juvenile idiopathic
arthritis, a septic arthritis, a spondyloarthropathy, a gout, a
pseudogout, or Still's disease, an asthma, an autoimmune deficiency
syndrome (AIDS), an autoimmune hemolytic anemia, an autoimmune
hepatitis, an autoimmune inner ear disease, a bullous pemphigoid, a
celiac disease, a Chagas disease, a chronic obstructive pulmonary
disease (COPD), a diabetes mellitus type 1 (IDDM), an
endometriosis, a gastrointestinal disorder such as, e.g., an
irritable bowel disease or an inflammatory bowel disease like
Crohn's disease or an ulcerative colitis, a Goodpasture's syndrome,
a Graves' disease, a Guillain-Barre syndrome (GBS), a Hashimoto's
thyroiditis, a hidradenitis suppurativa, an idiopathic
thrombocytopenic purpura, an interstitial cystitis, a lupus, such
as, e.g., a discoid lupus erythematosus, a drug-induced lupus
erythematosus. a lupus nephritis, a neonatal lupus, a subacute
cutaneous lupus erythematosus, or a systemic lupus erythematosus, a
morphea, a multiple sclerosis (MS), a myasthenia gravis, a myopathy
such as, e.g., a dermatomyositis, an inclusion body myositis, or a
polymyositis, a myositis, a narcolepsy, a neuromyotonia, a
Parkinson's disease, a pemphigus vulgaris, a pernicious anaemia, a
primary biliary cirrhosis, a psoriasis, a recurrent disseminated
encephalomyelitis, a rheumatic fever, a schizophrenia, a
scleroderma, a Sjogren's syndrome, a skin disorder such as, e.g.,
dermatitis, an eczema, a statis dermatitis, a hidradenitis
suppurativa, a psoriasis, a rosacea or a scleroderma, a
tenosynovitis, a uveitis, vasculitis such as, e.g., a Buerger's
disease, a cerebral vasculitis, a Churg-Strauss arteritis, a
cryoglobulinemia, an essential cryoglobulinemic vasculitis, a giant
cell arteritis, a Golfers vasculitis, a Henoch-Schonlein purpura, a
hypersensitivity vasculitis, a Kawasaki disease, a microscopic
polyarteritis/polyangiitis, a polyarteritis nodosa, a polymyalgia
rheumatica (PMR), a rheumatoid vasculitis, a Takayasu arteritis, or
a Wegener's granulomatosis, or a vitiligo. See Pamela D. Van
Schaack & Kenneth L. Tong, Treatment of Autoimmune Disorder
with a Neurotoxin, U.S. Patent Publication 2006/138059, which is
hereby incorporated by reference in its entirety.
[0091] One type of autoimmune disorder is an arthritis. Arthritis
includes a group of conditions involving damage to the joints of
the body due to the inflammation of the synovium including, without
limitation osteoarthritis, rheumatoid arthritis, juvenile
idiopathic arthritis, spondyloarthropathies like ankylosing
spondylitis, reactive arthritis (Reiter's syndrome), psoriatic
arthritis, enteropathic arthritis associated with inflammatory
bowel disease, Whipple's disease and Behcet's disease, septic
arthritis, gout (also known as gouty arthritis, crystal synovitis,
metabolic arthritis), pseudogout (calcium pyrophosphate deposition
disease), and Still's disease. Arthritis can affect a single joint
(monoarthritis), two to four joints (oligoarthritis) or five or
more joints (polyarthritis) and can be either an auto-immune
disease or a non-autoimmune disease.
[0092] Another type of autoimmune disorder is a myopathy.
Myopathies are caused by problems with the immune system attacking
components of the muscle, leading to signs of inflammation in the
muscle Inflammatory myopathies include, without limitation,
dermatomyositis, inclusion body myositis, and polymyositis.
[0093] Another type of autoimmune disorder is a vasculitis.
Vasculitis is a varied group of disorders featuring inflammation of
a vessel wall including lymphatic vessels and blood vessels like
veins (phlebitis), arteries (arteritis) and capillaries due to
leukocyte migration and resultant damage. The inflammation may
affect any size blood vessel, anywhere in the body. It may affect
either arteries and/or veins. The inflammation may be focal,
meaning that it affects a single location within a vessel; or it
may be widespread, with areas of inflammation scattered throughout
a particular organ or tissue, or even affecting more than one organ
system in the body. Vasculitis include, without limitation,
Buerger's disease (thromboangiitis obliterans), cerebral vasculitis
(central nervous system vasculitis), Churg-Strauss arteritis,
cryoglobulinemia, essential cryoglobulinemic vasculitis, giant cell
(temporal) arteritis, Golfers vasculitis, Henoch-Schonlein purpura,
hypersensitivity vasculitis (allergic vasculitis), Kawasaki
disease, microscopic polyarteritis/polyangiitis, polyarteritis
nodosa, polymyalgia rheumatica (PMR), rheumatoid vasculitis,
Takayasu arteritis, Wegener's granulomatosis, and vasculitis
secondary to connective tissue disorders like systemic lupus
erythematosus (SLE), rheumatoid arthritis (RA), relapsing
polychondritis, Behcet's disease, or other connective tissue
disorders, vasculitis secondary to viral infection.
[0094] Another type of autoimmune disorder is a skin disorder. Skin
disorders include, without limitation, a dermatitis, including
chronic actinic dermatitis, an eczema like atopic eczema, contact
eczema, xerotic eczema, seborrhoeic dermatitis, dyshidrosis,
discoid eczema, venous eczema, dermatitis herpetiformis,
neurodermatitis, and autoeczematization, and statis dermatitis,
hidradenitis suppurativa, psoriasis including plaqure psoriasis,
nail psoriasis, guttate psoriasis, scalp psoriasis, inverse
psoriasis, pustular psoriasis, and erythrodermis psoriasis, rosacea
and scleroderma including morphea.
[0095] Another type of autoimmune disorder is a gastrointestinal
disorder. A gastrointestinal disorder includes, without limitation,
irritable bowel disease, an inflammatory bowel disease including
Crohn's disease and an ulcerative colitis like ulcerative
proctitis, left-sided colitis, pancolitis and fulminant
colitis.
[0096] Aspects of the present invention provide, in part, a
transplant rejection. Transplant rejection occurs when a
transplanted organ or tissue is not accepted by the body of the
transplant recipient because the immune system of the recipient
attacks the transplanted organ or tissue. An adaptive immune
response, transplant rejection is mediated through both T cell
mediated and humoral immune (antibodies) mechanisms. The number of
mismatched alleles determines the speed and magnitude of the
rejection response. Different mechanisms tend to act against
different transplants.
[0097] A transplant rejection can be classified as a hyperacute
rejection, an acute rejection, or a chronic rejection. Hyperacute
rejection is a complement-mediated response in recipients with
pre-existing antibodies to the donor (for example, ABO blood type
antibodies). Hyperacute rejection occurs within minutes after the
transplant and must be immediately removed to prevent a severe
systemic inflammatory response. Rapid agglutination of the blood
occurs.
[0098] Acute rejection may begin as early as one week after
transplantation (as opposed to hyperacute rejection, which is
immediate). The risk of acute rejection is highest in the first
three months after transplantation. However, acute rejection can
also occur months to years after transplantation. The reason that
acute rejection usually begins one week after transplantation is
that T-cells are involved in the rejection mechanism. These T-cells
must differentiate before rejection begins. The T-cells cause cells
in the transplanted tissue to lyse, or produce cytokines that cause
necrosis of the transplanted tissue. A single episode of acute
rejection is not a cause for concern if recognized and treated
promptly, and rarely leads to organ failure. Acute rejection occurs
to some degree in all transplants (except those between identical
twins) unless the immune response in altered through the use of
immunosuppressive drugs. It is caused by mismatched HLA, which are
present on all cells of the body. There are a large number of
different alleles of each HLA, so a perfect match between all HLA
in the donor tissue and the recipient's body is extremely rare.
[0099] Chronic rejection of a transplanted organ or tissue is where
the rejection is due to a poorly understood chronic inflammatory
and immune response against the transplanted tissue. Chronic
rejection after lung transplantation is the leading cause of
long-term morbidity and mortality in lung transplant patients
[0100] Also included in the term "transplant rejection" is a
graft-versus-host disease (GVHD). GVHD is a common complication of
allogeneic bone marrow transplantation in which functional immune
cells in the transplanted marrow recognize the recipient as
"foreign" and mount an immunologic attack. It can also take place
in a blood transfusion under certain circumstances. GVHD is divided
into acute and chronic forms. The acute or fulminant form of the
disease (aGVHD) is normally observed within the first 100 days
post-transplant,[2] and is a major challenge to transplants owing
to associated morbidity and mortality. The chronic form of
graft-versus-host-disease (cGVHD) normally occurs after 100 days.
The appearance of moderate to severe cases of cGVHD adversely
influences long-term survival. Acute and chronic GVHD appear to
involve different immune cell subsets, different cytokine profiles,
somewhat different host targets, and respond differently to
treatment.
[0101] Acute GVHD is characterized by selective damage to the
liver, skin and mucosa, gastrointestinal tract, immune system (the
hematopoietic system, e.g., the bone marrow and the thymus) itself,
and the lungs in the form of idiopathic pneumonitis. Acute GVHD of
the GI tract can result in severe intestinal inflammation,
sloughing of the mucosal membrane, severe diarrhea, abdominal pain,
nausea, and vomiting. This is typically diagnosed via intestinal
biopsy. Liver GVHD is measured by the bilirubin level in acute
patients. Skin GVHD results in a diffuse maculopapular rash,
sometimes in a lacy pattern. Acute GVHD is staged as follows:
overall grade (skin-liver-gut) with each organ staged individually
from a low of 1 to a high of 4. Patients with grade IV GVHD usually
have a poor prognosis. If the GVHD is severe and requires intense
immunosuppression involving steroids and additional agents to get
under control, the patient may develop severe infections as a
result of the immunosuppression and may die of infection. Chronic
GVHD also attacks the above organs, but over its long-term course
can also cause damage to the connective tissue and exocrine
glands.
[0102] Aspects of the present invention provide, in part, reducing
a symptom associated with an autoimmune disorder or transplant
rejection. The actual symptoms associated with an autoimmune
disorder or transplant rejection disclosed herein are well known
and can be determined by a person of ordinary skill in the art by
taking into account factors, including, without limitation, the
location of the autoimmune disorder or transplant rejection, the
cause of the autoimmune disorder or transplant rejection, the
severity of the autoimmune disorder or transplant rejection, the
tissue or organ affected by the autoimmune disorder or transplant
rejection, and the autoimmune disorder or transplant rejection
associated with the inflammation. Non-limiting examples of a
symptom reduced by a method of treating an autoimmune disorder or
transplant rejection disclosed herein include inflammation,
fatigue, dizziness, malaise, elevated fever and high body
temperature, extreme sensitivity to cold in the hands and feet,
weakness and stiffness in muscles and joints, weight changes,
digestive or gastrointestinal problems, low or high blood pressure,
irritability, anxiety, or depression, infertility or reduced sex
drive (low libido), blood sugar changes, and depending on the type
of autoimmune disorder or transplant rejection, an increase in the
size of an organ or tissue, or the destruction of an organ or
tissue. Non-limiting examples of an inflammation symptom reduced by
a method of treating an autoimmune disorder disclosed herein
include edema, hyperemia, erythema, bruising, tenderness,
stiffness, swollenness, fever, a chill, congestion of the
respiratory tract including nose and/or bronchi, congestion of a
sinus, a breathing problem, fluid retention, a blood clot, a loss
of appetite, an increased heart rate, a formation of granulomas,
fibrinous, pus, or non-viscous serous fluid, a formation of an
ulcer, or pain.
[0103] Aspects of the present invention provide, in part, a mammal.
A mammal includes a human, and a human can be a patient. Other
aspects of the present invention provide, in part, an individual.
An individual includes a mammal and a human, and a human can be a
patient.
[0104] Aspects of the present invention provide, in part,
administering a compound or a composition disclosed herein. As used
herein, the term "administering" means any delivery mechanism that
provides a compound or a composition disclosed herein to an
individual that potentially results in a clinically,
therapeutically, or experimentally beneficial result.
[0105] Administration of a compound or a composition disclosed
herein include a variety of enteral or parenteral approaches
including, without limitation, oral administration in any
acceptable form, such as, e.g., tablet, liquid, capsule, powder, or
the like; topical administration in any acceptable form, such as,
e.g., drops, spray, creams, gels or ointments; buccal, nasal,
and/or inhalation administration in any acceptable form; rectal
administration in any acceptable form; vaginal administration in
any acceptable form; intravascular administration in any acceptable
form, such as, e.g., intravenous bolus injection, intravenous
infusion, intra-arterial bolus injection, intra-arterial infusion
and catheter instillation into the vasculature; peri- and
intra-tissue administration in any acceptable form, such as, e.g.,
intraperitoneal injection, intramuscular injection, subcutaneous
injection, subcutaneous infusion, intraocular injection, retinal
injection, or sub-retinal injection or epidural injection;
intravesicular administration in any acceptable form, such as,
e.g., catheter instillation; and by placement device, such as,
e.g., an implant, a stent, a patch, a pellet, a catheter, an
osmotic pump, a suppository, a bioerodible delivery system, a
non-bioerodible delivery system or another implanted extended or
slow release system. An exemplary list of biodegradable polymers
and methods of use are described in, e.g., Handbook of
Biodegradable Polymers (Abraham J. Domb et al., eds., Overseas
Publishers Association, 1997).
[0106] A compound or a composition disclosed herein can be
administered to a mammal using a variety of routes. Routes of
administration suitable for treating an autoimmune disorder or
transplant rejection as disclosed herein include both local and
systemic administration. Local administration results in
significantly more delivery of a composition to a specific location
as compared to the entire body of the mammal, whereas, systemic
administration results in delivery of a composition to essentially
the entire body of the individual. Routes of administration
suitable for or treating an autoimmune disorder or transplant
rejection as disclosed herein also include both central and
peripheral administration. Central administration results in
delivery of a compound or a composition to essentially the central
nervous system of the individual and includes, e.g., intrathecal
administration, epidural administration as well as a cranial
injection or implant. Peripheral administration results in delivery
of a compound or a composition to essentially any area of an
individual outside of the central nervous system and encompasses
any route of administration other than direct administration to the
spine or brain. The actual route of administration of a compound or
a composition disclosed herein used can be determined by a person
of ordinary skill in the art by taking into account factors,
including, without limitation, the type of an autoimmune disorder
or transplant rejection, the location of the autoimmune disorder or
transplant rejection, the cause of the autoimmune disorder or
transplant rejection, the severity of the autoimmune disorder or
transplant rejection, the duration of treatment desired, the degree
of relief desired, the duration of relief desired, the particular
compound or composition used, the rate of excretion of the compound
or composition used, the pharmacodynamics of the compound or
composition used, the nature of the other compounds to be included
in the composition, the particular route of administration, the
particular characteristics, history and risk factors of the
individual, such as, e.g., age, weight, general health and the
like, the response of the individual to the treatment, or any
combination thereof. An effective dosage amount of a compound or a
composition disclosed herein can thus readily be determined by the
person of ordinary skill in the art considering all criteria and
utilizing his best judgment on the individual's behalf.
[0107] In an embodiment, a compound or a composition disclosed
herein is administered systemically to a mammal. In another
embodiment, a compound or a composition disclosed herein is
administered locally to a mammal. In an aspect of this embodiment,
a compound or a composition disclosed herein is administered to a
site of autoimmune disorder or transplant rejection of a mammal. In
another aspect of this embodiment, a compound or a composition
disclosed herein is administered to the area surrounding an
autoimmune disorder or transplant rejection of a mammal.
[0108] Aspects of the present specification provide, in part,
administering a therapeutically effective amount of a compound or a
composition disclosed herein. As used herein, the term
"therapeutically effective amount" is synonymous with
"therapeutically effective dose" and when used in reference to
treating an autoimmune disorder means the minimum dose of a
compound or composition disclosed herein necessary to achieve the
desired therapeutic effect and includes a dose sufficient to reduce
a symptom associated with an autoimmune disorder or transplant
rejection. In aspects of this embodiment, a therapeutically
effective amount of a compound or a composition disclosed herein
reduces a symptom associated with an autoimmune disorder or
transplant rejection by, e.g., at least 10%, at least 20%, at least
30%, at least 40%, at least 50%, at least 60%, at least 70%, at
least 80%, at least 90% or at least 100%. In other aspects of this
embodiment, a therapeutically effective amount of a compound or a
composition disclosed herein reduces a symptom associated with an
autoimmune disorder or transplant rejection by, e.g., at most 10%,
at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, at
most 70%, at most 80%, at most 90% or at most 100%. In yet other
aspects of this embodiment, a therapeutically effective amount of a
compound or a composition disclosed herein reduces a symptom
associated with an autoimmune disorder or transplant rejection by,
e.g., about 10% to about 100%, about 10% to about 90%, about 10% to
about 80%, about 10% to about 70%, about 10% to about 60%, about
10% to about 50%, about 10% to about 40%, about 20% to about 100%,
about 20% to about 90%, about 20% to about 80%, about 20% to about
20%, about 20% to about 60%, about 20% to about 50%, about 20% to
about 40%, about 30% to about 100%, about 30% to about 90%, about
30% to about 80%, about 30% to about 70%, about 30% to about 60%,
or about 30% to about 50%. In still other aspects of this
embodiment, a therapeutically effective amount of a compound or a
composition disclosed herein is the dosage sufficient to reduces a
symptom associated with an autoimmune disorder or transplant
rejection for, e.g., at least one week, at least one month, at
least two months, at least three months, at least four months, at
least five months, at least six months, at least seven months, at
least eight months, at least nine months, at least ten months, at
least eleven months, or at least twelve months.
[0109] The amount of active component in a compound or a
composition disclosed herein for treating an autoimmune disorder or
transplant rejection can be varied so that a suitable dosage is
obtained. The actual therapeutically effective amount of a compound
or a composition disclosed herein to be administered to a mammal
can be determined by a person of ordinary skill in the art by
taking into account factors, including, without limitation, the
type of the autoimmune disorder or transplant rejection, the
location of the autoimmune disorder or transplant rejection, the
cause of the autoimmune disorder or transplant rejection, the
severity of the autoimmune disorder or transplant rejection, the
duration of treatment desired, the degree of relief desired, the
duration of relief desired, the particular compound or composition
used, the rate of excretion of the compound or composition used,
the pharmacodynamics of the compound or composition used, the
nature of the other compounds to be included in the composition,
the particular route of administration, the particular
characteristics, history and risk factors of the individual, such
as, e.g., age, weight, general health and the like, the response of
the individual to the treatment, or any combination thereof. An
effective dosage amount of a compound or a composition disclosed
herein can thus readily be determined by the person of ordinary
skill in the art considering all criteria and utilizing his best
judgment on the individual's behalf.
[0110] Additionally, where repeated administration of a compound or
a composition disclosed herein is used, the actual effect amount of
a compound or a composition disclosed herein will further depend
upon factors, including, without limitation, the frequency of
administration, the half-life of the compound or composition
disclosed herein, or any combination thereof. In is known by a
person of ordinary skill in the art that an effective amount of a
compound or a composition disclosed herein can be extrapolated from
in vitro assays and in vivo administration studies using animal
models prior to administration to humans. Wide variations in the
necessary effective amount are to be expected in view of the
differing efficiencies of the various routes of administration. For
instance, oral administration generally would be expected to
require higher dosage levels than administration by intravenous or
intravitreal injection. Variations in these dosage levels can be
adjusted using standard empirical routines of optimization, which
are well-known to a person of ordinary skill in the art. The
precise therapeutically effective dosage levels and patterns are
preferably determined by the attending physician in consideration
of the above-identified factors.
[0111] As a non-limiting example, when administering a compound or
a composition disclosed herein to a mammal, a therapeutically
effective amount generally is in the range of about 0.001 mg/kg/day
to about 100.0 mg/kg/day. In aspects of this embodiment, an
effective amount of a compound or a composition disclosed herein
can be, e.g., about 0.01 mg/kg/day to about 0.1 mg/kg/day, about
0.03 mg/kg/day to about 3.0 mg/kg/day, about 0.1 mg/kg/day to about
3.0 mg/kg/day, or about 0.3 mg/kg/day to about 3.0 mg/kg/day. In
yet other aspects of this embodiment, a therapeutically effective
amount of a compound or a composition disclosed herein can be,
e.g., at least 0.001 mg/kg/day, at least 0.01 mg/kg/day, at least
0.1 mg/kg/day, at least 1.0 mg/kg/day, at least 10 mg/kg/day, or at
least 100 mg/kg/day. In yet other aspects of this embodiment, a
therapeutically effective amount of a compound or a composition
disclosed herein can be, e.g., at most 0.001 mg/kg/day, at most
0.01 mg/kg/day, at most 0.1 mg/kg/day, at most 1.0 mg/kg/day, at
most 10 mg/kg/day, or at most 100 mg/kg/day.
[0112] As another non-limiting example, when administering a
compound or a composition disclosed herein to a mammal, a
therapeutically effective amount generally is in the range of about
0.001 mg/m.sup.2/day to about 100.0 mg/m.sup.2/day. In aspects of
this embodiment, an effective amount of a compound or a composition
disclosed herein can be, e.g., about 0.01 mg/m.sup.2/day to about
0.1 mg/m.sup.2/day, about 0.03 mg/m.sup.2/day to about 3.0
mg/m.sup.2/day, about 0.1 mg/m.sup.2/day to about 3.0
mg/m.sup.2/day, or about 0.3 mg/m.sup.2/day to about 3.0
mg/m.sup.2/day. In yet other aspects of this embodiment, a
therapeutically effective amount of a compound or a composition
disclosed herein can be, e.g., at least 0.001 mg/m.sup.2/day, at
least 0.01 mg/m.sup.2/day, at least 0.1 mg/m.sup.2/day, at least
1.0 mg/m.sup.2/day, at least 10 mg/m.sup.2/day, or at least 100
mg/m.sup.2/day. In yet other aspects of this embodiment, a
therapeutically effective amount of a compound or a composition
disclosed herein can be, e.g., at most 0.001 mg/m.sup.2/day, at
most 0.01 mg/m.sup.2/day, at most 0.1 mg/m.sup.2/day, at most 1.0
mg/m.sup.2/day, at most 10 mg/m.sup.2/day, or at most 100
mg/m.sup.2/day.
[0113] Dosing can be single dosage or cumulative (serial dosing),
and can be readily determined by one skilled in the art. For
instance, treatment of an autoimmune disorder or transplant
rejection may comprise a one-time administration of an effective
dose of a compound or a composition disclosed herein. As a
non-limiting example, an effective dose of a compound or a
composition disclosed herein can be administered once to a mammal,
e.g., as a single injection or deposition at or near the site
exhibiting a symptom of an autoimmune disorder or transplant
rejection or a single oral administration of the compound or a
composition. Alternatively, treatment of an autoimmune disorder or
transplant rejection may comprise multiple administrations of an
effective dose of a compound or a composition disclosed herein
carried out over a range of time periods, such as, e.g., daily,
once every few days, weekly, monthly or yearly. As a non-limiting
example, a compound or a composition disclosed herein can be
administered once or twice weekly to a mammal. The timing of
administration can vary from mammal to mammal, depending upon such
factors as the severity of a mammal's symptoms. For example, an
effective dose of a compound or a composition disclosed herein can
be administered to a mammal once a month for an indefinite period
of time, or until the mammal no longer requires therapy. A person
of ordinary skill in the art will recognize that the condition of
the mammal can be monitored throughout the course of treatment and
that the effective amount of a compound or a composition disclosed
herein that is administered can be adjusted accordingly.
[0114] A compound or a composition disclosed herein as disclosed
herein can also be administered to a mammal in combination with
other therapeutic compounds to increase the overall therapeutic
effect of the treatment. The use of multiple compounds to treat an
indication can increase the beneficial effects while reducing the
presence of side effects.
[0115] Aspects of the present specification may also be described
as follows: [0116] 1. A method of treating an autoimmune disorder,
the method comprising the step of administering to an individual in
need thereof a therapeutically effective amount of a RXR agonist,
wherein administration of the RXR agonist reduces a symptom
associated with the autoimmune disorder, thereby treating the
individual. [0117] 2. A method of treating inflammation as a result
of an autoimmune disorder, the method comprising the step of
administering to an individual in need thereof a therapeutically
effective amount of a RXR agonist, wherein administration of the
compound or composition reduces a symptom associated with
inflammation, thereby treating the individual. [0118] 3. A method
of treating a transplant rejection, the method comprising the step
of administering to an individual in need thereof a therapeutically
effective amount of a RXR agonist, wherein administration of the
RXR agonist reduces a symptom associated with the transplant
rejection, thereby treating the individual. [0119] 4. Use of a RXR
agonist in the manufacture of a medicament in the treatment of an
autoimmune disorder, an inflammation as a result of an autoimmune
disorder, and/or a transplant rejection. [0120] 5. Use of a RXR
agonist to treat an autoimmune disorder, an inflammation as a
result of an autoimmune disorder, or a transplant rejection,
wherein administration of the RXR agonist reduces a symptom
associated with the autoimmune disorder or transplant rejection,
thereby treating the individual. [0121] 6. The method or use
according to any one of embodiments 1-5, wherein the RXR agonist is
a compound having the structure of formula I:
##STR00034##
[0121] wherein Z is a radical shown in Formula II:
##STR00035##
Y is cycloalkyl or cycloalkenyl of 3 to 8 carbons optionally
substituted with one or two R.sup.4 groups, or Y is selected from
phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyridazinyl, pyrimidiyl,
pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, the groups being
optionally substituted with one or two R.sup.4 groups, the divalent
Y radical being substituted by the Z and
--(CR.sup.1.dbd.CR.sup.1.dbd.CR.sup.1.dbd.CR.sup.1)-- groups on
adjacent carbons; R.sup.1 and R.sup.2 independently are H, lower
alkyl or fluoroalkyl; R.sup.3 is hydrogen, lower alkyl, Cl or Br;
R.sup.4 is lower alkyl, fluoroalkyl or halogen, and B is hydrogen,
--COOH or a pharmaceutically acceptable salt thereof, --COOR.sup.8,
--CONR.sup.9R.sup.10, --CH.sub.2OH, --CH.sub.2OR.sup.11,
--CH.sub.2OCOR.sup.11, --CHO, --CH(OR.sup.12).sub.2,
--CHOR.sup.13O, --OCOR.sup.7, --CR.sup.7(OR.sup.12).sub.2,
--CR.sup.7OR.sup.13O, or tri-lower alkylsilyl, where R.sup.7 is an
alkyl, cycloalkyl or alkenyl group, containing 1 to 5 carbons,
R.sup.9 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of
5 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1
to 10 carbons, or R.sup.9 is phenyl or lower alkylphenyl, R.sup.9
and R.sup.10 independently are hydrogen, an alkyl group of 1 to 10
carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower
alkylphenyl, R.sup.11 is lower alkyl, phenyl or lower alkylphenyl,
R.sup.12 is lower alkyl, and R.sup.13 is divalent alkyl radical of
2-5 carbons; and n is 1 or 2. [0122] 7. The method or use according
to any one of embodiments 1-5, wherein the RXR agonist is a
compound having the structure of formula I:
##STR00036##
[0122] wherein Z is a radical shown in Formula II:
##STR00037##
Y is selected from thienyl and furyl, the groups being optionally
with one or two R.sup.4 groups, the divalent Y radical being
substituted by the Z and
--(CR.sup.1.dbd.CR.sup.1.dbd.CR.sup.1.dbd.CR.sup.1)-- groups on
adjacent carbons; R.sup.1 and R.sup.2 independently are H, lower
alkyl or fluoroalkyl; R.sup.3 is hydrogen, lower alkyl, Cl or Br;
R.sup.4 is lower alkyl, fluoroalkyl or halogen, and B is hydrogen,
--COOH or a pharmaceutically acceptable salt thereof, --COOR.sup.8,
--CONR.sup.9R.sup.10, --CH.sub.2OH, --CH.sub.2OR.sup.11,
--CH.sub.2OCOR.sup.11, --CHO, --CH(OR.sup.12).sub.2,
--CHOR.sup.13O, --OCOR.sup.7, --CR.sup.7(OR.sup.12).sub.2,
--CR.sup.7OR.sup.13O, or tri-lower alkylsilyl, where R.sup.7 is an
alkyl, cycloalkyl or alkenyl group, containing 1 to 5 carbons,
R.sup.9 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of
5 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1
to 10 carbons, or R.sup.9 is phenyl or lower alkylphenyl, R.sup.9
and R.sup.10 carbons, or a cycloalkyl groups of 5-10 carbons, or
phenyl or lower alkylphenyl, R.sup.11 is lower alkyl, phenyl or
lower alkylphenyl, R.sup.12 is lower alkyl, and R.sup.13 is
divalent alkyl radical of 2-5 carbons; and n is 1 or 2. [0123] 8.
The method or use according to any one of embodiments 1-7, wherein
the RXR agonist is a compound having the structure of formula
III:
##STR00038##
[0123] wherein R.sup.2 is hydrogen or lower alkyl; R.sup.3 is
hydrogen or lower alkyl, and B is hydrogen, COOH or a
pharmaceutically acceptable salt thereof, --COOR.sup.8,
--CONR.sup.9R.sup.10, --CH.sub.2OH, --CH.sub.2OR.sup.11,
--CH.sub.2OCOR.sup.11, --CHO, --CH(OR.sup.12).sub.2,
--CHOR.sup.13O, --COR.sup.7, --CR.sup.7(OR.sup.12).sub.2,
--CR.sup.7OR.sup.13O, or tri-lower alkylsilyl, where R.sup.7 is an
alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons,
R.sup.9 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of
5 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1
to 10 carbons, or R.sup.9 is phenyl or lower alkylphenyl, R.sup.9
and R.sup.10 independently are hydrogen, an alkyl group of 1 to 10
carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower
alkylphenyl, R.sup.11 is lower alkyl, phenyl or lower alkylphenyl,
R.sup.12 is lower alkyl, and R.sup.13 is divalent alkyl radical of
2-5 carbons. [0124] 9. The method or use according to any one of
embodiments 1-8, wherein the RXR agonist is a compound having the
structure of formula IV:
##STR00039##
[0124] wherein n is 1 or 2; R.sup.1 and R.sup.2 independently are
H, lower alkyl or fluoroalkyl; R.sup.3 is hydrogen, lower alkyl, Cl
or Br; R.sup.4 is H, lower alkyl, fluoroalkyl or halogen, and B is
hydrogen, --COOH or a pharmaceutically acceptable salt thereof,
--COOR.sup.8, --CONR.sup.9R.sup.10, --CH.sub.2OH,
--CH.sub.2OR.sup.11, --CH.sub.2OCOR.sup.11, --CHO,
--CH(OR.sup.12).sub.2, --CHOR.sup.13O, --COR.sup.7,
--CR.sup.7(OR.sup.12).sub.2, --CR.sup.7OR.sup.13O, or trilower
alkylsilyl where R.sup.7 is an alkyl, cycloalkyl or alkenyl group
containing 1 to 5 carbons, R.sup.9 is an alkyl group of 1 to 10
carbons, or R.sup.8 is phenyl or lower alkylphenyl, R.sup.9 and
R.sup.10 independently are hydrogen, an alkyl group of 1 to 10
carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower
alkylphenyl, R.sup.11 is lower alkyl, phenyl or lower alkylphenyl,
R.sup.12 is lower alkyl, and R.sup.13 is divalent alkyl radical of
2-5 carbons. [0125] 10. The method or use according to any one of
embodiments 1-9, wherein the RXR agonist is a compound having the
structure of formula V:
##STR00040##
[0125] where R.sup.4 is lower alkyl of 1 to 6 carbons; B is --COOH
or --COOR.sup.8 where R.sup.8 is lower alkyl of 1 to 6 carbons, and
the configuration about the cyclopropane ring is cis, and the
configuration about the double bonds in the pentadienoic acid or
ester chain attached to the cyclopropane ring is trans in each of
the double bonds, or a pharmaceutically acceptable salt of the
compound. [0126] 11. The method or use according to any one of
embodiments 1-10, wherein the RXR agonist is a compound having the
structure of formula VI:
##STR00041##
[0126] wherein Z is a radical shown in Formula VII:
##STR00042##
Y is cycloalkyl or cycloalkenyl of 3 to 8 carbons optionally
substituted with one or two R.sup.4 groups, or Y is selected from
phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyridazinyl, pyrimidiyl,
pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, the groups being
optionally substituted with one or two R.sup.4 groups, the divalent
Y radical being substituted by the Z and
--(CR.sup.1.dbd.CR.sup.1.dbd.CR.sup.1.dbd.CR.sup.1)-- groups on
adjacent carbons; X is S or O; R.sup.1 and R.sup.2 independently
are H, lower alkyl or fluoroalkyl; R.sup.3 is hydrogen, lower
alkyl, Cl or Br; R.sup.4 is lower alkyl, fluoroalkyl or halogen,
and B is hydrogen, --COOH or a pharmaceutically acceptable salt
thereof, --COOR.sup.8, --CONR.sup.9R.sup.10, --CH.sub.2OH,
--CH.sub.2OR.sup.11, --CH.sub.2OCOR.sup.11, --CHO,
--CH(OR.sup.12).sub.2, --CHOR.sup.13O, --OCOR.sup.7,
--CR.sup.7(OR.sup.12).sub.2, --CR.sup.7OR.sup.13O, or tri-lower
alkylsilyl, where R.sup.7 is an alkyl, cycloalkyl or alkenyl group,
containing 1 to 5 carbons, R.sup.9 is an alkyl group of 1 to 10
carbons, a cycloalkyl group of 5 to 10 carbons or
trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or
R.sup.9 is phenyl or lower alkylphenyl, R.sup.9 and R.sup.10
independently are hydrogen, an alkyl group of 1 to 10 carbons, or a
cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl,
R.sup.11 is lower alkyl, phenyl or lower alkylphenyl, R.sup.12 is
lower alkyl, and R.sup.13 is divalent alkyl radical of 2-5 carbons.
[0127] 12. The method or use according to any one of embodiments
1-11, wherein the RXR agonist is a compound having the structure of
formula VIII:
##STR00043##
[0127] wherein X is S or O; R.sup.2 is hydrogen or lower alkyl;
R.sup.3 is hydrogen or lower alkyl, and B is hydrogen, --COOH or a
pharmaceutically acceptable salt thereof, --COOR.sup.8,
--CONR.sup.9R.sup.10, --CH.sub.2OH, --CH.sub.2OR.sup.11,
--CH.sub.2OCOR.sup.11, --CHO, --CH(OR.sup.12).sub.2,
--CHOR.sup.13O, .sup.--COR.sup.7, --CR.sup.7(OR.sup.12).sub.2,
--CR.sup.7OR.sup.13O, or trilower alkylsilyl, where R.sup.7 is an
alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons,
R.sup.9 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of
5 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1
to 10 carbons, or R.sup.9 is phenyl or lower alkylphenyl, R.sup.9
and R.sup.10 independently are hydrogen, an alkyl group of 1 to 10
carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower
alkylphenyl, R.sup.11 is lower alkyl, phenyl or lower alkylphenyl,
R.sup.12 is lower alkyl, and R.sup.13 is divalent alkyl radical of
2-5 carbons. [0128] 13. The method or use according to any one of
embodiments 1-12, wherein the RXR agonist is a compound having the
structure of formula IX:
##STR00044##
[0128] wherein Z is a radical shown in Formula X:
##STR00045##
Y is selected from pyridyl, pyrrolyl, pyridazinyl, pyrimidinyl,
pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, the groups being
optionally substituted with one or two R.sup.4 groups, the divalent
Y radical being substituted by the Z and
--(CR.sup.1.dbd.CR.sup.1.dbd.CR.sup.1.dbd.CR.sup.1)-- groups on
adjacent carbons; X is NR.sup.5; n is 1 or 2; R.sup.1 and R.sup.2
independently are H, lower alkyl or fluoroalkyl; R.sup.3 is
hydrogen, lower alkyl, Cl or Br; R.sup.4 is lower alkyl,
fluoroalkyl or halogen; R.sup.5 is H or lower alkyl, and B is
hydrogen, --COOH or a pharmaceutically acceptable salt thereof,
--COOR.sup.8, --CONR.sup.9R.sup.10, --CH.sub.2OH,
--CH.sub.2OR.sup.11, --CH.sub.2OCOR.sup.11, --CHO,
--CH(OR.sup.12).sub.2, --CHOR.sup.13O, --COR.sup.7,
--CR.sup.7(OR.sup.12).sub.2, --CR.sup.7OR.sup.13O, or trilower
alkylsilyl, where R.sup.7 is an alkyl, cycloalkyl or alkenyl group
containing 1 to 5 carbons, R.sup.9 is an alkyl group of 1 to 10
carbons, a cycloalkyl group of 5 to 10 carbons or
trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or
R.sup.8 is phenyl or lower alkylphenyl, R.sup.9 and R.sup.10
independently are hydrogen, an alkyl group of 1 to 10 carbons, or a
cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl,
R.sup.11 is lower alkyl, phenyl or lower alkylphenyl, R.sup.12 is
lower alkyl, and R.sup.13 is divalent alkyl radical of 2 to 5
carbons. [0129] 14. The method or use according to any one of
embodiments 1-13, wherein the RXR agonist is a compound having the
structure of formula IX:
##STR00046##
[0129] wherein Z is a radical shown in Formula XI:
##STR00047##
Y is selected from pyridyl, pyrrolyl, pyridazinyl, pyrimidinyl,
pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, the groups being
optionally substituted with one or two R.sup.4 groups, the divalent
Y radical being substituted by the Z and
--(CR.sup.1.dbd.CR.sup.1.dbd.CR.sup.1.dbd.CR.sup.1)-- groups on
adjacent carbons; X is NR.sup.5; n is 1 or 2; R.sup.1 and R.sup.2
independently are H, lower alkyl or fluoroalkyl; R.sup.3 is
hydrogen, lower alkyl, Cl or Br; R.sup.4 is lower alkyl,
fluoroalkyl or halogen; R.sup.5 is H or lower alkyl, and B is
hydrogen, --COOH or a pharmaceutically acceptable salt thereof,
--COOR.sup.8, --CONR.sup.9R.sup.10, --CH.sub.2OH,
--CH.sub.2OR.sup.11, --CH.sub.2OCOR.sup.11, --CHO,
--CH(OR.sup.12).sub.2, --CHOR.sup.13O, --COR.sup.7,
--CR.sup.7(OR.sup.12).sub.2, --CR.sup.7OR.sup.13O, or trilower
alkylsilyl, where R.sup.7 is an alkyl, cycloalkyl or alkenyl group
containing 1 to 5 carbons, R.sup.9 is an alkyl group of 1 to 10
carbons, a cycloalkyl group of 5 to 10 carbons or
trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or
R.sup.9 is phenyl or lower alkylphenyl, R.sup.9 and R.sup.10
independently are hydrogen, an alkyl group of 1 to 10 carbons, or a
cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl,
R.sup.11 is lower alkyl, phenyl or lower alkylphenyl, R.sup.12 is
lower alkyl, and R.sup.13 is divalent alkyl radical of 2 to 5
carbons. [0130] 15. The method or use according to any one of
embodiments 1-14, wherein the RXR agonist is a compound having the
structure of formula XII:
##STR00048##
[0130] wherein R is H, lower alkyl or 1 to 6 carbons, or a
pharmaceutically acceptable salt of the compound. [0131] 16. The
method or use according to any one of embodiments 1-5, wherein the
RXR agonist is a compound having the structure of formula XII:
##STR00049##
[0131] wherein Z is a radical shown in Formula XIV:
##STR00050##
Y is cyclopropyl, the Y group being optionally substituted with one
or two R.sup.4 groups, the divalent Y radical being substituted by
the Z and --(CR.sup.1.dbd.CR.sup.1.dbd.CR.sup.1.dbd.CR.sup.1)--
groups on adjacent carbons; X is NR.sup.5; R.sup.1 and R.sup.2
independently are H, lower alkyl or fluoroalyl; R.sup.3 is
hydrogen, lower alkyl, Cl or Br; R.sup.4 is lower alkyl,
fluoroalkyl or hydrogen; R.sup.5 is H or lower alkyl, and B is
hydrogen, --COOH or a pharmaceutically acceptable salt thereof,
--COOR.sup.8, --CONR.sup.9R.sup.10, --CH.sub.2OH,
--CH.sub.2OR.sup.11, --CH.sub.2OCOR.sup.11, --CHO,
--CH(OR.sup.12).sub.2, --CHOR.sup.13O, --COR.sup.7,
--CR.sup.7(OR.sup.12).sub.2, --CR.sup.7OR.sup.13O, or trilower
alkylsilyl, where R.sup.7 is an alkyl, cycloalkyl or alkenyl group
containing 1 to 5 carbons, R.sup.8 is an alkyl group of 1 to 10
carbons, a cycloalkyl group of 5 to 10 carbons or
trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or
R.sup.8 is phenyl or lower alkylphenyl, R.sup.9 and R.sup.10
independently are hydrogen, an alkyl group of 1 to 10 carbons, or a
cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl,
R.sup.11 is lower alkyl, phenyl or lower alkylphenyl, R.sup.12 is
lower alkyl, and R.sup.13 is divalent alkyl radical of 2 to 5
carbons. 17. The method or use according to any one of embodiments
1-16, wherein the RXR agonist is a compound having the structure of
formula XV:
##STR00051##
wherein X is NR.sup.5; R.sup.5 is H or lower alkyl; R.sup.2 is H or
lower alkyl; R.sup.3 is H or lower alkyl, and B is hydrogen, --COOH
or a pharmaceutically acceptable salt thereof, --COOR.sup.8,
--CONR.sup.9R.sup.10, --CH.sub.2OH, --CH.sub.2OR.sup.11,
--CH.sub.2OCOR.sup.11, --CHO, --CH(OR.sup.12).sub.2,
--CHOR.sup.13O, --COR.sup.7, --CR.sup.7(OR.sup.12).sub.2,
--CR.sup.7OR.sup.13O, or trilower alkylsilyl, where R.sup.7 is an
alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons,
R.sup.8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of
5 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1
to 10 carbons, or R.sup.8 is phenyl or lower alkylphenyl, R.sup.9
and R.sup.10 independently are hydrogen, an alkyl group of 1 to 10
carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower
alkylphenyl, R.sup.11 is lower alkyl, phenyl or lower alkylphenyl,
R.sup.12 is lower alkyl, and R.sup.13 is divalent alkyl radical of
2 to 5 carbons. 18. The method or use according to any one of
embodiments 1-17, wherein the RXR agonist is a compound having the
structure of formula XVI:
##STR00052##
where Y is a bivalent radical having Formula XVII:
##STR00053##
the two X.sup.1 groups jointly represent an oxo (.dbd.O) or thione
(.dbd.S) function, or X.sup.1 is independently selected from H or
alkyl of 1 to 6 carbons; the two X.sup.2 groups jointly represent
an oxo (.dbd.O) or a thione (.dbd.S) function, or X.sup.2
independently selected from H or alkyl of 1 to 6 carbons, with the
proviso that one of the joint X.sup.1 grouping or of the joint
X.sup.2 grouping represents an oxo (.dbd.O) or thione (.dbd.S)
function; W is O, C(R.sup.1).sub.2, or W does not exist; R.sup.1 is
independently H, lower alkyl of 1 to 6 carbons, or lower
fluoroalkyl of 1 to 6 carbons; R.sup.2 is independently H, lower
alkyl of 1 to 6 carbons, or lower fluoroalkyl of 1 to 6 carbons;
R.sup.3 is hydrogen, lower alkyl of 1 to 6 carbons, OR.sup.1,
fluoro substituted lower alkyl of 1 to 6 carbons halogen, NO.sub.2,
NH.sub.2, --NHCO(C.sub.1-C.sub.6) alkyl, or --NHCO(C.sub.1-C.sub.6)
alkenyl; A is hydrogen, --COOH or a pharmaceutically acceptable
salt thereof, --COOR.sup.8, --CONR.sup.9R.sup.10, --CH.sub.2OH,
--CH.sub.2OR.sup.11, --CH.sub.2OCOR.sup.11, --CHO,
--CH(OR.sup.12).sub.2, --CH(OR.sup.13O), --COR.sup.7,
--CR.sup.7(OR.sup.12).sub.2, --CR.sup.7(OR.sup.13O), or
--Si(C.sub.1-C.sub.6).sub.3, where R.sup.7 is an alkyl, cycloalkyl
or alkenyl group containing 1 to 5 carbons, R.sup.9 is an alkyl
group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl
group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10
carbons, or R.sup.8 is phenyl or lower alkyphenyl, R.sup.9 and
R.sup.10 independently are hydrogen, an alkyl group of 1 to 10
carbons, or a cycloalkyl group of 5-10 carbons, or phenyl,
hydroxyphenyl or lower alkylphenyl, R.sup.11 is lower alkyl, phenyl
or lower alkylphenyl, R.sup.12 is lower alkyl, and R.sup.13 is
divalent alkyl radical of 2 to 5 carbons, and R.sup.14 is H, alkyl
of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons,
alkenyl of 2 to 10 carbons and having 1 to 3 double bonds. [0132]
19. The method or use according to any one of embodiments 1-18,
wherein the RXR agonist is a compound having the structure of
formula XVIII:
##STR00054##
[0132] wherein R.sup.1 is independently H, lower alkyl of 1 to 6
carbons, or lower fluoroalkyl of 1 to 6 carbons; R.sup.1* is
hydrogen or C.sub.1-6-alkyl; R.sup.2* is independently H, lower
alkyl of 1 to 6 carbons, or lower fluoroalkyl of 1 to 6 carbons;
R.sup.3* is hydrogen, lower alkyl of 1 to 6 carbons, fluoro
substituted lower alkyl of 1 to 6 carbons or halogen; X.sup.1* is
an oxo (.dbd.O) or a thione (.dbd.S) group; A* is hydrogen, --COOH
or a pharmaceutically acceptable salt thereof, --COOR.sup.8,
--CONR.sup.9R.sup.10, where R.sup.8 is an alkyl group of 1 to 10
carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10
carbons, or a cycloalkyl group of 5 to 10 carbons, or R.sup.8 is
phenyl or lower alkylphenyl, R.sup.9 and R.sup.19 independently are
hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group
of 5-10 carbons, or phenyl, hydroxyphenyl or lower alkylphenyl, and
the cyclopropyl group is attached to the 6 or 7 position of the
tetrahydroquinoline moiety, and R.sup.14* is alkyl of 1 to 10
carbons or fluoro-substituted alkyl of 1 to 10 carbons. [0133] 20.
The method or use according to any one of embodiments 1-19, wherein
the RXR agonist is a compound having the structure of formulae XIX,
XX, or XXI:
##STR00055##
##STR00056##
[0133] where X is O, S, or (CR.sup.1R.sup.1).sub.n where n is 0, 1
or 2; Y is a bivalent radical having Formulae XXII or XXIII where o
is an integer between 1 through 4
##STR00057##
or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical
having 1 to 3 heteroatoms selected from N, S and O, the aryl or
heteroaryl groups being unsubstituted, or substituted with 1 to 3
C.sub.1-6 alkyl or with 1 to 3 C.sub.1-6 fluoroalkyl groups with
the proviso that when the compound is in accordance with Formula II
then Y is not a 5 or 6 membered ring; X.sup.1 is S or NH; R.sup.1
is independently H, lower alkyl of 1 to 6 carbons, or lower
fluoroalkyl of 1 to 6 carbons; R.sup.2 is independently H, lower
alkyl of 1 to 6 carbons, OR.sup.1, adamantly, or lower fluoroalkyl
of 1 to 6 carbons, or the two R.sup.2 groups jointly represent an
oxo (.dbd.O) group with the proviso that when the compound is in
accordance with Formula II then at least one of the R.sup.2
substituents is branched-chain alkyl or adamantly; R.sup.3 is
hydrogen, lower alkyl of 1 to 6 carbons, OR.sup.1, fluoro
substituted lower alkyl of 1 to 6 carbons or halogen, NO.sub.2,
NH.sub.2, --NHCO(C.sub.1-C.sub.6) alkyl, or --NHCO(C.sub.1-C.sub.6)
alkenyl; A is --COOH or a pharmaceutically acceptable salt thereof,
COOR.sup.8, --CONR.sup.9R.sup.10, --CH.sub.2OH,
--CH.sub.2OR.sup.11, --CH.sub.2OCOR.sup.11, --CHO,
--CH(OR.sup.12).sub.2, --CH(OR.sup.13O), --COR.sup.7,
--CR.sup.7(OR.sup.12).sub.2, --CR.sup.7(OR.sup.13O), or
--Si(C.sub.1-6alkyl).sub.3, where R.sup.7 is an alkyl, cycloalkyl
or alkenyl group containing 1 to 5 carbons, R.sup.8 is an alkyl
group of 1 to 10 carbons or (trimethylsilyl) alkyl where the alkyl
group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10
carbons, or R.sup.8 is phenyl or lower alkylphenyl, R.sup.9 and
R.sup.19 independently are hydrogen, an alkyl group of 1 to 10
carbons, or a cycloalkyl group of 5-10 carbons, or phenyl,
hydroxyphenyl or lower alkylphenyl, R.sup.12 is lower alkyl, and
R.sup.13 is divalent alkyl radical of 2-5 carbons, and R.sup.14 is
alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10
carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds,
alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic
aryl selected from the group consisting of phenyl,
C.sub.1-C.sub.10-alkylphenyl, naphthyl,
C.sub.1-C.sub.10-alkylnaphthyl, phenyl-C.sub.1-C.sub.10-alkyl,
naphthyl-C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10-alkenylphenyl
having 1 to 3 double bonds, C.sub.1-C.sub.10-alkynylphenyl having 1
to 3 triple bonds, phenyl-C.sub.1-C.sub.10 alkenyl having 1 to 3
double bonds, phenyl-C.sub.1-C.sub.10 alkenyl having 1 to 3 triple
bonds, hydroxyl alkyl of 1 to 10 carbons, hydroxyalkenyl having 2
to 10 carbons and 1 to 3 double bonds, hydroxyalkynyl having 2 to
10 carbons and 1 to 3 triple bonds, acyloxyalkyl of 1 to 10
carbons, acyloxyalkenyl having 2 to 10 carbons and 1 to 3 double
bonds, or acyloxyalkynyl of 2 to 10 carbons and 1 to 3 triple
bonds, acyloxyalkyl of 1 to 10 carbons, acyloxyalkenyl having 2 to
10 carbons and 1 to 3 double bonds, or acyloxyalkynyl of 2 to 10
carbons and 1 to 3 triple bonds where the acyl group is represented
by --COR.sup.8, or R.sup.14 is a 5 or 6 membered heteroaryl group
having 1 to 3 heteroatoms, the heteroatoms being selected from a
group consisting of O, S, and N, the heteroaryl group being
unsubstituted or substituted with a C.sub.1-C.sub.10 alkyl group,
with a C.sub.1-C.sub.10-fluoroalkyl group, or with halogen, and the
dashed line in Formula XXII represents a bond or absence of a bond.
[0134] 21. The method or use according to any one of embodiments
1-20, wherein the RXR agonist is a compound having the structure of
formula XXIV:
##STR00058##
[0134] wherein R is H, lower alkyl of 1 to 6 carbons, or a
pharmaceutically acceptable salt of the compound. [0135] 22. The
method or use according to any one of embodiments 1-21, wherein the
RXR agonist is a compound having the structure of formula XXV:
##STR00059##
[0135] wherein R is H, lower alkyl of 1 to 6 carbons, and R.sup.1
is iso-propyl or tertiary-butyl, or a pharmaceutically acceptable
salt of the compound. [0136] 23. The method or use according to any
one of embodiments 1-22, wherein the RXR agonist is a compound
having the structure of formula XXVI:
##STR00060##
[0136] wherein R is H, lower alkyl of 1 to 6 carbons, and R.sup.1
is iso-propyl, n-butyl or tertiary-butyl, or a pharmaceutically
acceptable salt of the compound. [0137] 24. The method or use
according to any one of embodiments 1-23, wherein the RXR agonist
is a compound having the structure of formula XXVII:
##STR00061##
[0137] where X is O or S; Y is a bivalent cycloalkyl or
cycloalkenyl radical optionally substituted with one to four
R.sup.4 groups, the cycloalkenyl radical having 5 to 6 carbons and
one double bond, or Y is a bivalent aryl or 5 or 6 membered
heteroaryl radical having 1 to 3 heteroatoms selected from N, S and
O, the aryl or heteroaryl groups optionally substituted with 1 to 4
R.sup.4 groups with the proviso that the cycloalkyl or the
cycloalkenyl radical is not substituted on the same carbon with the
condensed cyclic moiety and with the diene containing moiety;
R.sup.1 is independently H, alkyl of 1 to 6 carbons, or fluoroalkyl
of 1 to 6 carbons; R.sup.2 is independently H, alkyl of 1 to 8
carbons, or fluoroalkyl of 1 to 8 carbons; R.sup.12 is
independently H, alkyl of 1 to 8 carbons, or fluoroalyl of 1 to 8
carbons; R.sup.3 is hydrogen, alkyl of 1 to 10 carbons, fluoro
substituted alkyl of 1 to 10 carbons, halogen, alkoxy of 1 to 10
carbons, or alkylthio of 1 to 10 carbons; NO.sub.2, NH.sub.2,
--NHCO(C.sub.1-C.sub.6) alkyl, --NHCO(C.sub.1-C.sub.6) alkenyl,
--NR.sup.1H or N(R.sup.1).sub.2, benzyloxy, C.sub.1-C.sub.6
alkyl-substituted benzyloxy, or R.sup.3 is selected from the groups
shown below,
##STR00062##
R.sup.4 is H, halogen, alkyl of 1 to 10 carbons, fluoro substituted
alkyl of 1 to 6 carbons, alkoxy of 1 to 10 carbons, or alkylthio of
1 to 10 carbons; m is an integer having the values of 0 to 3; r is
an integer having the values of 1 to 10; s is an integer having the
values 1 to 4; t is an integer having the values 1 to 5;
##STR00063##
represents a 5 or 6 membered heteroaryl ring having 1 to 3
heteroatoms selected from the group consisting of N, S and O; B is
hydrogen, COOH or a pharmaceutically acceptable salt thereof,
--COOR.sup.8, --CONR.sup.9R.sup.10, --CH.sub.2OH,
--CH.sub.2OR.sup.11, --CH.sub.2OCOR.sup.11, --CHO,
--CH(OR.sup.12).sub.2, --CHOR.sup.13O, --COR.sup.7,
--CR.sup.7(OR.sup.12).sub.2, --CR.sup.7OR.sup.13O, or trilower
alkylsilyl, where R.sup.7 is an alkyl, cycloalkyl or alkenyl group
containing 1 to 5 carbons, R.sup.8 is an alkyl group of 1 to 10
carbons, a cycloalkyl group of 5 to 10 carbons or
trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or
R.sup.8 is phenyl or lower alkylphenyl, R.sup.9 and R.sup.10
independently are hydrogen, an alkyl group of 1 to 10 carbons, or a
cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl,
R.sup.11 is lower alkyl, phenyl or lower alkylphenyl, R.sup.12 is
lower alkyl, and R.sup.13 is divalent alkyl radical of 2 to 5
carbons. [0138] 25. The method or use according to any one of
embodiments 1-24, wherein the RXR agonist is a compound having the
structure of formula XXVIII:
##STR00064##
[0138] wherein R.sup.1 is H or methyl; R.sup.8 is H, alkyl of 1 to
6 carbons, or a pharmaceutically acceptable cation, and R.sup.3 is
hydrogen, alkyl of 1 to 10 carbons, halogen, alkoxy of 1 to 10
carbons, or R.sup.3 is selected from the groups shown below
##STR00065##
where R.sup.4 is H, halogen, alkyl of 1 to 10 carbons, carbons,
alkoxy of 1 to 10; r is an integer having the values of 1 to 10; s
is an integer having the values 1 to 4;
##STR00066##
represents a 5 or 6 membered heteroaryl ring having 1 to 3
heteroatoms selected from the group consisting of N, S and O, and t
is an integer having the values 1 to 5. [0139] 26. The method or
use according to any one of embodiments 1-25, wherein the RXR
agonist is
3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydron-
aphth-7-yl]2(E),4(E) heptadienoic acid, and has the structure of
formula XXIX:
[0139] ##STR00067## [0140] 27. The method or use according to any
one of embodiments 1, 2, or 4-26, wherein the autoimmune disorder
is systemic autoimmune disorder or organ-specific autoimmune
disorder. [0141] 28. The method or use according to any one of
embodiments 1, 2, or 4-27, wherein the autoimmune disorder is an
acute disseminated encephalomyelitis (ADEM), an Addison's disease,
an allergy, allergic rhinitis, an Alzheimer's disease, an
anti-phospholipid antibody syndrome (APS), an arthritis, an asthma,
an autoimmune deficiency syndrome (AIDS), an autoimmune hemolytic
anemia, an autoimmune hepatitis, an autoimmune inner ear disease, a
bullous pemphigoid, a celiac disease, a Chagas disease, a chronic
obstructive pulmonary disease (COPD), a diabetes mellitus type 1
(IDDM), an endometriosis, a gastrointestinal disorder, a
Goodpasture's syndrome, a Graves' disease, a Guillain-Barre
syndrome (GBS), a Hashimoto's thyroiditis, a hidradenitis
suppurativa, an idiopathic thrombocytopenic purpura, an
interstitial cystitis, a lupus, a morphea, a multiple sclerosis
(MS), a myasthenia gravis, a myopathy such as, e.g., a
dermatomyositis, an inclusion body myositis, or a polymyositis, a
myositis, a narcolepsy, a neuromyotonia, a Parkinson's disease, a
pemphigus vulgaris, a pernicious anaemia, a primary biliary
cirrhosis, a psoriasis, a recurrent disseminated encephalomyelitis,
a rheumatic fever, a schizophrenia, a scleroderma, a Sjogren's
syndrome, a skin disorder, a tenosynovitis, a uveitis, a
vasculitis, or a vitiligo. [0142] 29. The method or use according
to embodiment 28, wherein the skin disorder is a dermatitis, an
eczema, a statis dermatitis, a hidradenitis suppurativa, a
psoriasis, a rosacea or a scleroderma. [0143] 30. The method or use
according to embodiment 29, wherein the eczema is an atopic eczema,
a contact eczema, a xerotic eczema, a seborrhoeic dermatitis, a
dyshidrosis, a discoid eczema, a venous eczema, a dermatitis
herpetiformis, a neurodermatitis, or an autoeczematization. [0144]
31. The method or use according to embodiment 29, wherein the
psoriasis is a plaqure psoriasis, a nail psoriasis, a guttate
psoriasis, a scalp psoriasis, an inverse psoriasis, a pustular
psoriasis, or an erythrodermis psoriasis. [0145] 32. The method or
use according to embodiment 28, wherein the arthritis is a
monoarthritis, an oligoarthritis, or a polyarthritis. [0146] 33.
The method or use according to embodiment 28, wherein the arthritis
is an auto-immune disease or a non-autoimmune disease. [0147] 34.
The method or use according to embodiment 28, wherein the arthritis
is an osteoarthritis, a rheumatoid arthritis, a juvenile idiopathic
arthritis, a septic arthritis, a spondyloarthropathy, a gout, a
pseudogout, or Still's disease [0148] 35. The method or use
according to embodiment 34, wherein the spondyloarthropathy is an
ankylosing spondylitis, a reactive arthritis (Reiter's syndrome), a
psoriatic arthritis, an enteropathic arthritis associated with
inflammatory bowel disease, a Whipple disease or a Behcet disease.
[0149] 36. The method or use according to embodiment 28, wherein
the gastrointestinal disorder is an irritable bowel disease or an
inflammatory bowel. [0150] 37. The method or use according to
embodiment 36, wherein the inflammatory bowel is a Crohn's disease
or an ulcerative colitis. [0151] 38. The method or use according to
embodiment 28, wherein the lupus is a discoid lupus erythematosus,
a drug-induced lupus erythematosus, a lupus nephritis, a neonatal
lupus, a subacute cutaneous lupus erythematosus, or a systemic
lupus erythematosus. [0152] 39. The method or use according to
embodiment 28, wherein the vasculitis is a Buerger's disease, a
cerebral vasculitis, a Churg-Strauss arteritis, a cryoglobulinemia,
an essential cryoglobulinemic vasculitis, a giant cell arteritis, a
Golfers vasculitis, a Henoch-Schonlein purpura, a hypersensitivity
vasculitis, a Kawasaki disease, a microscopic
polyarteritis/polyangiitis, a polyarteritis nodosa, a polymyalgia
rheumatica (PMR), a rheumatoid vasculitis, a Takayasu arteritis, or
a Wegener's granulomatosis. [0153] 40. The method or use according
to any one of embodiments 3-26, wherein the transplant rejection is
a hyperacute rejection, an acute rejection, or a chronic rejection.
[0154] 41. The method or use according to any one of embodiments
3-27, wherein the transplant rejection is a
graft-versus-host-disease. [0155] 42. The method or use according
to any one of embodiments 1-41, wherein the therapeutically
effective amount is about 0.01 mg/kg/day to about 100 mg/kg/day.
[0156] 43. The method or use according to any one of embodiment 42,
wherein the therapeutically effective amount is about 0.1 mg/kg/day
to about 10 mg/kg/day. [0157] 44. The method or use according to
any one of embodiments 1-41, wherein the therapeutically effective
amount is about 0.1 mg/m.sup.2/day to about 100 mg/m.sup.2/day.
[0158] 45. The method or use according to embodiment 44, wherein
the therapeutically effective amount is about 15 mg/m.sup.2/day to
about 60 mg/m.sup.2/day. [0159] 46. The method or use according to
any one of embodiment 1 or 3-45, wherein the symptom reduced is
inflammation, fatigue, dizziness, malaise, elevated fever and high
body temperature, extreme sensitivity to cold in the hands and
feet, weakness and stiffness in muscles and joints, weight changes,
digestive or gastrointestinal problems, low or high blood pressure,
irritability, anxiety, or depression, infertility or reduced sex
drive (low libido), blood sugar changes, and depending on the type
of autoimmune disorder or a transplant rejection, an increase in
the size of an organ or tissue, or the destruction of an organ or
tissue. [0160] 47. The method or use according to embodiment 2 or
46, wherein the inflammation symptom reduced is edema, hyperemia,
erythema, bruising, tenderness, stiffness, swollenness, fever, a
chill, congestion of the respiratory tract including nose and
bronchi, congestion of a sinus, a breathing problem, fluid
retention, a blood clot, a loss of appetite, an increased heart
rate, a formation of granulomas, fibrinous, pus, or non-viscous
serous fluid, a formation of an ulcer, or pain. [0161] 48. The
method or use according to any one of embodiments 1-47, wherein the
RXR agonist is a pure RXR agonist. [0162] 49. The method or use
according to embodiment 48, wherein the RXR agonist is a pure RXR
agonist that activates a permissive heterodimer by 1% or less, 2%
or less, 3% or less, 4% or less, 5% or less, 6% or less, 7% or
less, 8% or less, 9% or less, or 10% or less relative to the
ability of a non-pure RXR agonist to activate the same permissive
heterodimer. [0163] 50. The method or use according to any one of
embodiments 1-49, wherein the RXR agonist has activity that
promotes Treg cell differentiation. [0164] 51. The method or use
according to embodiment 1-50, wherein the RXR agonist promotes Treg
cell differentiation by at least 10%, at least 20%, at least 30%,
at least 40%, at least 50%, at least 60%, at least 70%, at least
80%, at least 90%, at least 100%, at least 200%, at least 300%, at
least 400%, or at least 500%. [0165] 52. The method or use
according to any one of embodiments 1-51, wherein the RXR agonist
increases Foxp3 and/or .alpha.4.beta.7 expression in cells exposed
to the RXR agonist. [0166] 53. The method or use according to
embodiment 52, wherein the RXR agonist increases Foxp3 and/or
.alpha.4.beta.7 expression by at least 10%, at least 20%, at least
30%, at least 40%, at least 50%, at least 60%, at least 70%, at
least 80%, at least 90%, at least 100%, at least 200%, at least
300%, at least 400%, or at least 500%, relative to cells not
exposed to the same RXR agonist. [0167] 54. The method or use
according to any one of embodiments 1-51, wherein the RXR agonist
increases Foxp3 and/or .alpha.4.beta.7 expression in naive
CD4.sup.+ CD25.sup.- FoxP3.sup.- cells cultured under Treg cell
differentiation conditions. [0168] 55. The method or use according
to embodiment 54, wherein the RXR agonist increases Foxp3 and/or
.alpha.4.beta.7 expression in naive CD4.sup.+ CD25.sup.-
FoxP3.sup.- cells cultured under Treg cell differentiation by at
least 10%, at least 20%, at least 30%, at least 40%, at least 50%,
at least 60%, at least 70%, at least 80%, at least 90%, at least
100%, at least 200%, at least 300%, at least 400%, or at least
500%, relative to naive CD4.sup.+ CD25.sup.- FoxP3.sup.- cells
cultured under Treg cell differentiation not exposed to the same
RXR agonist. [0169] 56. The method or use according to any one of
embodiments 1-55, wherein the RXR agonist has activity that
inhibits Th17 cell differentiation. [0170] 57. The method or use
according to embodiment 1-56, wherein the RXR agonist inhibits Th17
cell differentiation by at least 10%, at least 20%, at least 30%,
at least 40%, at least 50%, at least 60%, at least 70%, at least
80%, at least 90%, at least 100%, at least 200%, at least 300%, at
least 400%, or at least 500%. [0171] 58. The method or use
according to any one of embodiments 1-57, wherein the RXR agonist
decreases IL-17A expression in cells exposed to the RXR agonist.
[0172] 59. The method or use according to embodiment 58, wherein
the RXR agonist decreases IL-17A expression by at least 10%, at
least 20%, at least 30%, at least 40%, at least 50%, at least 60%,
at least 70%, at least 80%, at least 90%, at least 100%, at least
200%, at least 300%, at least 400%, or at least 500%, relative to
cells not exposed to the same RXR agonist. [0173] 60. The method or
use according to any one of embodiments 1-59, wherein the RXR
agonist decreases IL-17A expression in naive CD4.sup.+ CD25.sup.-
FoxP3.sup.- cells cultured under Th17 cell differentiation
conditions. [0174] 61. The method or use according to embodiment
60, wherein the RXR agonist decreases IL-17A expression in naive
CD4.sup.+ CD25.sup.- FoxP3.sup.- cells cultured under Th17 cell
differentiation by at least 10%, at least 20%, at least 30%, at
least 40%, at least 50%, at least 60%, at least 70%, at least 80%,
at least 90%, at least 100%, at least 200%, at least 300%, at least
400%, or at least 500%, relative to naive CD4.sup.+ CD25.sup.-
FoxP3.sup.- cells cultured under Treg cell differentiation not
exposed to the same RXR agonist. [0175] 62. A method of promoting
Treg cell differentiation in an individual, the method comprising
the step of administering to the individual in need thereof a
therapeutically effective amount of a RXR agonist, wherein
administration of the RXR agonist promotes Treg cell
differentiation. [0176] 63. Use of a RXR agonist to promote Treg
cell differentiation in an individual, wherein administration of
the RXR agonist to the individual promotes Treg cell
differentiation. [0177] 64. The method according to embodiment 62
or use according to embodiment 63, wherein administration of the
RXR agonist to the individual also inhibits Th17 cell
differentiation. [0178] 65. The method or use according to any one
of embodiments 62-64, wherein the RXR agonist is according to any
one of embodiments 6-26 or 48-61.
EXAMPLES
[0179] The following non-limiting examples are provided for
illustrative purposes only in order to facilitate a more complete
understanding of representative embodiments now contemplated. These
examples should not be construed to limit any of the embodiments
described in the present specification, including those pertaining
to the methods of treating an autoimmune disorder, inflammation
associated with an autoimmune disorder, or a transplant rejection
using the RXR agonists disclosed herein, uses of a RXR agonists
disclosed herein to manufacture a medicament and/or treat an
autoimmune disorder, inflammation associated with an autoimmune
disorder, or a transplant rejection, methods of promoting Treg cell
differentiation in an individual, inhibiting Th17 cell
differentiation, or both, as well as uses of a RXR agonists
disclosed herein to promote Treg cell differentiation in an
individual, inhibit Th17 cell differentiation, or both.
Example 1
RXR Agonists Induce Treg Cell Differentiation
[0180] To determine whether a RXR agonist can induce Treg cell
differentiation, the ability of an RXR agonist to promote Treg cell
differentiation under Treg cell differentiation conditions was
assessed by monitoring Foxp3 and .alpha.4.beta.7 expression. Naive
CD4' CD25.sup.- FoxP3.sup.- cells were purified from a Foxp3-GFP
mouse using flow cytometry by sorting and isolating based upon a
GFP.sup.- phenotype. These cells were then cultured under Treg cell
differentiation conditions by treating the cells with .alpha.CD3
and .alpha.CD28 polyclonal antibodies in the presence of IL-2 and
TGF-.beta.. The cultured cells were incubated with RXR agonist
194204 (Formula XXIX) at 0.1 nM, 1.0 nM and 10 nM and the
expression of Foxp3 and .alpha.4.beta.7 was analyzed. The results
indicate that RXR agonist exerted significant impact on the
expression of Foxp3, inducing nearly 100% Foxp3 T cells at
concentrations of 1 nM or higher. FIG. 1A. These results also
indicate that RXR agonist 194204 also induced expression of
.alpha.4.beta.7 (a gut homing receptor). FIG. 1B. These results
indicate that RXR agonists could be useful in reducing a symptom of
an autoimmune disorder or a transplant rejection.
Example 2
RXR Agonists Regulate T Cell Differentiation
[0181] To determine whether a RXR agonist can regulate T cell
differentiation, the ability of an RXR agonist to promote Treg cell
differentiation and inhibit Th17 cell differentiation under Th17
cell differentiation conditions was assessed by monitoring Foxp3
and IL-17A expression. Naive CD4' CD25.sup.- FoxP3.sup.- cells were
purified from a Foxp3-GFP mouse using flow cytometry by sorting and
isolating based upon a GFP.sup.- phenotype. These cells were then
cultured under Th17 cell differentiation conditions in media with 0
nM, 1 nM, 10 nM, and 100 nM of RXR agonist 194204 (Formula XXIX)
and the expression of Foxp3 and IL-17A was analyzed. See, e.g.,
Elias, et al., Retinoic Acid Inhibits Th17 Polarization and
Enhances FoxP3 Expression through a Stat-3/Stat-5 Independent
Pathway, Blood 111(3): 1-13-1020 (2008). The results indicated that
as the concentration of the RXR agonist increased, Foxp3 expression
increased, indicating an increased presence of Treg cells. FIG. 2A.
Additionally, the data demonstrate that as the concentration of the
RXR agonist increased, IL-17A expression decreased, indicating a
decreased presence of Th17 cells. FIG. 2B. These results indicate
that RXR agonists regulate T cell differentiation by promoting
differentiation of immunosuppressive Treg cells and concurrently
inhibiting differentiation of inflammatory Th17 cells from naive T
cells in vitro.
Example 3
RXR Agonists Regulate T Cell Differentiation Independent of RAR
Signaling
[0182] To determine whether a RXR agonist can mediate its effects
via RAR/RXR receptor heterodimers, via RXR receptor homodimers, or
via some other RXR containing complex, T cells were incubated with
a RXR agonist in the presence of a pan-RAR antagonist and the
expression of Foxp3 was assessed. Naive CD4' CD25.sup.- FoxP3.sup.-
cells were purified from a Foxp3-GFP mouse using flow cytometry by
sorting and isolating based upon a GFP.sup.- phenotype. These cells
were then cultured under Treg cell differentiation conditions by
treating the cells with .alpha.CD3 and .alpha.CD28 polyclonal
antibodies in the presence of IL-2 and TGF-.beta.. The cultured
cells were incubated with RXR agonist 194204 (Formula XXIX) at 1.0
nM together with 0 nM, 1 nM, or 10 nM of a pan-RAR antagonist
194310. The cultured cells were then assayed for the expression of
Foxp3. The results indicate that the inclusion of a pan-RAR
antagonist only partially blocked the induction of Foxp3 expression
observed with an RXR agonist alone. FIG. 3. However, this partial
inhibition of Fox3p expression may actually be due to the blocking
of the effects of endogenous RA in the culture medium. As such,
these results indicate that the observed conversion of T cells into
Treg cells appears to occur through the use of RXR receptor
homodimers and/or some other RXR containing complex, and not
through a RAR-mediated mechanism.
Example 4
T Cell Differentiation is Mediated Through RXR Signaling by RXR
Agonists
[0183] To determine whether a RXR agonist can mediate its effects
via an RXR.alpha. receptor homodimers, RXR.beta. receptor
homodimers, RXR.gamma. receptor homodimers, or any combination
thereof, or the corresponding RAR/RXR heterodimers,
receptor-mediated transactivation assays were performed. For
transactivation assays assessing RXR homodimer signaling, CV-1
cells were transfected with 1) an expression construct including a
full length RXR.alpha., RXR.beta., or RXR.gamma.; and 2) a
rCRBPII/RXRE-tk-Luc reporter construct that included RXR
homodimer-specific RXRE/DR1 responsive element linked to a
luciferase gene. For transactivation assays assessing RAR/RXR
heterodimer signaling, CV-1 cells were transfected with 1) an
expression construct comprising a fusion protein including an
estrogen receptor (ER) DNA binding domain linked to the ligand
binding domain of RAR.alpha., RAR.beta., or RAR.gamma. and 2) a
ERE-tk-Luc reporter construct that included an estrogen receptor
responsive element linked to a luciferase gene. The ER-RAR fusion
proteins provided an accurate readout of only the transfected
ER-RAR. After transfection, CV-1 cells were treated with RXR
agonist 194204 (Formula XXIX) at increasing concentrations for 20
hours before measuring luciferase activity. Luciferase activity is
expressed as percent of maximal activity obtained using 1 .mu.M RXR
agonist 194204 for RXRs and 1 .mu.M all-trans-retinoic acid (ATRA)
for RARs (Table 1). Data are mean values.+-.SE from five
independent experiments.
TABLE-US-00001 TABLE 1 RXR Agonist Potencies in Activating RXRs and
RARs EC.sub.50 (nM) EC.sub.50 (nM) Efficacy (% of 1 .mu.M 194204)
Efficacy (% of 1 .mu.M ATRA) Compound Structure RXR.alpha.
RXR.beta. RXR.gamma. RAR.alpha. RAR.beta. RAR.gamma. 194204
##STR00068## 0.08.+-. 0.01 100 0.47.+-. 0.05 100 0.09.+-. 0.01 100
>1,000 >1,000 >1,000
[0184] These results indicate that RXR agonist 194204 activated RXR
receptors with very high potency (EC.sub.50<0.5 nM) for all
three RXR subtypes (Table 1). In contrast, EC.sub.50 of the RXR
agonist for RARs was >1,000 nM with minimal activity detected at
.gtoreq.1 .mu.M. This difference represents >2.000-fold
selectivity for RXRs over RARs in functional transactivation
assays. Additionally, these data demonstrate that RXR agonist
194204 was more than 1.000-fold more potent in activating RXR
receptors rather than RAR receptors. FIG. 4. These results indicate
that Treg differentiation was mediated through a RXR signaling
pathway and not via a RAR signaling pathway. Also, using
appropriate receptor and reporter constructs, RXR agonist 194204
was shown not to transactivate so called "permissive RXR
heterodimers", such as, e.g., PPAR/RXR, FXR/RXR and LXR/RXR. In
this regard, RXR agonist 194204 is distinct from other RXR
agonists.
Example 5
Binding Affinity of RXR Agonists
[0185] To determine the binding affinity for a RXR agonist,
competitive displacement assays were performed. RXR.alpha.,
RXR.beta., RXR.gamma., RAR.alpha., RAR.beta., or RAR.gamma. were
expressed in SF21 cells using a baclovirus expression system and
the resulting proteins were purified. To determine the binding
affinity for a RXR agonist for an RXR, purified RXR.alpha.,
RXR.beta., and RXR.gamma. were separately incubated with 10 nM
[.sup.3H]-9CRA, and the binding affinity of the RXR agonist 194204
(Formula XXIX) was determined by competitive displacement of
[.sup.3H]-9CRA from the receptor. To determine the binding affinity
for a RXR agonist for an RAR, purified RAR.alpha., RAR.beta., and
RAR.gamma. were incubated with 5 nM [.sup.3H]-ATRA, and the binding
affinity of the RXR agonist 194204 (XXIX) was determined by
competitive displacement of [.sup.3H]-ATRA from the receptor. Ki
values are mean values of at least two independent experiments
(Table 2). Standard errors (.+-.) among independent experiments are
indicated.
[0186] As shown in Table 2, RXR agonist 194204 displayed high
affinity for RXR.alpha., RXR.beta., and RXR.gamma. with Ki values
being 1.7, 16, and 43 nM, respectively. In contrast, the RXR
agonist 194204 bound with very low affinity to each of the RARs (Ki
values being >1,000 nM). These data indicate that 194204 is
highly selective for the RXRs relative to the RARs.
TABLE-US-00002 TABLE 2 RXR Agonist Binding Affinities RXR Binding
Affinity RAR Binding Affinity Ki (nM) Ki (nM) Compound Structure
RXR.alpha. RXR.beta. RXR.gamma. RAR.alpha. RAR.beta. RAR.gamma.
194204 ##STR00069## 1.7 .+-. 0.1 16 .+-. 1.0 43 .+-. 3.0 6344 .+-.
674 7552 .+-. 638 4742 .+-. 405
Example 6
RXR Agonists Attenuate EAE in B6 Mice
[0187] To determine whether a RXR agonist can attenuate multiple
sclerosis, C57BL/6 (B6) mice were immunized (day 0) to induce EAE
by subcutaneous (s.c.) injection at the base of their spine with
200 uL of adjuvant containing 125 ug myelin oligodendrocyte
glycoprotein peptide (35-55) (MOG peptide; Peptides International,
Louisville, Ky.) and 400 ug non-viable M. tuberculosis H37
desiccate emulsified in a mixture of incomplete Freund's adjuvant
and phosphate buffered saline (PBS). Mice were also given 200 ng of
pertussis toxin in PBS administered by inter-peritoneal (i.p.)
injection on the same day as MOG emulsion injection (day 0) and 2
days later (day 2). Starting on day 7 after immunization, mice were
given the RXR agonist 194204 (50 ug) or vehicle control i.p. every
other day for the duration of the experiment (n=6-7 mice/group).
Statistics show the results of a Mann Whitney test (analyzed from
start of treatment to the end of the experiment). Mice were scored
using the following scale: 0--Mice have no disease, 1--Mice have
distal limp tail or rear leg weakness (paresis), 1.5--Mice have
distal limp tail and rear leg weakness, 2--Mice have complete limp
tail and rear leg weakness, 2.5--Mice have complete limp tail and
weakness in both rear legs, 3--Mice have complete limp tail and
paralysis in both rear legs, 3.5--Mice have complete limp tail,
paralysis in both rear legs, and forelimb weakness. Mice receiving
a score of 3.5 were immediately euthanized.
[0188] FIG. 5 depicts scores of disease severity over time. The
results indicate that administration of a RXR agonist significantly
reduces the symptoms of EAE in mice. Efficacy of the RXR agonist
was observed after the first administration (day 7) and maintained
throughout the course of the study (day 20).
Example 7
RXR Agonist-Treated Mice have Reduced Central Nervous System
Infiltrating Cells
[0189] To determine whether a RXR agonist can reduce central
nervous system (CNS) infiltrating cells, C57BL/6 (B6) mice were
treated as described in Example 6. On day 20 after immunization,
mice were sacrificed and perfused with phosphate buffered saline
(PBS). Brain and spinal cord tissue was isolated, digested with
DNase and Liberase DL (Roche Diagnostics, Indianapolis, Ind.) for
30 minutes, and homogenized through 70 micron nylon mesh filters.
Resulting cells were placed over a Percoll gradient to remove
myelin. The remaining cells (microglia and CNS infiltrating cells)
were counted, stained for molecules of interest, and run on a flow
cytometer. Based on the frequencies obtained by FACS of these cell
populations, total cell numbers of CNS infiltrating leukocytes
expressing CD45, including CD4' T cells and CD11c.sup.+ CD11b.sup.+
myeloid dendritic cells (DC), were calculated.
[0190] FIG. 6 compares the number of CD4.sup.+ cells or CD11c.sup.+
CD11b.sup.+ cells (myeloid DC) in mice treated with the RXR agonist
194204 verses the vehicle control. There was a significant
reduction in the infiltration of both CD4.sup.+ cells and
CD11c.sup.+ CD11b.sup.+ cells in animals treated with a RXR agonist
as compared to the control. As disease is propagated in the CNS
through the CD4.sup.+ cells infiltrating the CNS and becoming
re-activated by CD11c.sup.+ CD11b.sup.+ cells, this suggests that
part of the mechanism of action in this model is to limit the
presence of the cells in the CNS.
Example 8
RXR Agonists Attenuate EAE in SJL Mice
[0191] To determine whether a RXR agonist can attenuate multiple
sclerosis, SJL mice were immunized to induce EAE by s.c. injection
at the base of their spine with 200 uL of adjuvant containing 200
ug proteolipid proteins (139-151) (PLP peptide; Peptides
International, Louisville, Ky.) and 400 ug of non-viable M.
tuberculosis H37 desiccate emulsified in a mixture of incomplete
Freund's adjuvant and PBS. Mice were also given 150 ng of pertussis
toxin in PBS i.p. on the same day as PLP emulsion injection and 2
days later. Starting day 7 after immunization, mice were given the
RXR agonist 194204 (50 ug) or vehicle control i.p. every other day
for the duration of the experiment (n=6 mice/group). Mice were
scored using the scale described in Example 6.
[0192] The results indicate that administration of a RXR agonist
significantly reduces the symptoms of EAE in mice. Table 3 shows
the features of a RXR agonist 194204 treatment in SLJ mice. FIG. 7
depicts scores of disease severity over time. Efficacy of the RXR
agonist was observed after the second administration (day 8) and
maintained throughout the course of the study (day 14).
TABLE-US-00003 TABLE 3 RXR agonist Treatment in SJL Mice Clinical
Features Vehicle 4204 Mean Maximum Score 3.2 .+-. 0.6 1.5 .+-. 1.4
Disease Incidence 6/6 4/6 Death from Disease 4/6 0/6
[0193] In closing, it is to be understood that although aspects of
the present specification are highlighted by referring to specific
embodiments, one skilled in the art will readily appreciate that
these disclosed embodiments are only illustrative of the principles
of the subject matter disclosed herein. Therefore, it should be
understood that the disclosed subject matter is in no way limited
to a particular methodology, protocol, and/or reagent, etc.,
described herein. As such, various modifications or changes to or
alternative configurations of the disclosed subject matter can be
made in accordance with the teachings herein without departing from
the spirit of the present specification. Lastly, the terminology
used herein is for the purpose of describing particular embodiments
only, and is not intended to limit the scope of the present
invention, which is defined solely by the claims. Accordingly, the
present invention is not limited to that precisely as shown and
described.
[0194] Certain embodiments of the present invention are described
herein, including the best mode known to the inventors for carrying
out the invention. Of course, variations on these described
embodiments will become apparent to those of ordinary skill in the
art upon reading the foregoing description. The inventor expects
skilled artisans to employ such variations as appropriate, and the
inventors intend for the present invention to be practiced
otherwise than specifically described herein. Accordingly, this
invention includes all modifications and equivalents of the subject
matter recited in the claims appended hereto as permitted by
applicable law. Moreover, any combination of the above-described
embodiments in all possible variations thereof is encompassed by
the invention unless otherwise indicated herein or otherwise
clearly contradicted by context.
[0195] Groupings of alternative embodiments, elements, or steps of
the present invention are not to be construed as limitations. Each
group member may be referred to and claimed individually or in any
combination with other group members disclosed herein. It is
anticipated that one or more members of a group may be included in,
or deleted from, a group for reasons of convenience and/or
patentability. When any such inclusion or deletion occurs, the
specification is deemed to contain the group as modified thus
fulfilling the written description of all Markush groups used in
the appended claims.
[0196] Unless otherwise indicated, all numbers expressing a
characteristic, item, quantity, parameter, property, term, and so
forth used in the present specification and claims are to be
understood as being modified in all instances by the term "about."
As used herein, the term "about" means that the characteristic,
item, quantity, parameter, property, or term so qualified
encompasses a range of plus or minus ten percent above and below
the value of the stated characteristic, item, quantity, parameter,
property, or term. Accordingly, unless indicated to the contrary,
the numerical parameters set forth in the specification and
attached claims are approximations that may vary. At the very
least, and not as an attempt to limit the application of the
doctrine of equivalents to the scope of the claims, each numerical
indication should at least be construed in light of the number of
reported significant digits and by applying ordinary rounding
techniques. Notwithstanding that the numerical ranges and values
setting forth the broad scope of the invention are approximations,
the numerical ranges and values set forth in the specific examples
are reported as precisely as possible. Any numerical range or
value, however, inherently contains certain errors necessarily
resulting from the standard deviation found in their respective
testing measurements. Recitation of numerical ranges of values
herein is merely intended to serve as a shorthand method of
referring individually to each separate numerical value falling
within the range. Unless otherwise indicated herein, each
individual value of a numerical range is incorporated into the
present specification as if it were individually recited
herein.
[0197] The terms "a," "an," "the" and similar referents used in the
context of describing the present invention (especially in the
context of the following claims) are to be construed to cover both
the singular and the plural, unless otherwise indicated herein or
clearly contradicted by context. All methods described herein can
be performed in any suitable order unless otherwise indicated
herein or otherwise clearly contradicted by context. The use of any
and all examples, or exemplary language (e.g., "such as") provided
herein is intended merely to better illuminate the present
invention and does not pose a limitation on the scope of the
invention otherwise claimed. No language in the present
specification should be construed as indicating any non-claimed
element essential to the practice of the invention.
[0198] Specific embodiments disclosed herein may be further limited
in the claims using consisting of or consisting essentially of
language. When used in the claims, whether as filed or added per
amendment, the transition term "consisting of" excludes any
element, step, or ingredient not specified in the claims. The
transition term "consisting essentially of" limits the scope of a
claim to the specified materials or steps and those that do not
materially affect the basic and novel characteristic(s).
Embodiments of the present invention so claimed are inherently or
expressly described and enabled herein.
[0199] All patents, patent publications, and other publications
referenced and identified in the present specification are
individually and expressly incorporated herein by reference in
their entirety for the purpose of describing and disclosing, for
example, the compositions and methodologies described in such
publications that might be used in connection with the present
invention. These publications are provided solely for their
disclosure prior to the filing date of the present application.
Nothing in this regard should be construed as an admission that the
inventors are not entitled to antedate such disclosure by virtue of
prior invention or for any other reason. All statements as to the
date or representation as to the contents of these documents is
based on the information available to the applicants and does not
constitute any admission as to the correctness of the dates or
contents of these documents.
* * * * *