U.S. patent application number 15/765801 was filed with the patent office on 2019-04-18 for activators of autophagic flux and phospholipase d and clearance of protein aggregates including tau and treatment of proteinopathies.
The applicant listed for this patent is NY STATE PSYCHIATRIC INSTITUTE, The Trustees of Columbia University in the City of New York. Invention is credited to Shi-Xian Deng, Karen Duff, Donald Landry, Kirsten Alison Rinderspacher, Wai Yu.
Application Number | 20190112317 15/765801 |
Document ID | / |
Family ID | 58488491 |
Filed Date | 2019-04-18 |
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United States Patent
Application |
20190112317 |
Kind Code |
A1 |
Rinderspacher; Kirsten Alison ;
et al. |
April 18, 2019 |
ACTIVATORS OF AUTOPHAGIC FLUX AND PHOSPHOLIPASE D AND CLEARANCE OF
PROTEIN AGGREGATES INCLUDING TAU AND TREATMENT OF
PROTEINOPATHIES
Abstract
The present application discloses compounds which are activators
of autophagic flux and pharmaceutical compositions comprising said
activators. It further discloses use of said compounds and
pharmaceutical compositions in the treatment of neurodegenerative
diseases, particularly proteinopathies and tauopathies such as
Alzheimer's disease. It further discloses methods of enhancing
autophagic flux.
Inventors: |
Rinderspacher; Kirsten Alison;
(Bronx, NY) ; Yu; Wai; (New York, NY) ;
Duff; Karen; (New York, NY) ; Landry; Donald;
(New York, NY) ; Deng; Shi-Xian; (White Plains,
NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
The Trustees of Columbia University in the City of New York
NY STATE PSYCHIATRIC INSTITUTE |
New York
New York |
NY
NY |
US
US |
|
|
Family ID: |
58488491 |
Appl. No.: |
15/765801 |
Filed: |
October 5, 2016 |
PCT Filed: |
October 5, 2016 |
PCT NO: |
PCT/US16/55561 |
371 Date: |
April 4, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62237342 |
Oct 5, 2015 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 239/88 20130101;
C07D 401/12 20130101; C07D 239/94 20130101; C07D 513/04 20130101;
C07D 217/22 20130101; A61P 25/28 20180101; C07D 491/048 20130101;
C07D 239/86 20130101; C07D 239/93 20130101; C07D 471/04 20130101;
C07D 403/12 20130101; C07D 405/12 20130101; A61K 31/517 20130101;
C07D 495/04 20130101; C07D 491/04 20130101 |
International
Class: |
C07D 513/04 20060101
C07D513/04; A61K 31/517 20060101 A61K031/517; C07D 217/22 20060101
C07D217/22; C07D 239/88 20060101 C07D239/88; C07D 239/93 20060101
C07D239/93; C07D 239/94 20060101 C07D239/94; C07D 401/12 20060101
C07D401/12; C07D 403/12 20060101 C07D403/12; C07D 405/12 20060101
C07D405/12; C07D 491/048 20060101 C07D491/048; A61P 25/28 20060101
A61P025/28 |
Claims
1. A compound having the formula (II): ##STR00171## wherein Y.sup.1
and Y.sup.2 are, independently selected from the group consisting
of CH and wherein X is selected from the group consisting of H,
halide, and aryl; wherein R.sup.1 is selected from the group
consisting of optionally substituted thioheteroaryl,
hydroxyl-substituted (2-aminoethyl)aryl, halide, optionally
substituted thiocycloalkyl wherein 1-3 carbon atoms of the
cycloalkyl is optionally replaced with a heteroatom selected from
the group consisting of O, S and N, and thioaryl, or a salt,
enantiomer, racemate, mixture thereof, or combination thereof.
2. The compound of claim 1, wherein the compound is selected from
the group consisting of: ##STR00172## ##STR00173## or a salt,
enantiomer, racemate, mixture thereof, or combination thereof.
3. The compound of claim 1, wherein the compound is: ##STR00174##
or a salt, enantiomer, racemate, mixture thereof, or combination
thereof.
4. The compound of claim 1, wherein the compound is: ##STR00175##
or a salt, enantiomer, racemate, mixture thereof, or combination
thereof.
5. A compound having the formula (III): ##STR00176## wherein
Y.sup.1 is CH; wherein Y.sup.2 is N; wherein X is halide; wherein
R.sup.1 is selected from the group consisting of optionally
substituted thioheteroaryl, optionally substituted
(2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl
wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced
with a heteroatom selected from the group consisting of O, S and N,
and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or
combination thereof.
6. The compound of claim 5, wherein the compound is selected from
the group consisting of: ##STR00177## or a salt, enantiomer,
racemate, mixture thereof, or combination thereof.
7. A compound having the formula (IV): ##STR00178## wherein X is
halide; wherein R.sup.1 is selected from the group consisting of
optionally substituted thioheteroaryl, optionally substituted
(2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl
wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced
with a heteroatom selected from the group consisting of O, S and N,
and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or
combination thereof.
8. The compound of claim 7, wherein the compound is selected from
the group consisting of: ##STR00179## or a salt, enantiomer,
racemate, mixture thereof, or combination thereof.
9. A compound having the formula (V): ##STR00180## wherein X is H;
wherein R.sup.1 is selected from the group consisting of optionally
substituted thioheteroaryl, optionally substituted
(2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl
wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced
with a heteroatom selected from the group consisting of O, S and N,
and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or
combination thereof.
10. The compound of claim 9, wherein the compound is selected from
the group consisting of: ##STR00181## or a salt, enantiomer,
racemate, mixture thereof, or combination thereof.
11. A compound having the formula (VI): ##STR00182## wherein X is
H; wherein R.sup.1 is selected from the group consisting of
optionally substituted thioheteroaryl, optionally substituted
(2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl
wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced
with a heteroatom selected from the group consisting of O, S and N,
and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or
combination thereof.
12. The compound of claim 11, wherein the compound is selected from
the group consisting of: ##STR00183## or a salt, enantiomer,
racemate, mixture thereof, or combination thereof.
13. A compound having the formula (VII): ##STR00184## wherein
R.sup.1 is selected from the group consisting of optionally
substituted thioheteroaryl, optionally substituted
(2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl
wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced
with a heteroatom selected from the group consisting of O, S and N,
and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or
combination thereof.
14. The compound of claim 13, wherein the compound is selected from
the group consisting of: ##STR00185## or a salt, enantiomer,
racemate, mixture thereof, or combination thereof.
15. A compound having the formula (VIII): ##STR00186## wherein
R.sup.1 is selected from the group consisting of optionally
substituted thioheteroaryl, optionally substituted
(2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl
wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced
with a heteroatom selected from the group consisting of O, S and N,
and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or
combination thereof.
16. The compound of claim 15, wherein the compound is selected from
the group consisting of: ##STR00187## or a salt, enantiomer,
racemate, mixture thereof, or combination thereof.
17. A compound having the formula (IX): ##STR00188## wherein
Y.sup.3 is CH or N; wherein R.sup.2 is optionally substituted
(2-aminoethyl)aryl, or a salt, enantiomer, racemate, mixture
thereof, or combination thereof.
18. The compound of claim 17, wherein the compound is selected from
the group consisting of: ##STR00189## or a salt, enantiomer,
racemate, mixture thereof, or combination thereof.
19. A compound having the formula (X): ##STR00190## wherein Y.sup.3
is CH; wherein R.sup.2 is selected from the group consisting of
optionally substituted thioheteroaryl, optionally substituted
(2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl
wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced
with a heteroatom selected from the group consisting of O, S and N,
and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or
combination thereof.
20. The compound of claim 19, wherein the compound is selected from
the group consisting of: ##STR00191## or a salt, enantiomer,
racemate, mixture thereof, or combination thereof.
21. A compound having the formula (XI): ##STR00192## wherein
R.sup.2 is selected from the group consisting of optionally
substituted thioheteroaryl, optionally substituted
(2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl
wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced
with a heteroatom selected from the group consisting of O, S and N,
and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or
combination thereof.
22. The compound of claim 21, wherein the compound is selected from
the group consisting of: ##STR00193## or a salt, enantiomer,
racemate, mixture thereof, or combination thereof.
23. A compound having the formula (XII): ##STR00194## wherein
Y.sup.4 is CH or N; wherein R.sup.3 is selected from the group
consisting of optionally substituted thioheteroaryl, optionally
substituted (2-aminoethyl)aryl, halide, optionally substituted
thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is
optionally replaced with a heteroatom selected from the group
consisting of O, S and N, and thioaryl, or a salt, enantiomer,
racemate, mixture thereof, or combination thereof.
24. The compound of claim 23, wherein the compound is selected from
the group consisting of: ##STR00195## or a salt, enantiomer,
racemate, mixture thereof, or combination thereof.
25. A compound having the formula (XIII): ##STR00196## wherein
R.sup.2 is selected from the group consisting of optionally
substituted thioheteroaryl, optionally substituted
(2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl
wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced
with a heteroatom selected from the group consisting of O, S and N,
and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or
combination thereof.
26. The compound of claim 25, wherein the compound is selected from
the group consisting of: ##STR00197## or a salt, enantiomer,
racemate, mixture thereof, or combination thereof.
27. A compound having the formula (XIV): ##STR00198## wherein
R.sup.2 is selected from the group consisting of optionally
substituted thioheteroaryl, optionally substituted
(2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl
wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced
with a heteroatom selected from the group consisting of O, S and N,
and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or
combination thereof.
28. The compound of claim 27, wherein the compound is selected from
the group consisting of: ##STR00199## or a salt, enantiomer,
racemate, mixture thereof, or combination thereof.
29. A compound having the formula (XV): ##STR00200## wherein X is H
or halide; wherein Z.sup.1 is O; wherein R.sup.4 is selected from
the group consisting of H, optionally substituted alkyl, Et,
CF.sub.3, optionally substituted cycloalkyl, optionally substituted
aryl, optionally substituted heteroaryl, and ##STR00201##
30. The compound of claim 29, wherein the compound is selected from
the group consisting of: ##STR00202## or a salt, enantiomer,
racemate, mixture thereof, or combination thereof.
31. The compound of claim 29 wherein the compound is: ##STR00203##
or a salt, enantiomer, racemate, mixture thereof, or combination
thereof.
32. A pharmaceutical composition comprising a compound of any one
of claims 1-31 or a pharmaceutically acceptable salt thereof.
33. A method of treating a neurodegenerative disease comprising
administering to a subject in need thereof an effective amount of a
compound of any one of claims 1-31 or pharmaceutical composition of
claim 32.
34. The method of claim 33, wherein the neurodegenerative disease
is a proteinopathy.
35. The method of claim 34, wherein the proteinopathy is a
tauopathy.
36. The method of claim 33, wherein the neurodegenerative disease
is Alzheimer's disease.
37. A method of enhancing autophagic flux comprising providing to a
cell or a protein aggregate an effective amount of a compound of
any one of claims 1-31 or pharmaceutical composition of claim 32.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims benefit to U.S. Provisional
Application Ser. No. 62/237,342, filed Oct. 5, 2015. The entire
contents of the above application are incorporated by reference as
if recited in full herein.
FIELD OF THE DISCLOSURE
[0002] The present disclosure relates to compounds which are
activators of autophagic flux and pharmaceutical compositions
comprising said compounds. It further relates to use of said
compounds in the treatment of neurodegenerative diseases,
particularly Alzheimer's disease.
BACKGROUND OF THE INVENTION
[0003] Alzheimer's disease (AD) affects approximately five million
Americans and this number is predicted to triple by 2050. At
present, there are no therapies to treat Alzheimer's or other
related tauopathies. While clinical trials using immunotherapy
targeting amyloid beta (A.beta.) have had limited success, this in
only subset of those afflicted with AD or other neurodegenerative
diseases. Moreover, there are no therapies targeting other
proteinopathies, including tau, the other major neuropathological
component of AD. AD accounts for most of the dementias afflicting
individuals over 65 and is estimated to cost $226 billion in
healthcare, long-term care, and hospice for people with AD and
other dementias annually. This extensive economic and societal
burden does not account for lost income of many at-home primary
caregivers including spouses and other family members.
[0004] Enhancing autophagy has been shown to have therapeutic
potential in the treatment of Alzheimer's disease. Autophagic flux
(including the fusion of autophagosomes to lysosomes) is a novel
regulator of autophagy as it leads to the clearance of protein
aggregates and reversal of pathophysiological decline. Therefore,
there exists an ongoing need for promoters of autophagic flux and
the clearance of autophagosomes bearing proteinopathies.
SUMMARY OF THE INVENTION
[0005] In some embodiments, compounds including pharmaceutically
acceptable salts thereof, which are disclosed herein, are
provided.
[0006] In some embodiments a pharmaceutical composition is provided
comprising a compound disclosed herein or a pharmaceutically
acceptable salt thereof. In other embodiments, methods of making
the compounds and pharmaceutical compositions are also provided in,
e.g., the Examples provided below.
[0007] In some embodiments a method of treating a neurodegenerative
disease comprising administering to a subject in need thereof an
effective amount of a compound or pharmaceutical composition
disclosed herein is provided.
[0008] In some embodiments a method of enhancing autophagic flux is
provided. This method comprises providing to a cell or a protein
aggregate an effective amount of a compound or pharmaceutical
composition disclosed herein.
[0009] These and other aspects of the invention are further
disclosed in the detailed description and examples which
follow.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] The following drawings form part of the present
specification and are included to further demonstrate certain
aspects of the present invention. The invention may be better
understood by reference to one or more of these drawings in
combination with the detailed description of specific embodiments
presented herein.
[0011] FIG. 1 is a graph showing a photodiode array (PDA) spectrum
of WHYKD8 in mouse brain.
[0012] FIG. 2 shows Western blots of LC3-II levels in primary
cortical neurons following a 6 hour treatment with WHYKD1
(.+-.BafA1) or WHYKD5.
[0013] FIG. 3 shows Western blots of LC3-II, tau, and p62 levels in
organotypic slice cultures following a 6 hour treatment with WHYKD1
(top) or WHYKD3, WHYKD5, WHYKD8, WHYKD9, or WHYKD12 (bottom).
[0014] FIG. 4 is a bar graph showing the activation of
phospholipase D (PLD) by the WHYKD series compounds (10 .mu.M), and
their ability to convert phospholipids to phosphatidylethanols in
the presence of ethanol. C=Control, 12=WHYKD12, 15=WHYKD15,
19=WHYKD19, 5=WHYKD5, 8=WHYKD8, Fipi=a noncompetitive inhibitor of
PLD activity.
[0015] FIG. 5 is a bar graph showing the activation of
phospholipase D (PLD) by the WHYKD series compounds (1 .mu.M), and
their ability to convert phospholipids to phosphatidylethanols in
the presence of ethanol.
DETAILED DESCRIPTION OF THE INVENTION
[0016] Although macroautophagy is known to be an essential
degradative process whereby autophagosomes mediate the engulfment
and delivery of cytoplasmic components into lysosomes, the lipid
changes underlying autophagosomal membrane dynamics are
undetermined. The inventors have previously shown that PLD1, which
is primarily associated with the endosomal system, partially
relocalizes to the outer membrane of autophagosome-like structures
upon nutrient starvation (Dall'Armi, 2010). The localization of
PLD1, as well as the starvation-induced increase in PLD activity,
are altered by wortmannin, a phosphatidylinositol 3-kinase
inhibitor, suggesting PLD1 may act downstream of Vps34.
Pharmacological inhibition of PLD and genetic ablation of PLD1 in
mouse cells decreased the starvation-induced expansion of
LC3-positive compartments, consistent with a role of PLD1 in the
regulation of autophagy. Furthermore, inhibition of PLD results in
higher levels of tau and p62 aggregates in organotypic brain
slices. These in vitro and in vivo findings establish a role for
PLD1 in autophagy.
[0017] In some embodiments, a compound is provided having the
formula (II):
##STR00001##
wherein Y.sup.1 and Y.sup.2 are independently selected from the
group consisting of CH and wherein X is selected from the group
consisting of H, halide, and aryl; wherein R.sup.1 is selected from
the group consisting of optionally substituted thioheteroaryl,
hydroxyl-substituted (2-aminoethyl)aryl, halide, optionally
substituted thiocycloalkyl wherein 1-3 carbon atoms of the
cycloalkyl is optionally replaced with a heteroatom selected from
the group consisting of O, S and N, and thioaryl, or a salt,
enantiomer, racemate, mixture thereof, or combination thereof.
[0018] In some embodiments, the compound is selected from the group
consisting of:
##STR00002## ##STR00003## ##STR00004##
or a salt, enantiomer, racemate, mixture thereof, or combination
thereof.
[0019] In one embodiment the compound is:
##STR00005##
or a salt, enantiomer, racemate, mixture thereof, or combination
thereof.
[0020] In another embodiment the compound is:
##STR00006##
or a salt, enantiomer, racemate, mixture thereof, or combination
thereof.
[0021] In some embodiments, a compound is provided having the
formula (III):
##STR00007##
wherein Y.sup.1 is CH; wherein Y.sup.2 is N; wherein X is halide;
wherein R.sup.1 is selected from the group consisting of optionally
substituted thioheteroaryl, optionally substituted
(2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl
wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced
with a heteroatom selected from the group consisting of O, S and N,
and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or
combination thereof.
[0022] In some embodiments, the compound is selected from the group
consisting of:
##STR00008##
or a salt, enantiomer, racemate, mixture thereof, or combination
thereof.
[0023] In some embodiments, a compound is provided having the
formula (IV):
##STR00009##
wherein X is halide; wherein R.sup.1 is selected from the group
consisting of optionally substituted thioheteroaryl, optionally
substituted (2-aminoethyl)aryl, halide, optionally substituted
thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is
optionally replaced with a heteroatom selected from the group
consisting of O, S and N, and thioaryl, or a salt, enantiomer,
racemate, mixture thereof, or combination thereof.
[0024] In some embodiments, the compound is selected from the group
consisting of:
##STR00010##
or a salt, enantiomer, racemate, mixture thereof, or combination
thereof.
[0025] In some embodiments, a compound is provided having the
formula (V):
##STR00011##
wherein X is H; wherein R.sup.1 is selected from the group
consisting of optionally substituted thioheteroaryl, optionally
substituted (2-aminoethyl)aryl, halide, optionally substituted
thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is
optionally replaced with a heteroatom selected from the group
consisting of O, S and N, and thioaryl, or a salt, enantiomer,
racemate, mixture thereof, or combination thereof.
[0026] In some embodiments, the compound is selected from the group
consisting of:
##STR00012##
or a salt, enantiomer, racemate, mixture thereof, or combination
thereof.
[0027] In some embodiments, a compound is provided having the
formula (VI):
##STR00013##
wherein X is H; wherein R.sup.1 is selected from the group
consisting of optionally substituted thioheteroaryl, optionally
substituted (2-aminoethyl)aryl, halide, optionally substituted
thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is
optionally replaced with a heteroatom selected from the group
consisting of O, S and N, and thioaryl, or a salt, enantiomer,
racemate, mixture thereof, or combination thereof.
[0028] In some embodiments, the compound is selected from the group
consisting of:
##STR00014##
or a salt, enantiomer, racemate, mixture thereof, or combination
thereof.
[0029] In some embodiments, a compound is provided having the
formula (VII):
##STR00015##
wherein R.sup.1 is selected from the group consisting of optionally
substituted thioheteroaryl, optionally substituted
(2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl
wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced
with a heteroatom selected from the group consisting of O, S and N,
and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or
combination thereof.
[0030] In some embodiments, the compound is selected from the group
consisting of:
##STR00016##
or a salt, enantiomer, racemate, mixture thereof, or combination
thereof.
[0031] In some embodiments, a compound is provided having the
formula (VIII):
##STR00017##
wherein R.sup.1 is selected from the group consisting of optionally
substituted thioheteroaryl, optionally substituted
(2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl
wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced
with a heteroatom selected from the group consisting of O, S and N,
and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or
combination thereof.
[0032] In some embodiments, the compound is selected from the group
consisting of:
##STR00018##
or a salt, enantiomer, racemate, mixture thereof, or combination
thereof.
[0033] In some embodiments, a compound is provided having the
formula (IX):
##STR00019##
wherein Y.sup.3 is CH or N; wherein R.sup.2 is optionally
substituted (2-aminoethyl)aryl, or a salt, enantiomer, racemate,
mixture thereof, or combination thereof.
[0034] In some embodiments, the compound is selected from the group
consisting of:
##STR00020##
or a salt, enantiomer, racemate, mixture thereof, or combination
thereof.
[0035] In some embodiments, a compound is provided having the
formula (X):
##STR00021##
wherein Y.sup.3 is CH; wherein R.sup.2 is selected from the group
consisting of optionally substituted thioheteroaryl, optionally
substituted (2-aminoethyl)aryl, halide, optionally substituted
thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is
optionally replaced with a heteroatom selected from the group
consisting of O, S and N, and thioaryl, or a salt, enantiomer,
racemate, mixture thereof, or combination thereof.
[0036] In some embodiments, the compound is selected from the group
consisting of:
##STR00022##
or a salt, enantiomer, racemate, mixture thereof, or combination
thereof.
[0037] In some embodiments, a compound is provided having the
formula (XI):
##STR00023##
wherein R.sup.2 is selected from the group consisting of optionally
substituted thioheteroaryl, optionally substituted
(2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl
wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced
with a heteroatom selected from the group consisting of O, S and N,
and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or
combination thereof.
[0038] In some embodiments, the compound is selected from the group
consisting of:
##STR00024##
or a salt, enantiomer, racemate, mixture thereof, or combination
thereof.
[0039] In some embodiments, a compound is provided having the
formula (XII):
##STR00025##
wherein Y.sup.4 is CH or N; wherein R.sup.3 is selected from the
group consisting of optionally substituted thioheteroaryl,
optionally substituted (2-aminoethyl)aryl, halide, optionally
substituted thiocycloalkyl wherein 1-3 carbon atoms of the
cycloalkyl is optionally replaced with a heteroatom selected from
the group consisting of O, S and N, and thioaryl, or a salt,
enantiomer, racemate, mixture thereof, or combination thereof.
[0040] In some embodiments, the compound is selected from the group
consisting of:
##STR00026##
or a salt, enantiomer, racemate, mixture thereof, or combination
thereof.
[0041] In some embodiments, a compound is provided having the
formula (XIII):
##STR00027##
wherein R.sup.2 is selected from the group consisting of optionally
substituted thioheteroaryl, optionally substituted
(2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl
wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced
with a heteroatom selected from the group consisting of O, S and N,
and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or
combination thereof.
[0042] In some embodiments, the compound is selected from the group
consisting of:
##STR00028##
or a salt, enantiomer, racemate, mixture thereof, or combination
thereof.
[0043] In some embodiments, a compound is provided having the
formula (XIV):
##STR00029##
wherein R.sup.2 is selected from the group consisting of optionally
substituted thioheteroaryl, optionally substituted
(2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl
wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced
with a heteroatom selected from the group consisting of O, S and N,
and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or
combination thereof.
[0044] In some embodiments, the compound is selected from the group
consisting of:
##STR00030##
or a salt, enantiomer, racemate, mixture thereof, or combination
thereof.
[0045] In some embodiments, a compound is provided having the
formula (XV):
##STR00031##
wherein X is H or halide; wherein Z.sup.1 is O; wherein R.sup.4 is
selected from the group consisting of H, optionally substituted
alkyl, Et, CF.sub.3, optionally substituted cycloalkyl, optionally
substituted aryl, optionally substituted heteroaryl, and
##STR00032##
[0046] In some embodiments, the compound is selected from the group
consisting of:
##STR00033##
or a salt, enantiomer, racemate, mixture thereof, or combination
thereof.
[0047] In one embodiment the compound is
##STR00034##
or a salt, enantiomer, racemate, mixture thereof, or combination
thereof.
[0048] In some embodiments a pharmaceutical composition is provided
comprising a compound disclosed herein or a pharmaceutically
acceptable salt thereof.
[0049] In some embodiments a method of treating a neurodegenerative
disease comprising administering to a subject in need thereof an
effective amount of a compound or pharmaceutical composition
disclosed herein is provided. In some embodiments the
neurodegenerative disease is a proteinopathy. Proteinopathies
include, but are not limited to, Parkinson's disease, Alzheimer's
disease, Amyotrophic Lateral Sclerosis (ALS), Huntington's disease,
chronic traumatic encephalopathy (CTE), frontotemporal dementia
(FTD), inclusion body myopathy (IBM), Paget's disease of bone
(PDB), cerebral .beta.-amyloid angiopathy, prion diseases, familial
dementia, CADASIL, amyloidosis, Alexander disease, seipinopathies,
type II diabetes, pulmonary alveolar proteinosis, cataracts, cystic
fibrosis and sickle cell disease. In some aspects of this
embodiment, the proteinopathy is a tauopathy. Tauopothies include
but are not limited to, Alzheimer's disease, Parkinson's disease,
Huntington's disease, progressive supranuclear palsy, chronic
traumatic encephalopathy (CTE), frontotemporal dementia (FTD),
Lytico-Bodig disease, subacute sclerosing panencephalitis,
ganglioglioma, gangliocytoma, and argyrophilic grain disease. In a
preferred embodiment, the neurodegenerative disease is Alzheimer's
disease.
[0050] In some embodiments a method of enhancing autophagic flux is
provided. This method comprises providing to a cell or a protein
aggregate an effective amount of a compound or pharmaceutical
composition disclosed herein.
[0051] The embodiments described in this disclosure can be combined
in various ways. Any aspect or feature that is described for one
embodiment can be incorporated into any other embodiment mentioned
in this disclosure. While various novel features of the inventive
principles have been shown, described and pointed out as applied to
particular embodiments thereof, it should be understood that
various omissions and substitutions and changes may be made by
those skilled in the art without departing from the spirit of this
disclosure. Those skilled in the art will appreciate that the
inventive principles can be practiced in other than the described
embodiments, which are presented for purposes of illustration and
not limitation.
EXAMPLES
[0052] The following examples are provided to further illustrate
certain aspects of the present invention. These examples are
illustrative only and are not intended to limit the scope of the
invention in any way.
Example 1
Example Synthetic Schemes
[0053] Scheme 1 shows the synthesis of compounds of the
formula:
##STR00035##
e.g., compounds of formula (II) and formula (III).
##STR00036##
[0054] Scheme 2 shows preparation of
1-chloro-7-fluoroisoquinoline.
##STR00037##
[0055] Scheme 3 shows the synthesis of compounds of the
formula:
##STR00038##
e.g., compounds of formula (IV), formula (V), formula (VI), formula
(VII), and formula (VIII).
##STR00039##
[0056] Scheme 4 shows the synthesis of compounds of the
formula:
##STR00040##
e.g., compounds of formula (XII), and formula (XIII).
##STR00041##
[0057] Scheme 5 shows the synthesis of compounds of the
formula:
##STR00042##
e.g., compounds of formula (IX), formula (X), and formula (XI).
##STR00043##
[0058] Scheme 6 shows the synthesis of compounds of the
formula:
##STR00044##
e.g., compounds of formula (XIV).
##STR00045##
Example 2
Activators of Autophagic Flux and Phospholipase D
[0059] The WHYKD series of compounds were synthesized for optimal
brain penetrance based on the molecular weight (MW) and partition
coefficient (log P), according to Lipinski's Rule for CNS
penetrance: MW.ltoreq.400, log P.ltoreq.5.
[0060] Activators according to the formula:
##STR00046##
were synthesized according to the schemes above. Molecular weights
and log P were calculated. Results are shown in Table 1 below.
TABLE-US-00001 TABLE 1 PROJECT STRUCTURE ID M.W. log P X Y.sup.1
Y.sup.2 R.sup.1 ##STR00047## WHYKD3 323.17 3.85 Br N N
thioheteroaryl ##STR00048## WHYKD4 369.44 5.69 aryl N N
Thioheteroaryl ##STR00049## WHYKD5 262.27 3.18 F N N Thioheteroaryl
##STR00050## WHYKD6 244.48 3.02 H N N thioheteroaryl ##STR00051##
WHYKD7 278.72 3.58 Cl N N thioheteroaryl ##STR00052## WHYKD8 299.76
3.91 Cl N N (2- aminoethyl)aryl ##STR00053## WHYKD9 182.58 2.58 F N
N Cl ##STR00054## WHYKD10 243.29 2.9 H N CH thioheteroaryl
##STR00055## WHYKD11 261.28 3.06 F N CH thioheteroaryl ##STR00056##
WHYKD12 262.35 4.35 F N N thiocycloalkyl ##STR00057## WHYKD13
316.44 5.21 F N N thiocycloalkyl ##STR00058## WHYKD14 314.42 4.66 F
N N thiocycloalkyl ##STR00059## WHYKD15 248.32 3.96 F N N
thiocycloalkyl ##STR00060## WHYKD16 274.36 4.19 F N N
thiocycloalkyl ##STR00061## WHYKD17 357.49 4.09 F N N
thiocycloalkyl ##STR00062## WHYKD18 386.48 4.41 F N N
thiocycloalkyl ##STR00063## WHYKD19 264.32 2.63 F N N
thiocycloalkyl ##STR00064## WHYKD20 296.36 4.8 F N N thioaryl
[0061] Activators according to the formula:
##STR00065##
were synthesized according to the schemes above. Molecular weights
and log P were calculated. Results are shown in Table 2 below.
TABLE-US-00002 TABLE 2 PROJECT STRUCTURE ID M.W. log P Y.sup.3
R.sup.2 ##STR00066## WHYKD21 272.33 3.36 N (2- aminoethyl)aryl
##STR00067## WHYKD23 271.34 3.66 CH (2- aminoethyl)aryl
Activators according to the formula:
##STR00068##
were synthesized according to the schemes above. Molecular weights
and log P were calculated. Results are shown in Table 3 below.
TABLE-US-00003 TABLE 3 PROJECT STRUCTURE ID M.W. log P Y.sup.4
R.sup.3 ##STR00069## WHYKD1 251.29 2.56 N thioheteroaryl
##STR00070## WHYKD2 272.33 2.89 N (2- aminoethyl)aryl ##STR00071##
WHYKD22 271.34 3.34 CH (2- aminoethyl)aryl
[0062] Activators according to the formula:
##STR00072##
were synthesized according to the schemes above. Molecular weights
and log P were calculated. Results are shown in Table 4 below.
TABLE-US-00004 TABLE 4 PROJECT log STRUCTURE ID M.W. P X Y.sup.1
Y.sup.2 R.sup.4 Z.sup.1 ##STR00073## WHYKD24 164.14 1.02 F N N H
O
Example 3
Design of Derivatives
[0063] Several series of derivatives were synthesized based on the
following lead compounds:
##STR00074##
In addition to log P, the topological polar surface area (tPSA), C
Log P (log P calculated by group contribution method), and Log S
(solubility) were calculated. Results are shown in the Tables
below.
TABLE-US-00005 TABLE 5 Modifications to the core and side chain
(Series 1) STRUCTURE log P tPSA CLogP LogS ##STR00075## 3.35 52.68
2.65154 -3.235 ##STR00076## 3.12 61.47 2.34241 -3.295 ##STR00077##
2.94 40.32 1.83259 -4.663 ##STR00078## 3.19 27.96 3.25375 -3.864
##STR00079## 4.14 12.36 4.64041 -4.354 ##STR00080## 2.71 49.11
2.01759 -4.354 ##STR00081## 2.95 36.75 3.23654 -3.554 ##STR00082##
2.8 21.59 2.80041 -3.813 ##STR00083## 4.56 12.36 5.19941 -4.832
TABLE-US-00006 TABLE 6 Modifications to the core and side chain
(Series 2) STRUCTURE log P tPSA CLogP LogS ##STR00084## 2.31 77.4
0.803829 -1.704 ##STR00085## 2.07 86.19 0.539011 -1.765
##STR00086## 1.9 65.04 -0.0366305 -3.133 ##STR00087## 1.66 73.83
0.148224 -2.824 ##STR00088## 2.14 52.68 1.40054 -2.334 ##STR00089##
1.91 61.47 1.38428 -2.024 ##STR00090## 3.09 37.08 2.83701 -2.823
##STR00091## 3.51 37.08 3.39601 -3.301 ##STR00092## 1.76 46.31
0.997011 -2.283
TABLE-US-00007 TABLE 7 Modifications to the core and side chain
(Series 3) STRUCTURE log P tPSA CLogP LogS ##STR00093## 2.89 77.4
0.647513 -1.626 ##STR00094## 2.65 86.19 0.382662 -1.686
##STR00095## 2.48 65.04 -0.192932 -3.117 ##STR00096## 2.25 73.83
-0.00808129 -2.806 ##STR00097## 2.73 52.68 1.24423 -2.303
##STR00098## 2.49 61.47 1.22796 -1.992 ##STR00099## 3.68 37.08
2.68066 -2.893 ##STR00100## 4.09 37.08 3.23966 -3.372 ##STR00101##
2.34 46.31 0.840662 -2.256
TABLE-US-00008 TABLE 8 Modifications to the core and side chain
(Series 4) STRUCTURE log P tPSA CLogP LogS ##STR00102## 1.68 77.4
0.647513 -1.441 ##STR00103## 1.45 86.19 0.382662 -1.501
##STR00104## 1.28 65.04 -0.192932 -2.932 ##STR00105## 1.04 73.83
-0.00808129 -2.621 ##STR00106## 1.52 52.68 1.24423 -2.119
##STR00107## 1.28 61.47 1.22796 -1.808 ##STR00108## 2.47 37.08
2.68066 -2.704 ##STR00109## 2.89 37.08 3.23966 -3.183 ##STR00110##
1.13 46.31 0.840662 -2.071
TABLE-US-00009 TABLE 9 Modifications to the core and side chain
(Series 5) STRUCTURE log P tPSA CLogP LogS ##STR00111## 1.68 77.4
0.647513 -1.466 ##STR00112## 1.45 86.19 0.382662 -1.526
##STR00113## 1.28 65.04 -0.192932 -2.957 ##STR00114## 1.04 73.83
-0.00808129 -2.646 ##STR00115## 1.52 52.68 1.24423 -2.144
##STR00116## 1.28 61.47 1.22796 -1.832 ##STR00117## 2.47 37.08
2.68066 -2.733 ##STR00118## 2.89 37.08 3.23966 -3.212 ##STR00119##
1.13 46.31 0.840662 -2.096
TABLE-US-00010 TABLE 10 Modifications to the core and side chain
(Series 6) STRUCTURE log P tPSA CLogP LogS ##STR00120## 2.11 77.4
0.857513 -1.525 ##STR00121## 1.87 86.19 0.592663 -1.585
##STR00122## 1.7 65.04 0.0170677 -3.017 ##STR00123## 1.46 73.83
0.201919 -2.705 ##STR00124## 1.94 52.68 1.45423 -2.203 ##STR00125##
1.71 61.47 1.43796 -1.892 ##STR00126## 2.89 37.08 2.89066 -2.787
##STR00127## 3.31 37.08 3.44966 -3.266 ##STR00128## 1.55 46.31
1.05066 -2.155
TABLE-US-00011 TABLE 11 Modifications to the core and side chain
(Series 7) STRUCTURE log P tPSA CLogP LogS ##STR00129## 1.63 74.27
1.1096 -1.275 ##STR00130## 1.4 83.06 0.834 -1.333 ##STR00131## 1.23
61.91 0.272969 -2.704 ##STR00132## 0.99 70.7 0.457768 -2.391
##STR00133## 1.47 49.55 1.70682 -1.904 ##STR00134## 1.24 58.34
1.69005 -1.592 ##STR00135## 2.42 33.95 3.132 -2.403 ##STR00136##
2.84 33.95 3.691 -2.883 ##STR00137## 1.08 43.18 1.292 -1.864
TABLE-US-00012 TABLE 12 Modifications to the core and side chain
(Series 8) STRUCTURE log P tPSA CLogP LogS ##STR00138## 1.96 74.27
0.8996 -1.745 ##STR00139## 1.72 83.06 0.624 -1.803 ##STR00140##
1.55 61.91 0.0629689 -3.174 ##STR00141## 1.31 70.7 0.247768 -2.862
##STR00142## 1.79 49.55 1.49682 -2.374 ##STR00143## 1.56 58.34
1.48005 -2.062 ##STR00144## 2.74 33.95 2.922 -2.874 ##STR00145##
3.16 33.95 3.481 -3.353 ##STR00146## 1.4 43.18 1.082 -2.335
TABLE-US-00013 TABLE 13 Modifications to the core and side chain
(Series 9) STRUCTURE log P tPSA CLogP LogS ##STR00147## 3.0 65.04
1.74907 -2.051 ##STR00148## 2.76 73.83 1.47586 -2.109 ##STR00149##
2.59 52.68 0.911314 -3.542 ##STR00150## 2.36 61.47 1.09641 -3.23
##STR00151## 2.84 40.32 2.34546 -2.728 ##STR00152## 2.6 49.11
2.32952 -2.416 ##STR00153## 3.79 24.72 3.77386 -3.323 ##STR00154##
4.2 24.72 4.33286 -3.802 ##STR00155## 2.45 33.95 1.93386 -2.687
TABLE-US-00014 TABLE 14 Modifications to the core and side chain
(Series 10) STRUCTURE log P tPSA CLogP LogS ##STR00156## 2.94 65.04
1.53907 -2.188 ##STR00157## 2.71 73.83 1.26586 -2.247 ##STR00158##
2.54 52.68 0.701314 -3.68 ##STR00159## 2.3 61.47 0.886405 -3.367
##STR00160## 2.78 40.32 2.13546 -2.866 ##STR00161## 2.55 49.11
2.11952 -2.554 ##STR00162## 3.73 24.72 3.56386 -3.468 ##STR00163##
4.15 24.72 4.12286 -3.947 ##STR00164## 2.39 33.95 1.72386
-2.824
TABLE-US-00015 TABLE 15 Quinazolinones (Series 11) STRUCTURE log P
tPSA CLogP LogS ##STR00165## 1.02 41.46 0.506065 -1.702
##STR00166## 1.42 41.46 1.07606 -2.152 ##STR00167## 1.69 41.46
1.22606 -2.273 ##STR00168## 0.86 41.46 0.305 -1.452 ##STR00169##
##STR00170##
Example 4
Detection and Results of WHYKD Compounds
[0064] A photodiode array (PDA) was used to detect WHYKD8 in mouse
brain (FIG. 1). The sample was readily detected with a discrete
peak based on time (left) and with a measurable area under the
curve (AUC) (inset).
[0065] LC3-II levels were measured in primary cortical neurons
following 6 hours of treatment with WHYKD1, WHYKD5, or WHYKD1+BafA1
(FIG. 2). The presence of LC3-II is an indication of autophagy.
[0066] LC3-II levels were then measured in organotypic slice
cultures following 6 hours of treatment with WHYKD1 (FIG. 3, top
panel). Other compounds in the WHYKD series produced similar
results (FIG. 3, bottom panel). RFP is a tag on the tau protein and
also can be probed.
[0067] These experiments show that the WHYKD series of compounds
can induce autophagy and reduce the aggregated forms of tau as well
as its aggresome surrogate p62.
[0068] PLD activation converts phospholipids to
phosphatidylethanols in the presence of ethanol. This conversion
was measured to show that the WHYKD series of compounds activate
PLD at 10 .mu.M concentration (FIG. 4) and at 1 .mu.M (FIG. 5).
FIPI is a non-competitive inhibitor of PLD activity and was used as
a negative control.
[0069] All patents, patent applications, and publications cited
above are incorporated herein by reference in their entirety as if
recited in full herein.
[0070] The invention being thus described, it will be obvious that
the same may be varied in many ways. Such variations are not to be
regarded as a departure from the spirit and scope of the invention
and all such modifications are intended to be included within the
scope of the following claims.
* * * * *