Activators of autophagic flux and phospholipase D and clearance of protein aggregates including tau and treatment of proteinopathies
AssigneesThe Trustees of Columbia University in the City of New York, NY State Psychiatric Institute
InventorsKirsten Alison Rinderspacher, Wai Yu, Karen Duff, Donald Landry, Shi-Xian Deng
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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.
Claims23
A compound is selected from the group consisting of:
- or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
A compound having the formula (XV):
- wherein X is halide;
- wherein Z1 is O;
- wherein R4 is selected from the group consisting of unsubstituted alkyl, Et, CF3, optionally substituted cycloalkyl, optionally substituted heteroaryl, and
A method of treating a neurodegenerative disease comprising administering to a subject in need thereof an effective amount of a compound having the following formula:
- wherein X is H or halide;
- wherein Z1 is O;
- wherein R4 is selected from the group consisting of H, optionally substituted alkyl, Et, CF3, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and
- and
- wherein the neurodegenerative disease is a proteinopathy.
A method of treating a neurodegenerative disease comprising administering to a subject in need thereof an effective amount of a compound of formula (II):
- wherein Y1 and Y2 are N;
- wherein X is selected from the group consisting of H, halide, and aryl;
- wherein R1 is selected from the group consisting of optionally substituted thioheteroaryl, and 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,
- wherein the neurodegenerative disease is Alzheimer's disease.
A method of treating a neurodegenerative disease comprising administering to a subject in need thereof an effective amount of a compound of formula (II):
- wherein Y1 and Y2 are N;
- wherein X is selected from the group consisting of H, halide, and aryl;
- wherein R1 is selected from the group consisting of optionally substituted thioheteroaryl, and 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,
- wherein the neurodegenerative disease is a proteinopathy.
Dependencies are inferred from the claim text.