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 having the formula (II):
- wherein one of Y1 and Y2 is CH and one of Y1 and Y2 is 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, hydroxyl-substituted (2-aminoethyl)aryl, and optionally substituted thiocycloalkyl wherein the cycloalkyl is a 5 or 6-membered cycloalkyl and wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O and S,
- or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
A compound having the formula (III):
- wherein Y1 is CH;
- wherein Y2 is N;
- wherein X is halide;
- wherein R1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, and optionally substituted thiocycloalkyl wherein the cycloalkyl is a 5 or 6-membered cycloalkyl and wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O and S, and thioaryl,
- or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
A method of treating a neurodegenerative disease comprising adminstering to a subject in need thereof an effective amount of a compound having the following formula:
- wherein one of Y1 and Y2 is CH and one of Y1 and Y2 is 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, hydroxyl-substituted (2-aminoethyl)aryl, halide, 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 a combination thereof,
- 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 having the following formula:
- wherein Y1 is CH;
- wherein Y2 is N;
- wherein X is halide;
- wherein R1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, 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.