Compositions and methods for enhancing proteasome activity

Patent metadata

Field	Value
Publication number	US-10351568-B2
Application number	US-201514933671-A
Country	US
Kind code	B2
Filing date	Nov 5, 2015
Priority date	Jan 28, 2010
Publication date	Jul 16, 2019
Grant date	Jul 16, 2019

Abstract

Proteinopathies result from the proteasome not acting efficiently enough to eliminate harmful proteins and prevent the formation of the pathogenic aggregates. As described herein, inhibition of proteasome-associated deubiquitinase Usp14 results in increased proteasome efficiency. The present invention therefore provides novel compositions and methods for inhibition of Usp14, enhancement of proteasome activity and treatment of proteinopathies.

First claim

We claim:

1. A compound represented by formula II:

or a pharmaceutically acceptable salt thereof; wherein,
A is

R 1 and R 2 are the same and are selected from the group consisting of H, methyl, and ethyl;
Z is ═C(R 8 )—;
X is

Y is —CH 2 (N-heterocyclyl), wherein N-heterocyclyl is a saturated monocycle comprising at least one nitrogen atom through which the N-heterocyclyl moiety is bound to the —CH 2 —, wherein N-heterocyclyl is optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of alkyl, alkoxy, and amino; and
R 8 is hydrogen.

2. The compound of claim 1 , wherein R 1 is methyl; and R 2 is methyl.

3. The compound of claim 1 , wherein Y is —CH 2 (piperidin-1-yl), —CH 2 (piperazin-1-yl), —CH 2 (hexahydropyrimidin-1-yl), —CH 2 (morpholin-1-yl) or —CH 2 (1,3-oxazinan-3-yl), which is optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of alkyl, alkoxy, and amino.

4. The compound of claim 1 , wherein Y is

5. A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of

wherein W is chloro.

6. The compound of claim 1 , wherein R 1 is ethyl; and R 2 is ethyl.

7. The compound of claim 1 , wherein R 1 is hydrogen; and R 2 is hydrogen.

8. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

Assignees

• Harvard College

Inventors

• Finley Daniel J
• King Randall W
• Lee Byung-Hoon
• Lee Min Jae
• Gahman Timothy C

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P27/12

  for cataracts · CPC title