Compositions and Methods for Enhancing Proteasome Activity

摘要

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.

主权项

1. A compound represented by formula II: or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically-protected form, enantiomer or stereoisomer thereof; wherein, independently for each occurrence, A is aryl, heteroaryl, carbocyclyl, heterocyclyl, or biaryl; R1 is hydrogen, alkyl, haloalkyl, fluoroalkyl, lower alkoxy, halo or trifluoromethyl; Z is ═C(R8)—, ═C(R2)— or ═N—; R2 is hydrogen, alkyl, haloalkyl, fluoroalkyl, lower alkoxy, halo or trifluoromethyl; X isor heteroaryl;
Y is —CH2NR3R4, —CH2(N-heterocyclyl), —CH2NH(CH2)—NH(alkyl), —CH2NH(CH2)nN(alkyl)2, —CH2NH(CH2)—(N-heterocyclyl), —CH2N(alkyl)(CH2)—NH(alkyl), —CH2N(alkyl)(CH2)nN(alkyl)2, —CH2N(alkyl)(CH2)—(N-heterocyclyl), —CH2NH(CH2)nO(alkyl), —CH2N(alkyl)(CH2)nO(alkyl), —NR3R4, —NR5NR6R7 or —NR5(N-heterocyclyl); n is 1, 2, 3 or 4; R3 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; R4 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; R5 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; R6 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; R7 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; R8 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; R9 is alkyl; or two R9 taken together with the nitrogen to which they are bound are an N-heterocyclyl group; and R10 is hydrogen, alkyl, haloalkyl, fluoroalkyl, alkoxy, alkoxyalkyl, halo, trifluoromethyl, amino, amido, N-heterocyclyl, aminoalkyl, amidoalkyl, or N-heterocyclylalkyl; provided that the compound is not 1-[1-(4-fluorophenyl)-2,5-dimethlypyrrol-3-yl]-2-pyrrolidin-1-ylethanone; and that when A is 4-methylphenyl, R1 is methyl, R2 is methyl, X isand Y is —CH2(4-methylpiperidin-1-yl), Z is not ═C(H)—.