COMPOUNDS FOR PROTEASOME ENZYME INHIBITION

摘要

Peptide-based compounds including heteroatom-containing, three-membered rings efficiently and selectively inhibit specific activities of N-terminal nucleophile (Ntn) hydrolases. The activities of those Ntn having multiple activities can be differentially inhibited by the compounds described. For example, the chymotrypsin-like activity of the 20S proteasome may be selectively inhibited with the inventive compounds. The peptide-based compounds include an epoxide or aziridine, and functionalization at the N-terminus. Among other therapeutic utilities, the peptide-based compounds are expected to display anti-inflammatory properties and inhibition of cell proliferation.

主权项

1. A compound having a structure of formula I or a pharmaceutically acceptable salt thereof, wherein X is O, NH, or N-alkyl; Y is NH, N-alkyl, O, or C(R9)2; Z is O or C(R9)2; R1, R2, R3, and R4 are all hydrogen; each R5, R6, R7, R8, and R9 is independently selected from hydrogen, C1-6alkyl, C1-6hydroxyalkyl, C1-6alkoxyalkyl, aryl, and C1-6aralkyl, each of which is optionally substituted with a group selected from alkyl, amide, amine, carboxylic acid or a pharmaceutically acceptable salt thereof, carboxyl ester, thiol, and thioether; R10 and R11 are independently selected from hydrogen and C1-6alkyl, or R10 and R11 together form a 3- to 6-membered carbocyclic or heterocyclic ring; R12 and R13 are independently selected from hydrogen, a metal cation, C1-6alkyl, and C1-6aralkyl, or R12 and R13 together represent C1-6alkyl, thereby forming a ring; m is an integer from 0 to 2; and n is an integer from 0 to 2, preferably 0 or 1.