COMPUNDS FOR 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 associated with the proteasome. 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. Oral administration of these peptide-based proteasome inhibitors is possible due to their bioavailability profiles.

主权项

1. A compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof: wherein L is selected from C═O, C═S, and SO2; X is selected from O, S, NH, and N—C1-6alkyl; Z is absent, C1-6alkyl, or C1-6alkoxy; R1, R2, and R3 are each independently selected from hydrogen, C1-6alkyl, C1-6alkenyl, C1-6 alkynyl, C1-6hydroxyalkyl, C1-6alkoxyalkyl, aryl, C1-6 aralkyl, heteroaryl, heterocyclyl, C1-6heterocycloalkyl, C1-6heteroaralkyl, carbocyclyl, and C1-6carbocyclolalkyl; R4 is selected from hydrogen, C1-6aralkyl, and C1-6alkyl; R5 is heteroaryl; and R6 and R7 are independently selected from hydrogen, C1-6alkyl, and C1-6aralkyl.