Compounds 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 method for the treatment of a solid tumor in a patient, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound having a structure of formula (I): or a pharmaceutically acceptable salt thereof, wherein L is selected from C═O and C═S; X is selected from O, S, NH, and N—C1-6alkyl; Z is absent, C1-6 alkyl, or C1-6alkoxy; R1, R2, and R3 are each independently selected from hydrogen, C1-6 alkyl, C1-6 alkenyl, C1-6 alkynyl, C1-6 hydroxyalkyl, C1-6 alkoxyalkyl, aryl, C1-6 aralkyl, heteroaryl, heterocyclyl, C1-6 heterocycloalkyl, C1-6 heteroaralkyl, carbocyclyl, and C1-6 carbocyclolalkyl; R4 is selected from hydrogen, C1-6 aralkyl, and C1-6 alkyl; R5 is heteroaryl; and R6 and R7 are independently selected from hydrogen, C1-6 alkyl, and C1-6 aralkyl and a pharmaceutically acceptable diluent or carrier.