RESUMEN
A new class of chymase inhibitor featuring a benzimidazolone core with an acid side chain and a P(1) hydrophobic moiety is described. Incubation of the lead compound with GSH resulted in the formation of a GSH conjugate on the benzothiophene P(1) moiety. Replacement of the benzothiophene with different heterocyclic systems such as indoles and benzoisothiazole is feasible. Among the P(1) replacements, benzoisothiazole prevents the formation of GSH conjugate and an in silico analysis of oxidative potentials agreed with the experimental outcome.
Asunto(s)
Bencimidazoles/química , Quimasas/antagonistas & inhibidores , Inhibidores de Proteasas/química , Bencimidazoles/metabolismo , Bencimidazoles/farmacología , Sitios de Unión , Quimasas/metabolismo , Cristalografía por Rayos X , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Oxidación-Reducción , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Estructura Terciaria de Proteína , Relación Estructura-ActividadRESUMEN
Discovery and optimization of potency and selectivity of a non-Zn-chelating MMP-13 inhibitor with the aid of protein co-crystal structural information is reported. This inhibitor was observed to have a binding mode distinct from previously published MMP-13 inhibitors. Potency and selectivity were improved by extending the hit structure out from the active site into the S1' pocket.