Benzimidazolone as potent chymase inhibitor: Modulation of reactive metabolite formation in the hydrophobic (P 1) region

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.