Novel amidino-substituted benzimidazoles: Synthesis of compounds and inhibition of dipeptidyl peptidase III

Abstract

Dipeptidyl peptidase III (DPP III), also known as enkephalinase B, is a zinc-hydrolase with an indicated role in the mammalian pain modulatory system. In order to find a potent antagonist of this enzyme, we synthesized and screened the effect of a small set of benzimidazole derivatives on its activity. To improve the inhibitory potential, a cyclobutane ring was introduced as rigid conformation support to the diamidino substituted dibenzimidazoles. Two such compounds ( 1′ and 4′) from the group of cyclobutane derivatives containing amidino-substituted benzimidazole moieties, obtained by photochemical cyclization in water and by respecting rules of the “green chemistry” approach, were found to be strong DPP III inhibitors, with IC 50 value below 5 μM. Compound 1′ displayed time-dependent inhibition towards human DPP III, characterized by the second-order rate constant of 6924 ± 549 M −1 min −1 ( K i = 0.20 μM). The peptide substrate valorphin protected the enzyme from inactivation by 1′.