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

Dipeptidyl peptidase III (DPP 111), 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 IC50 value below 5 mu M. Compound 1' displayed time-dependent inhibition towards human DPP 111, characterized by the second-order rate constant of 6924 +/- 549 M-1 min(-1) (K-i = 0.20 mu M). The peptide substrate valorphin protected the enzyme from inactivation by 1'. (c) 2006 Elsevier Inc. All rights reserved.