engleski

Progressive inhibition of human dipeptidyl peptidase iii by new amidino-substituted-benzimidazoles

Dipeptidyl peptidase III (DPP III), also known as enkephalinase B, is a zinc-hydrolase for which the role in mammalian pain modulatory system is indicated. In search of new and more potent inhibitors of human DPP III, we have synthesized and screened the effect of 14 benzimidazole derivatives on its activity. Among them, two compounds (1' and 4') obtained by photochemical cyclization in water respecting the « green chemistry» approach were found to be strong inhibitors, with IC50 value below 5 μ M, both in the group of cyclobutane derivatives containing the amidino-substituted benzimidazole moieties. The inhibition with compound 1' was studied in more detail and it was shown that its mode of action is not via nonspecific chelation. Compound 1' displayed time-dependent inhibition towards human DPP III, characterized by the second-order rate constant of 6924± 549 M-1 min-1 (Ki = 0.20 μ M). Peptide substrate protected the enzyme from inactivation by 1'. This investigation yielded new non-peptidic inhibitors of human proteolytic enzyme DPP III, whose structural features important for strong inhibitory activity are amidino group (preferably cyclized) coupled to benzimidazole moiety and an additional aromatic ring which presumably interacts with DPP III hydrophobic pocket S1'.

Amidino-substituted benzimidazoles; Dipeptidyl peptidase III inhibitors

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