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 microM. 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 microM). The peptide substrate valorphin protected the enzyme from inactivation by 1'.

• Authors: Dejan Agić, Marijana Hranjec, Nina Jajcanin, Kristina Starcević, Grace Karminski-Zamola, Marija Abramić
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 35 Issue 2 Pg. 153-69 (Apr 2007) ISSN: 0045-2068 [Print] United States
• PMID: 17174378 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amides
• Benzimidazoles
• Protease Inhibitors
• valorphin
• Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
• dipeptidyl peptidase III
• Adamantane

Topics

• Adamantane (analogs & derivatives, pharmacology)
• Algorithms
• Amides (chemistry)
• Benzimidazoles (chemical synthesis, pharmacology)
• Chemical Phenomena
• Chemistry, Physical
• Dipeptidyl-Peptidases and Tripeptidyl-Peptidases (antagonists & inhibitors)
• Erythrocytes (drug effects, enzymology)
• Kinetics
• Models, Molecular
• Molecular Conformation
• Protease Inhibitors (chemical synthesis, pharmacology)
• Structure-Activity Relationship