Discovery, synthesis and in combo studies of a tetrazole analogue of clofibric acid as a potent hypoglycemic agent

Abstract

A tetrazole isosteric analogue of clofibric acid (1) was prepared using a short synthetic route and was characterized by elemental analysis, NMR (1H, 13C) spectroscopy, and single-crystal X-ray diffraction. The in vitro inhibitory activity of 1 against 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) was evaluated, showing a moderate inhibitory enzyme activity (51.17% of inhibition at 10μM), being more active than clofibrate and clofibric acid. The antidiabetic activity of compound 1 was determined at 50mg/Kg single dose using a non insulin dependent diabetes mellitus rat model. The results indicated a significant decrease of plasma glucose levels, during the 7h post-administration. Additionally, we performed a molecular docking of 1 into the ligand binding pocket of one subunit of human 11β-HSD1. In this model, compound 1 binds into the catalytic site of 11β-HSD1 in two different orientations. Both of them, show important short contacts with the catalytic residues Ser 170, Tyr 183, Asp 259 and also with the nicotinamide ring of NADP+.