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Discovery, synthesis and in combo studies of a tetrazole analogue of clofibric acid as a potent hypoglycemic agent.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2013 Jun 01; Vol. 23 (11), pp. 3244-7. Date of Electronic Publication: 2013 Apr 05. - Publication Year :
- 2013
-
Abstract
- A tetrazole isosteric analogue of clofibric acid (1) was prepared using a short synthetic route and was characterized by elemental analysis, NMR ((1)H, (13)C) 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 10 μM), being more active than clofibrate and clofibric acid. The antidiabetic activity of compound 1 was determined at 50 mg/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(+).<br /> (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Subjects :
- 11-beta-Hydroxysteroid Dehydrogenase Type 1 antagonists & inhibitors
11-beta-Hydroxysteroid Dehydrogenase Type 1 metabolism
Animals
Binding Sites
Blood Glucose analysis
Catalytic Domain
Crystallography, X-Ray
Diabetes Mellitus, Experimental drug therapy
Drug Evaluation, Preclinical
Humans
Hydrogen Bonding
Hypoglycemic Agents chemistry
Hypoglycemic Agents therapeutic use
Mice
Molecular Docking Simulation
Rats
Structure-Activity Relationship
Tetrazoles chemical synthesis
Tetrazoles therapeutic use
Clofibric Acid chemistry
Hypoglycemic Agents chemical synthesis
Tetrazoles chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 23
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 23597793
- Full Text :
- https://doi.org/10.1016/j.bmcl.2013.03.122