title: 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 ((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(+).
authors.affiliation: Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico. gabriel_navarrete@uaem.mx
authors.forename: Gabriel
authors.initials: G
authors.lastname: Navarrete-Vázquez
authors.forename: Alfredo
authors.initials: A
authors.lastname: Alaniz-Palacios
authors.forename: Sergio
authors.initials: S
authors.lastname: Hidalgo-Figueroa
authors.forename: Cristina
authors.initials: C
authors.lastname: González-Acevedo
authors.forename: Gabriela
authors.initials: G
authors.lastname: Ávila-Villarreal
authors.forename: Samuel
authors.initials: S
authors.lastname: Estrada-Soto
authors.forename: Scott P
authors.initials: SP
authors.lastname: Webster
authors.forename: José L
authors.initials: JL
authors.lastname: Medina-Franco
authors.forename: Fabian
authors.initials: F
authors.lastname: López-Vallejo
authors.forename: Jorge
authors.initials: J
authors.lastname: Guerrero-Álvarez
authors.forename: Hugo
authors.initials: H
authors.lastname: Tlahuext
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D001786:Blood Glucose / Q000032:analysis; D020134:Catalytic Domain; D002995:Clofibric Acid / Q000737:chemistry*; D018360:Crystallography, X-Ray; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006860:Hydrogen Bonding; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D051379:Mice; D062105:Molecular Docking Simulation; D051381:Rats; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D013777:Tetrazoles; D002995:Clofibric Acid; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1