Synthesis and Biological Evaluation of Gemfibrozil Chiral Analogues as Potential PPARα Agonists

Barbara      De Filippis; Letizia      Giampietro; Antonella      Giancristofaro; Alessandra      Ammazzalorso; Marialuigia      Fantacuzzi; Cristina      Maccallini; Michele      Petruzzelli; Rosa      Amoroso

Abstract

Two series of gemfibrozil chiral analogues were synthesized and evaluated for their agonistic activity on PPARα receptor, belonging to the transcription factor family. A simple method to synthesize ureidic and thioureidic fibrates is described. Their ability to interact with the PPARα receptor was evaluated by a transactivation assay in comparison with gemfibrozil, with the aim of obtaining new hypolipidemic compounds. Compounds characterized by a methyl and an ethyl group in α-position to the carboxylic group of gemfibrozil showed a good increase of the transcriptional activity of the receptor, and their capability to activate the receptor seems to be effected by the stereochemistry and the size of the substituent on chiral center. The ureidic and thioureidic compounds did not induce PPARα activity.

Keywords: PPARs, PPAR agonists, Fibrates, Gemfibrozil chiral analogues, Ureidofibrates, Transactivation assay, gemfibrozil, PPAR receptor, hypolipidemic compounds, Peroxisome proliferator-activated receptors, X receptor, oxidation, fatty acids, lipoprotein metabolism, aryloxyacid, clofibric acid, ureido-thioisobutyric acid, phenylisocyanates, luciferase, alkylphenylthioureas, HDL cholesterol in the rat, GC Perkin-Elmer apparatus, calcium phosphate, Retinoid X Receptor, Peroxisome Proliferator-Activated Receptor, Fold Activation