Synthesis, In Vitro Evaluation, And Molecular Modeling Investigation Of Benzenesulfonimide Peroxisome Proliferator-Activated Receptors Alpha Antagonists

Recent evidences suggest a moderate activation of Peroxisome Proliferator-Activated Receptors (PPARs) could be favorable in metabolic diseases, reducing side effects given from full agonists. PPAR partial agonists and antagonists represent, to date, interesting tools to better elucidate biological processes modulated by these receptors. In this work are reported new benzenesulfonimide compounds able to block PPAR alpha, synthesized and tested by transactivation assays and gene expression analysis. Some of these compounds showed a dose-dependent antagonistic behavior on PPAR alpha, submicromolar potency, different profiles of selectivity versus PPAR gamma, and a repressive effect on CPT1A expression. Dockings and molecular dynamics on properly selected benzenesulfonimide derivatives furnished fresh insights into the molecular determinant most likely responsible for PPARa antagonism. (C) 2016 Elsevier Masson SAS. All rights reserved.