Synthesis, biological evaluation and molecular modeling studies of the PPARβ/δ antagonist CC618
ForfatterKaupang, Åsmund; Paulsen, Steinar Martin; Steindal, Calin Constantin; Ravna, Aina Westrheim; Sylte, Ingebrigt; Halvorsen, Trine Grønhaug; Thoresen, G. Hege; Hansen, Trond Vidar
Abstract: Herein, we describe the synthesis, biological evaluation and molecular docking of the selective PPARb/ d antagonist (4-methyl-2-(4-(trifluoromethyl)phenyl)-N-(2-(5-(trifluoromethyl)-pyridin-2-ylsulfonyl) ethyl)thiazole-5-carboxamide)), CC618. Results from in vitro luciferase reporter gene assays against the three known human PPAR subtypes revealed that CC618 selectively antagonizes agonist-induced PPARb/ d activity with an IC50 ¼ 10.0 mM. As observed by LC-MS/MS analysis of tryptic digests, the treatment of PPARb/d with CC618 leads to a covalent modification of Cys249, located centrally in the PPARb/d ligand binding pocket, corresponding to the conversion of its thiol moiety to a 5-trifluoromethyl-2- pyridylthioether. Finally, molecular docking is employed to shed light on the mode of action of the antagonist and its structural consequences for the PPARb/d ligand binding pocket.
This is the accepted manuscript version. Published version available at http://dx.doi.org/10.1016/j.ejmech.2015.03.006