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Synthesis, biological evaluation and molecular modeling studies of the PPARβ/δ antagonist CC618

2015; Elsevier BV; Volume: 94; Linguagem: Inglês

10.1016/j.ejmech.2015.03.006

1768-3254

Åsmund Kaupang, Steinar M. Paulsen, Calin Constantin Steindal, Aina Westrheim Ravna, Ingebrigt Sylte, Trine Grønhaug Halvorsen, G. Hege Thoresen, Trond Vidar Hansen,

Receptor Mechanisms and Signaling

Herein, we describe the synthesis, biological evaluation and molecular docking of the selective PPARβ/δ 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 PPARβ/δ activity with an IC50 = 10.0 μM. As observed by LC-MS/MS analysis of tryptic digests, the treatment of PPARβ/δ with CC618 leads to a covalent modification of Cys249, located centrally in the PPARβ/δ 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 PPARβ/δ ligand binding pocket.