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

European Journal of Medicinal Chemistry
Åsmund KaupangTrond Vidar Hansen

Abstract

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.

References

Dec 15, 1995·Cell·D J MangelsdorfR M Evans
Apr 3, 2007·Biochimica Et Biophysica Acta·Liliane Michalik, Walter Wahli
Oct 26, 2011·ChemMedChem·Philipp M TothWibke E Diederich

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Citations

Jul 23, 2020·PPAR Research·Åsmund Kaupang, Trond Vidar Hansen
Jun 19, 2016·Chemical Biology & Drug Design·Jun ZhangRun-Ling Wang
Mar 21, 2020·International Journal of Molecular Sciences·Yaping WangNaoki Tanaka

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