Synthesis, biological evaluation and molecular modeling studies of the PPARβ/δ antagonist CC618
- Eur J Med Chem. 2015 Apr 13;94:229-36. doi: 10.1016/j.ejmech.2015.03.006.
- 1. Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, PO BOX 1068, Blindern, N-0316 Oslo, Norway.
- 2. MabCent-SFI, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, N-9037 Tromsø, Norway.
- 3. Medical Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, N-9037 Tromsø, Norway.
- 4. Department of Pharmaceutical Biosciences, School of Pharmacy, Faculty of Medicine, University of Oslo, PO BOX 1068, Blindern, N-0316 Oslo, Norway; Department of Pharmacology, Institute of Clinical Medicine, Faculty of Medicine, Oslo University Hospital, PO Box 1057, Blindern, N-0316 Oslo, Norway.
- 5. Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, PO BOX 1068, Blindern, N-0316 Oslo, Norway. Electronic address: [email protected].
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.