title: Synthesis, biological evaluation and molecular modeling studies of the PPARβ/δ antagonist CC618.
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.
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, PO BOX 1068, Blindern, N-0316 Oslo, Norway.
authors.forename: Åsmund
authors.initials: Å
authors.lastname: Kaupang
authors.affiliation: MabCent-SFI, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, N-9037 Tromsø, Norway.
authors.forename: Steinar Martin
authors.initials: SM
authors.lastname: Paulsen
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, PO BOX 1068, Blindern, N-0316 Oslo, Norway.
authors.forename: Calin C
authors.initials: CC
authors.lastname: Steindal
authors.affiliation: Medical Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, N-9037 Tromsø, Norway.
authors.forename: Aina W
authors.initials: AW
authors.lastname: Ravna
authors.affiliation: Medical Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, N-9037 Tromsø, Norway.
authors.forename: Ingebrigt
authors.initials: I
authors.lastname: Sylte
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, PO BOX 1068, Blindern, N-0316 Oslo, Norway.
authors.forename: Trine G
authors.initials: TG
authors.lastname: Halvorsen
authors.affiliation: 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.
authors.forename: G Hege
authors.initials: GH
authors.lastname: Thoresen
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, PO BOX 1068, Blindern, N-0316 Oslo, Norway. Electronic address: t.v.hansen@farmasi.uio.no.
authors.forename: Trond Vidar
authors.initials: TV
authors.lastname: Hansen
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047494:PPAR delta / Q000037:antagonists & inhibitors*; D048068:PPAR-beta / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C000603760:4-methyl-2-(4-(trifluoromethyl)phenyl)-N-(2-(5-(trifluoromethyl)-pyridin-2-ylsulfonyl)ethyl)thiazole-5-carboxamide; D047494:PPAR delta; D048068:PPAR-beta; D013450:Sulfones; D013844:Thiazoles
keywords: Antagonist; Covalent; Cys249; LC-MS/MS; PPARβ/δ