2. Academic Validation
  3. Synthesis, biological evaluation and molecular modeling studies of the PPARβ/δ antagonist CC618

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.
Åsmund Kaupang 1,  Steinar Martin Paulsen 2,  Calin C Steindal 1,  Aina W Ravna 3,  Ingebrigt Sylte 3,  Trine G Halvorsen 1,  G Hege Thoresen 4,  Trond Vidar Hansen 5
Affiliations

Affiliations

  • 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: t.v.hansen@farmasi.uio.no.
PMID: 25768705 DOI: 10.1016/j.ejmech.2015.03.006
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.

Keywords

Antagonist; Covalent; Cys249; LC-MS/MS; PPARβ/δ.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-120188
    PPARβ/δ拮抗剂
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