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

Åsmund Kaupang; Steinar Martin Paulsen; Calin C Steindal; Aina W Ravna; Ingebrigt Sylte; Trine G Halvorsen; G Hege Thoresen; Trond Vidar Hansen

doi:10.1016/j.ejmech.2015.03.006

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. Epub 2015 Mar 5.

Authors

Åsmund Kaupang¹, Steinar Martin Paulsen², Calin C Steindal¹, Aina W Ravna³, Ingebrigt Sylte³, Trine G Halvorsen¹, G Hege Thoresen⁴, Trond Vidar Hansen⁵

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
COS Cells
Chlorocebus aethiops
Dose-Response Relationship, Drug
Humans
Models, Molecular*
Molecular Structure
PPAR delta / antagonists & inhibitors*
PPAR-beta / antagonists & inhibitors*
Structure-Activity Relationship
Sulfones / chemical synthesis
Sulfones / chemistry*
Sulfones / pharmacology*
Thiazoles / chemical synthesis
Thiazoles / chemistry*
Thiazoles / pharmacology*

Substances

4-methyl-2-(4-(trifluoromethyl)phenyl)-N-(2-(5-(trifluoromethyl)-pyridin-2-ylsulfonyl)ethyl)thiazole-5-carboxamide
PPAR delta
PPAR-beta
Sulfones
Thiazoles