Synthesis of 5-trifluoromethyl-2-sulfonylpyridine PPARβ/δ antagonists: Effects on the affinity and selectivity towards PPARβ/δ

Bioorg Med Chem. 2016 Jan 15;24(2):247-60. doi: 10.1016/j.bmc.2015.12.012. Epub 2015 Dec 10.

Abstract

The covalent modification of peroxisome-proliferator activated receptor β/δ (PPARβ/δ) is part of the mode of action of 5-trifluoromethyl-2-sulfonylpyridine PPARβ/δ antagonists such as GSK3787 and CC618. Herein, the synthesis and in vitro biological evaluation of a range of structural analogues of the two antagonists are reported. The new ligands demonstrate that an improvement in the selectivity of 5-trifluoromethyl-2-sulfonylpyridine antagonists towards PPARβ/δ is achievable at the expense of their immediate affinity for PPARβ/δ. However, their putatively covalent and irreversible mode of action may ensure their efficacy over time, as observed in time-resolved fluorescence resonance energy transfer (TR-FRET)-based ligand displacement assays.

Keywords: Antagonist; Covalent; PPAR; Selectivity; TR-FRET.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Fluorescence Resonance Energy Transfer
  • Humans
  • Molecular Structure
  • PPAR delta / antagonists & inhibitors*
  • PPAR-beta / antagonists & inhibitors*
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Structure-Activity Relationship
  • Substrate Specificity / drug effects
  • Sulfones / chemical synthesis*
  • Sulfones / chemistry
  • Sulfones / pharmacology*

Substances

  • PPAR delta
  • PPAR-beta
  • Pyridines
  • Sulfones