Development of improved PPARβ/δ inhibitors

ChemMedChem. 2012 Jan 2;7(1):159-70. doi: 10.1002/cmdc.201100408. Epub 2011 Oct 24.


GSK0660 (1) is the first peroxisome proliferator-activated receptor (PPAR) β/δ-selective inhibitory ligand described in the literature. Based on its structure, we designed and synthesized a series of modified compounds to establish preliminary structure-activity relationships. Most beneficial for increased binding affinity towards the PPARβ/δ ligand binding domain was the replacement of the 4'-aminophenyl substituent by medium-length n-alkyl chains, such as n-butyl or iso-pentyl. These compounds show activity down to the one-digit nanomolar range, thus possessing up to a tenfold higher binding affinity compared with GSK0660. Additionally, the subtype-specific inhibition of PPARβ/δ was confirmed in a cell-based assay making these compounds invaluable tools for the further exploration of the functions of PPARβ/δ.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • PPAR delta / antagonists & inhibitors*
  • PPAR delta / metabolism
  • PPAR-beta / antagonists & inhibitors*
  • PPAR-beta / metabolism
  • Structure-Activity Relationship
  • Sulfones / chemistry*
  • Sulfones / pharmacology*
  • Thiophenes / chemistry*
  • Thiophenes / pharmacology*


  • Enzyme Inhibitors
  • GSK0660
  • PPAR delta
  • PPAR-beta
  • Sulfones
  • Thiophenes