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Keywords:

  • GSK0660;
  • inhibitors;
  • NR1C2;
  • nuclear receptors;
  • PPARβ/δ;
  • structure–activity relationships

Abstract

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.