Development of Improved PPAR β / δ Inhibitors

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 PPAR β / 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 PPAR β / δ was confirmed in a cell‐based assay making these compounds invaluable tools for the further exploration of the functions of PPAR β / δ .