Identification and Synthesis of a Novel Selective Partial PPARδ Agonist with Full Efficacy on Lipid Metabolism In Vitro and In Vivo

The aim was to identify a novel selective PPARδ agonist with full efficacy on free fatty acid (FFA) oxidation in vitro and plasma lipid correction in vivo. Using the triple PPARα,γ,δ agonist 1 as the structural starting point, we wanted to investigate the possibility of obtaining selective PPARδ agonists by modifying only the acidic part of 1, while holding the lipophilic half of the molecule constant. The structure−activity relationship was guided by in vitro transactivation data using the human PPAR receptors, FFA oxidation efficacy performed in the rat muscle L6 cell line, and in vivo rat pharmacokinetic properties. Compound 7 ([4-[3,3-bis-(4-bromo-phenyl)-allylthio]-2-chloro-phenoxy]-acetic acid) was identified as a selective, partial agonist with good oral pharmacokinetic properties in rat. Chronic treatment of high fat fed ApoB100/CETP-Tgn mice with 7 corrected the plasma lipid parameters and improved insulin sensitivity. These data suggest that selective PPARδ agonists have the potential to become a novel treatment of dyslipidemia.