| Abstract
| - The aim was to identify a novel selective PPARδ agonist with full efficacy on free fatty acid (FFA) oxidationin vitro and plasma lipid correction in vivo. Using the triple PPARα,γ,δ agonist 1 as the structural startingpoint, we wanted to investigate the possibility of obtaining selective PPARδ agonists by modifying onlythe acidic part of 1, while holding the lipophilic half of the molecule constant. The structure−activityrelationship was guided by in vitro transactivation data using the human PPAR receptors, FFA oxidationefficacy 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, partialagonist 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 suggestthat selective PPARδ agonists have the potential to become a novel treatment of dyslipidemia.
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