Utilizing medicinal chemistry design strategies such as benzo splitting and ring expansion, we converted PPARα/γ dual agonist 1 to selective PPARα agonists 19 and 20. Compounds 19 and 20 were 2- to 4-fold better than rosiglitazone at PPARγ receptor, with 80- to 100-fold PPARγ selectivity over PPARα receptor. X-ray cocrystal studies in PPARγ and modeling studies in PPARα give molecular insights for the improved PPARγ potency and selectivity for 19 when compared to 1.
Date:
2009-04-23
Relation:
Journal of Medicinal Chemistry. 2009 Apr 23;52(8):2618-2622.
