Design and Structural Analysis of Novel Pharmacophores for Potent and Selective Peroxisome Proliferator-activated Receptor gamma Agonists

Abstract

Utilizing medicinal chemistry design strategies Such as benzo splitting and ring expansion, we converted PPAR alpha/gamma dual agonist 1 to selective PPAR gamma agonists 19 and 20. Compounds 19 and 20 were 2- to 4-fold better than rosiglitazone at PPAR gamma receptor. with 80- to 100-fold PPAR gamma selectivity over PPAR alpha receptor. X-ray cocrystal studies in PPAR gamma and modeling studies in PPAR alpha give molecular insights for the improved PPAR gamma potency and selectivity for 19 when compared to 1.