Discovery of a Peroxisome Proliferator Activated Receptor 947; (PPAR947;) Modulator with Balanced PPARα Activity for the Treatment of Type 2 Diabetes and Dyslipidemia
A series of 3-acylindole-1-benzylcarboxylic acids were designed and synthesized while searching for a PPAR947; modulator with additional moderate intrinsic PPARα agonistic activity. 2-[3-[[3-(4-Chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl]phenoxy]-(2R)-butanoic acid (12d) was identified as such an agent which demonstrated potent efficacy in lowering both glucose and lipids in multiple animal models with significantly attenuated side effects such as fluid retention and heart weight gain associated with PPAR947; full agonists. The moderate PPARα activity of 12d not only contributed to the agent’s ability to manage lipid profiles but also appears to have potentiated its PPAR947; efficacy in lowering glucose levels in preclinical diabetic animal models.