Structure-based design of indole propionic acids as novel PPARα/γ co-agonists

In the quest for novel PPARα/γ co-agonists as putative drugs for the treatment of type 2 diabetes and dyslipidemia, we have used a structure-based design approach to identify propionic acids with a 1,5-disubstituted indole scaffold as potent PPARα/γ activators. Compounds 13, 24, and 28 are examples of submicromolar dual agonists with different α/γ EC50 ratios that are selective against the δ-isoform. Analysis of the X-ray complex structure of PPARγ with the indole propionic acid 13 provides a rationalization for some of the observed SAR.