Synthesis, biological evaluation, and molecular modeling investigation of chiral phenoxyacetic acid analogues with PPARα and PPARγ agonist activity

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that govern lipid and glucose homeostasis, and play a central role in cardiovascular disease, obesity, and diabetes. Thus, there is significant interest in developing new and specific agonists for these receptors. Herein we present screening results for a series of chiral phenoxyacetic acid analogues, some of which are potent PPAR alpha agonists as well as PPAR gamma agonists. The stereochemistry of these compounds plays an important role in determining their activity; the S isomers were observed to be more active than the corresponding R isomers. Interestingly, for one of these analogues, the stereoselectivity toward PPAR alpha was reversed, and for this reason docking experiments were performed to rationalize this peculiar behavior.