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

Peroxisome proliferator-activated receptors (PPARs) are ligand-ac- tivated transcription factors that govern lipid and glucose ho- meostasis, and play a central role in cardiovascular disease, obe- sity, 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 ana- logues, some of which are potent PPARa agonists as well as PPARg 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 isom- ers. Interestingly, for one of these analogues, the stereoselectivity toward PPARa was reversed, and for this reason docking experi- ments were performed to rationalize this peculiar behavior.