Synthesis, Biological Evaluation, and Molecular Modeling Investigation of Chiral Phenoxyacetic Acid Analogues with PPARα and PPARγ Agonist Activity

✍ Scribed by Giuseppe Fracchiolla; Antonio Laghezza; Luca Piemontese; Giuseppe Carbonara; Antonio Lavecchia; Paolo Tortorella; Maurizio Crestani; Ettore Novellino; Fulvio Loiodice

• Book ID: 102804102
• Publisher: John Wiley and Sons
• Year: 2007
• Tongue: English
• Weight: 705 KB
• Volume: 2
• Category: Article
• ISSN: 1860-7179
• DOI: 10.1002/cmdc.200600307

✦ Synopsis

Abstract

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 PPARα agonists as well as PPARγ 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 PPARα was reversed, and for this reason docking experiments were performed to rationalize this peculiar behavior.