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-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 PPARalpha agonists as well as PPARgamma 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 PPARalpha was reversed, and for this reason docking experiments were performed to rationalize this peculiar behavior.
Fracchiolla
Giuseppe
G
Dipartimento Farmaco-Chimico, Università degli Studi di Bari via Orabona 4, 70126 Bari, Italy.
Laghezza
Antonio
A
Piemontese
Luca
L
Carbonara
Giuseppe
G
Lavecchia
Antonio
A
Tortorella
Paolo
P
Crestani
Maurizio
M
Novellino
Ettore
E
Loiodice
Fulvio
F
D000085:Acetates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D008958:Models, Molecular; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D013237:Stereoisomerism
D000085:Acetates; D047493:PPAR alpha; D047495:PPAR gamma; C415326:phenoxyacetic acid