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.
Synthesis, biological evaluation, and molecular modeling investigation of chiral phenoxyacetic acid analogues with PPARalpha and PPARgamma agonist activity / G. Fracchiolla, A. Laghezza, L. Piemontese, G. Carbonara, A. Lavecchia, F. Tortorella, M. Crestani, E. Novellino, F. Loiodice. - In: CHEMMEDCHEM. - ISSN 1860-7179. - 2:5(2007 May), pp. 641-654.
Synthesis, biological evaluation, and molecular modeling investigation of chiral phenoxyacetic acid analogues with PPARalpha and PPARgamma agonist activity
M. Crestani;
2007
Abstract
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.Pubblicazioni consigliate
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