Synthesis, biological evaluation, and molecular modeling investigation of new chiral fibrates with PPARalpha and PPARgamma agonist activity

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that govern lipid and glucose homeostasis playing a central role in cardiovascular diseases, obesity, and diabetes. Medications targeted to PPARs have been established to treat hyperlipidemia (fibrates) an...

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Published in:Journal of medicinal chemistry 2005-08, Vol.48 (17), p.5509-5519
Main Authors: Pinelli, Alessandra, Godio, Cristina, Laghezza, Antonio, Mitro, Nico, Fracchiolla, Giuseppe, Tortorella, Vincenzo, Lavecchia, Antonio, Novellino, Ettore, Fruchart, Jean-Charles, Staels, Bart, Crestani, Maurizio, Loiodice, Fulvio
Format: Article
Language:English
Subjects:
3T3 Cells
Adipocytes - cytology
Adipocytes - drug effects
Animals
Binding Sites
Cell Differentiation
Cell Line, Tumor
Clofibric Acid - analogs & derivatives
Clofibric Acid - chemical synthesis
Clofibric Acid - chemistry
Clofibric Acid - pharmacology
Endopeptidase K - metabolism
Fibroblasts - cytology
Fibroblasts - drug effects
Humans
Ligands
Mice
Models, Molecular
Phenylpropionates - chemical synthesis
Phenylpropionates - chemistry
Phenylpropionates - pharmacology
PPAR alpha - agonists
PPAR alpha - chemistry
PPAR gamma - agonists
PPAR gamma - chemistry
Protein Conformation
Quantitative Structure-Activity Relationship
Stereoisomerism
Trypsin - metabolism
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Summary:Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that govern lipid and glucose homeostasis playing a central role in cardiovascular diseases, obesity, and diabetes. Medications targeted to PPARs have been established to treat hyperlipidemia (fibrates) and insulin resistance (glitazones). Thus, there is significant interest in developing new and specific ligands for these receptors. Here, we present the results of the screening of new ligands of PPARalpha and PPARgamma. Optical isomers of new chiral fibrates were synthesized and tested in cell-based assays. Compound (S)-7 showed a dual PPARalpha/gamma activity, and its stereochemistry was crucial in receptor activation. Protease protection experiments suggested that this compound binds directly to PPAR. Moreover, computational studies showed that it properly docks to PPARalpha and gamma ligand binding pockets. Interestingly, (S)-7 exhibited only a modest capacity to induce the differentiation of murine fibroblasts 3T3-L1 into adipocytes compared to rosiglitazone, a well-known PPARgamma agonist.
ISSN:0022-2623
1520-4804