title: Synthesis, biological evaluation, and molecular modeling investigation of new chiral fibrates with PPARalpha and PPARgamma agonist activity.
abstract: 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.
authors.affiliation: Dipartimento di Scienze Farmacologiche, Università degli Studi di Milano, via Balzaretti 9, 20133 Milano, Italia.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pinelli
authors.forename: Cristina
authors.initials: C
authors.lastname: Godio
authors.forename: Antonio
authors.initials: A
authors.lastname: Laghezza
authors.forename: Nico
authors.initials: N
authors.lastname: Mitro
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fracchiolla
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Tortorella
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavecchia
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Fruchart
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Maurizio
authors.initials: M
authors.lastname: Crestani
authors.forename: Fulvio
authors.initials: F
authors.lastname: Loiodice
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects; D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019286:Endopeptidase K / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D047493:PPAR alpha / Q000819:agonists* / Q000737:chemistry; D047495:PPAR gamma / Q000819:agonists* / Q000737:chemistry; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D013237:Stereoisomerism; D014357:Trypsin / Q000378:metabolism
chemical_list: C504521:2-(4-chlorophenoxy)-3-phenylpropanoic acid; D008024:Ligands; D047493:PPAR alpha; D047495:PPAR gamma; D010666:Phenylpropionates; D002995:Clofibric Acid; D014357:Trypsin; D019286:Endopeptidase K