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) 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.
Pinelli
Alessandra
A
Dipartimento di Scienze Farmacologiche, Università degli Studi di Milano, via Balzaretti 9, 20133 Milano, Italia.
Godio
Cristina
C
Laghezza
Antonio
A
Mitro
Nico
N
Fracchiolla
Giuseppe
G
Tortorella
Vincenzo
V
Lavecchia
Antonio
A
Novellino
Ettore
E
Fruchart
Jean-Charles
JC
Staels
Bart
B
Crestani
Maurizio
M
Loiodice
Fulvio
F
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
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