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

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Pinelli A, Godio C, Laghezza A, Mitro N, Fracchiolla G, Tortorella V, Lavecchia A, Novellino E, Fruchart JC, Staels B, Crestani M, Loiodice F

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

J Med Chem. 2005 Aug 25;48(17):5509-19.

PubMed ID

16107150 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
(2S)-2-(4-chlorophenoxy)-3-phenylpropanoic acid	Peroxisome proliferator-activated receptor gamma	EC 50 (nM)	2700	N/A	N/A	Details
(2S)-2-(4-ethylphenoxy)-3-phenylpropanoic acid	Peroxisome proliferator-activated receptor gamma	EC 50 (nM)	3600	N/A	N/A	Details
(2S)-2-(biphenyl-4-yloxy)-3-phenylpropanoic acid	Peroxisome proliferator-activated receptor gamma	EC 50 (nM)	500	N/A	N/A	Details
Rosiglitazone	Peroxisome proliferator-activated receptor gamma	EC 50 (nM)	39	N/A	N/A	Details