New 2-(aryloxy)-3-phenylpropanoic acids as peroxisome proliferator-activated receptor alpha/gamma dual agonists able to upregulate mitochondrial carnitine shuttle system gene expression.

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Laghezza A, Pochetti G, Lavecchia A, Fracchiolla G, Faliti S, Piemontese L, Di Giovanni C, Iacobazzi V, Infantino V, Montanari R, Capelli D, Tortorella P, Loiodice F

New 2-(aryloxy)-3-phenylpropanoic acids as peroxisome proliferator-activated receptor alpha/gamma dual agonists able to upregulate mitochondrial carnitine shuttle system gene expression.

J Med Chem. 2013 Jan 10;56(1):60-72. doi: 10.1021/jm301018z. Epub 2012 Dec 18.

PubMed ID

23171045 [ View in PubMed

]

Abstract

The preparation of a series of 2-(aryloxy)-3-phenylpropanoic acids, resulting from the introduction of different substituents into the biphenyl system of the previously reported peroxisome proliferator-activated receptor alpha/gamma (PPARalpha/gamma) dual agonist 1, allowed the identification of new ligands with higher potency on PPARalpha and fine-tuned moderate PPARgamma activity. For the most promising stereoisomer (S)-16, X-ray and calorimetric studies in PPARgamma revealed, at high ligand concentration, the presence of two molecules simultaneously bound to the receptor. On the basis of these results and docking experiments in both receptor subtypes, a molecular explanation was provided for its different behavior as a full and partial agonist of PPARalpha and PPARgamma, respectively. The effects of (S)-16 on mitochondrial acylcarnitine carrier and carnitine-palmitoyl-transferase 1 gene expression, two key components of the carnitine shuttle system, were also investigated, allowing the hypothesis of a more beneficial pharmacological profile of this compound compared to the less potent PPARalpha agonist fibrates currently used in therapy.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
(2S)-2-(biphenyl-4-yloxy)-3-phenylpropanoic acid	Peroxisome proliferator-activated receptor gamma	EC 50 (nM)	550	N/A	N/A	Details
Rosiglitazone	Peroxisome proliferator-activated receptor gamma	EC 50 (nM)	39	N/A	N/A	Details