PAR-5359, a well-balanced PPARalpha/gamma dual agonist, exhibits equivalent antidiabetic and hypolipidemic activities in vitro and in vivo

European Journal of Pharmacology
Mi-Kyung KimChang-Yell Shin

Abstract

Peroxisome proliferator-activated receptor (PPAR) alpha and gamma are key regulators of lipid homeostasis and insulin resistance. In this study, we characterize the pharmacological profiles of PAR-5359, a dual agonist of PPARalpha and gamma with well-balanced activities. In transient transactivation assay, PAR-5359 (3-(4-(2[4-(4chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-ethoxy)-phenyl)-(2S)-ethoxy-propionic acid) significantly activated human and mouse PPARalpha and gamma without activating PPARdelta. In functional assays using human mesenchymal stem cells and human hepatoma HepG2 cells, PAR-5359 significantly induced adipocyte differentiation and human ApoA1 secretion, which coincided with its transactivation potencies against the corresponding human receptor subtypes. Interestingly, PAR-5359 showed equivalent potencies against the mouse receptor subtypes (alpha and gamma; 2.84 microM and 3.02 microM, respectively), which suggests the possibility that PAR-5359 could simultaneously activates each subtype of receptors subtype in under physiological conditions. In an insulin-resistant ob/ob mouse model, PAR-5359 significantly reduced plasma insulin levels, improved insulin sensitivity (HOMA-IR), and completely normalized plasma ...Continue Reading

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Citations

Jun 16, 2012·Expert Opinion on Therapeutic Patents·Christina LamersDaniel Merk
Jul 6, 2017·Physiological Reports·Brianne L GuilfordDouglas E Wright
Jan 28, 2009·American Journal of Physiology. Endocrinology and Metabolism·Kieren Mather
Aug 6, 2021·Expert Opinion on Pharmacotherapy·Marc S Rendell
Jan 21, 2012·Journal of Medicinal Chemistry·Céline PiratPhilippe Chavatte

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