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

Abstract

Peroxisome proliferator-activated receptor (PPAR) α and γ are key regulators of lipid homeostasis and insulin resistance. In this study, we characterize the pharmacological profiles of PAR-5359, a dual agonist of PPARα and γ 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)-(2 S)-ethoxy-propionic acid) significantly activated human and mouse PPARα and γ without activating PPARδ. 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 (α and γ; 2.84 μM and 3.02 μM, 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 glucose levels. In a severe diabetic db/db mouse model, PAR-5359 dose-dependently reduced the plasma levels of glucose (ED 30 = 0.07 mg/kg). Furthermore, it lowered plasma levels of non HDL- (ED 30 = 0.13 mg/kg) and total cholesterol (ED 30 = 0.03 mg/kg) in high cholesterol diet-fed rats for 4 days treatment. These results suggest that PAR-5359 has the balanced activities for PPARα and PPARγ in vivo as well as in vitro. And its balanced activities may render PAR-5359 as a pharmacological tool in elucidating the complex roles of PPARα/γ dual agonists.