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

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...

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Veröffentlicht in:European journal of pharmacology 2008-10, Vol.595 (1-3), p.119-125
Hauptverfasser: Kim, Mi-Kyung, Chae, Yu Na, Son, Moon Ho, Kim, Soon Hoe, Kim, Jin Kwan, Moon, Ho Sang, Park, Chan Sun, Bae, Myung-Ho, Kim, Eunkyung, Han, Taedong, Choi, Hyun-Ho, Shin, Young Ah, Ahn, Byung-Nak, Lee, Chun Ho, Lim, Joong In, Shin, Chang Yell
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Sprache:eng
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Zusammenfassung: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 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 PPARalpha and PPARgamma 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 PPARalpha/gamma dual agonists.
ISSN:0014-2999
DOI:10.1016/j.ejphar.2008.07.066