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KMID : 0043320090320050721
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Archives of Pharmacal Research
2009 Volume.32 No. 5 p.721 ~ p.727
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PAR-1622 is a Selective Peroxisome Proliferator-Activated Receptor γ Partial Activator with Preserved Antidiabetic Efficacy and Broader Safety Profile for Fluid Retention
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Shin Chang-Yell
Kim Hae-Sun
Chae Yu-Na
Lim Joong-In
Lee Chun-Ho
Kim Jae-Gyu
Shin Young-Ah
Park Sang-Kuk
Moon Ho-Sang
Kim Jin-Kwan
Kim Soon-Hoe
Son Moon-Ho
Choi Song-Hyen
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Abstract
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Peroxisome proliferator-activated receptor (PPAR) γ is known to be a key regulator of insulin resistance. PAR-1622 is a novel small molecule compound synthesized in Dong-A research center. In this study, we characterized the pharmacological profiles of PAR-1622, a selective partial activator of PPARγ. In transient transactivation assays, PAR-1622 [(S)-2-ethoxy-3(4-(5-(4- (5-(methoxymethyl)isoxazol-3-yl)phenyl)-3-methylthiophen-2-yl)methoxy)phenyl)propanoic acid] showed a partial activator against human PPARγ with an EC50 of 41 nM and a maximal response of 37% relative to the full agonist rosiglitazone without activating human PPARδ. PAR-1622 was 56 folds more selective for human PPARγ than for human PPARα (EC50, 2304 nM), which means that it is a selective partial activator of PPARγ. PAR-1622 also showed a partial activator against mouse PPARγ with an EC50 of 427 nM and a maximal response was 57% of that of rosiglitazone. INT-131, a selective PPARγ partial agonist in clinical stage, also was a partial activator against human PPARγ with an EC50 of 83 nM and a maximal response achieved by INT-131 was 49% of that observed with full agonist rosiglitazone. In functional assays using human mesenchymal stem cells, PAR-1622 induced adipocyte differentiation, which was 3-fold more potent with a comparable maximum response compared to INT-131. Furthermore, PAR-1622 significantly improved hyperglycemia in db/db when orally administered at a dose of 1 mg/kg/day for 5 days. In hemodilution assays with Evans Blue, rosiglitazone significantly increased the plasma volume in ICR mice that were orally administered 30 mg/kg/day for 9 days; however, PAR-1622 showed no significant effects on plasma volume, similar to INT-131. These results suggest that PAR-1622 is a selective partial activator of PPARγ and has excellent antihyperglycemic activities and a broad safety profile for fluid retention.
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KEYWORD
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Peroxisome proliferator-activated receptor, PAR-1622, Partial activator, Insulin resistance, Plasma volume
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