KR-62980: A novel peroxisome proliferator-activated receptor γ agonist with weak adipogenic effects

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Title
KR-62980: A novel peroxisome proliferator-activated receptor γ agonist with weak adipogenic effects
Author(s)
K R Kim; Jeong-Hyung Lee; Seung Jun Kim; S D Rhee; W H Jung; S D Yang; S S Kim; J H Ahn; H G Cheon
Bibliographic Citation
Biochemical Pharmacology, vol. 72, no. 4, pp. 446-454
Publication Year
2006
Abstract
The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is the target for the anti-diabetic drugs including thiazolidinediones. We report here the identification and characterization of a novel PPARγ agonist KR-62980. KR-62980 acted as a selective PPARγ agonist in transactivation assay with an EC50 of 15 nM. In fully differentiated 3T3-L1 adipocytes, KR-62980 induced [3H]-deoxyglucose uptake in a concentration-dependent manner in the presence of insulin. KR-62980 was weakly adipogenic with little induction of aP2 mRNA, and was able to antagonize the adipogenic effects of rosiglitazone in C3H10T1/2 cells. In vivo pharmacokinetic profile of KR-62980 revealed that the compound exhibited good oral bioavailability of 65% with a terminal elimination half-life of 2.5 h in the rat. Treatment of high fat diet-induced C57BL/6J mice with KR-62980 for 14 days reduced plasma glucose levels with little side effects with regard to weight gain, cardiac hypertrophy and hepatotoxicity. These results suggest that KR-62980 acts as a selective PPARγ modulator with anti-hyperglycemic activity, and that the mechanism of actions of KR-62980 appears to be different from that of rosiglitazone with improved side effect profiles.
Keyword
AdipogenesisGlucose-loweringHigh fat diet-induced modelPharmacokineticsPPARγWeight gain
ISSN
0006-2952
Publisher
Elsevier
DOI
http://dx.doi.org/10.1016/j.bcp.2006.05.005
Type
Article
Appears in Collections:
Division of Biomedical Research > Disease Target Structure Research Center > 1. Journal Articles
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