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

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) is the target for the anti-diabetic drugs including thiazolidinediones. We report here the identification and characterization of a novel PPAR gamma agonist KR-62980. KR-62980 acted as a selective PPAR gamma agonist in transactivation assay with an EC50 of 15 nM. In fully differentiated 3T3-L1 adipocytes, KR-62980 induced [H-3]-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.S 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 PPAR gamma 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. (c) 2006 Elsevier Inc. All rights reserved.