Kim Kwang Rok, Lee Jeong Hyung, Kim Seung Jun, Rhee Sang Dal, Jung Won Hoon, Yang Sung-Don, Kim Sung Soo, Ahn Jin Hee, Cheon Hyae Gyeong
Medicinal Science Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Jang-Dong 100, Yuseong-Gu, Daejeon 305-343, South Korea.
Biochem Pharmacol. 2006 Aug 14;72(4):446-54. doi: 10.1016/j.bcp.2006.05.005. Epub 2006 May 12.
The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is the target for the anti-diabetic drugs including thiazolidinediones. We report here the identification and characterization of a novel PPARgamma agonist KR-62980. KR-62980 acted as a selective PPARgamma 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 PPARgamma 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.
核受体过氧化物酶体增殖物激活受体γ（PPARγ）是包括噻唑烷二酮类在内的抗糖尿病药物的作用靶点。我们在此报告一种新型PPARγ激动剂KR - 62980的鉴定与特性。在反式激活试验中，KR - 62980作为选择性PPARγ激动剂，其半数有效浓度（EC50）为15 nM。在完全分化的3T3 - L1脂肪细胞中，KR - 62980在胰岛素存在的情况下以浓度依赖方式诱导[3H] - 脱氧葡萄糖摄取。KR - 62980的成脂作用较弱，对aP2 mRNA的诱导作用较小，并且能够拮抗罗格列酮在C3H10T1/2细胞中的成脂作用。KR - 62980的体内药代动力学特征显示，该化合物在大鼠体内具有65%的良好口服生物利用度，终末消除半衰期为2.5小时。用KR - 62980治疗高脂饮食诱导的C57BL/6J小鼠14天，可降低血糖水平，在体重增加、心脏肥大和肝毒性方面几乎没有副作用。这些结果表明，KR - 62980作为一种具有抗高血糖活性的选择性PPARγ调节剂，其作用机制似乎与罗格列酮不同，副作用更小。
