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

• Published in: Biochemical pharmacology 2006-08, Vol.72 (4), p.446-454
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 3T3-L1 Cells; Adipocytes - cytology; Adipocytes - drug effects; Adipocytes - metabolism; Adipogenesis; Adipogenesis - drug effects; Animals; Area Under Curve; Biological and medical sciences; Biological Availability; Blood Glucose - metabolism; Deoxyglucose - pharmacokinetics; Dose-Response Relationship, Drug; Gene Expression - drug effects; Gene Expression - genetics; Glucose-lowering; High fat diet-induced model; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacokinetics; Hypoglycemic Agents - pharmacology; Indenes - chemistry; Indenes - pharmacokinetics; Indenes - pharmacology; Medical sciences; Mice; Mice, Inbred C57BL; Morpholines - chemistry; Morpholines - pharmacokinetics; Morpholines - pharmacology; NIH 3T3 Cells; Pharmacokinetics; Pharmacology. Drug treatments; PPAR gamma - agonists; PPAR gamma - genetics; PPARγ; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; Thiazolidinediones - pharmacology; Weight gain
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2006.05.005

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 EC 50 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.