title: KR-62980: a novel peroxisome proliferator-activated receptor gamma agonist with weak adipogenic effects.
abstract: 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.
authors.affiliation: Medicinal Science Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Jang-Dong 100, Yuseong-Gu, Daejeon 305-343, South Korea.
authors.forename: Kwang Rok
authors.initials: KR
authors.lastname: Kim
authors.forename: Jeong Hyung
authors.initials: JH
authors.lastname: Lee
authors.forename: Seung Jun
authors.initials: SJ
authors.lastname: Kim
authors.forename: Sang Dal
authors.initials: SD
authors.lastname: Rhee
authors.forename: Won Hoon
authors.initials: WH
authors.lastname: Jung
authors.forename: Sung-Don
authors.initials: SD
authors.lastname: Yang
authors.forename: Sung Soo
authors.initials: SS
authors.lastname: Kim
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Ahn
authors.forename: Hyae Gyeong
authors.initials: HG
authors.lastname: Cheon
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D001786:Blood Glucose / Q000378:metabolism; D003847:Deoxyglucose / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D007192:Indenes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D041681:NIH 3T3 Cells; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: C513115:1-(methylimino-N-oxy)-6-(2-morpholinoethoxy)-3-phenyl-1H-indene-2-carboxylic acid ethyl ester; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007192:Indenes; D009025:Morpholines; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D003847:Deoxyglucose