KR-62980: a novel peroxisome proliferator-activated receptor gamma agonist with weak adipogenic effects.
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.
Kim
Kwang Rok
KR
Medicinal Science Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Jang-Dong 100, Yuseong-Gu, Daejeon 305-343, South Korea.
Lee
Jeong Hyung
JH
Kim
Seung Jun
SJ
Rhee
Sang Dal
SD
Jung
Won Hoon
WH
Yang
Sung-Don
SD
Kim
Sung Soo
SS
Ahn
Jin Hee
JH
Cheon
Hyae Gyeong
HG
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
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