Novel 5-substituted 2,4-thiazolidinedione and 2,4-oxazolidinedione derivatives as insulin sensitizers with antidiabetic activities.
Two novel classes of 2,4-thiazolidinediones and 2,4-oxazolidinediones with an omega-(azolylalkoxyphenyl)alkyl substituent at the 5-position were prepared and their antidiabetic effects were evaluated in two genetically obese and diabetic animal models, KKA(y) mice and Wistar fatty rats. A large number of the 2,4-thia(oxa)zolidinediones showed potent glucose- and lipid-lowering activities. The antidiabetic activities of the 2,4-oxazolidinediones were superior to those of the 2,4-thiazolidinediones. Among the compounds, both enantiomers of 5-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]propyl]-2,4-oxazolidinedione (64), one of the most interesting compounds in terms of activity, were synthesized by using an asymmetric O-acetylation of the corresponding alpha-hydroxyvalerate (26) with immobilized lipase, followed by cyclization of the oxazolidinedione ring. (R)-(+)-64 showed more potent glucose-lowering activity (effective dose (ED)25 = 0.561 mg/kg/d) than (S)-(-)-64 (ED25 > 1.5 mg/kg/d) or pioglitazone (ED25 = 6 mg/kg/d) in KKA(y) mice. It also exhibited a 10-fold more potent antidiabetic activity (ED25 = 0.05 mg/kg/d) than pioglitazone (ED25 = 0.5 mg/kg/d) in Wistar fatty rats. The antidiabetic effects of this compound are considered to be due to its potent agonistic activity for peroxisome proliferator-activated receptor gamma (EC(50) = 8.87 nM).
Momose
Yu
Y
Medicinal Chemistry Research Laboratories II, and Strategic Research Planning, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., 17-85, Jusohonmachi 2-Chome, Yodogawaku, Osaka 532-8686, Japan. Momose_Yu@takeda.co.jp
Maekawa
Tsuyoshi
T
Yamano
Tohru
T
Kawada
Mitsuru
M
Odaka
Hiroyuki
H
Ikeda
Hitoshi
H
Sohda
Takashi
T
D000818:Animals; D019556:COS Cells; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D003920:Diabetes Mellitus / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D023303:Oxazolidinones / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013696:Temperature; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology*; D045162:Thiazolidinediones
D007004:Hypoglycemic Agents; D007328:Insulin; D023303:Oxazolidinones; D013844:Thiazoles; D045162:Thiazolidinediones; C089946:2,4-thiazolidinedione