Novel 5-Substituted 2,4-Thiazolidinedione and 2,4-Oxazolidinedione Derivatives as Insulin Sensitizers with Antidiabetic Activities

• Published in: Journal of medicinal chemistry 2002-03, Vol.45 (7), p.1518-1534
• Main Authors: Momose, Yu, Maekawa, Tsuyoshi, Yamano, Tohru, Kawada, Mitsuru, Odaka, Hiroyuki, Ikeda, Hitoshi, Sohda, Takashi
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Chromatography, High Pressure Liquid; COS Cells; Crystallography, X-Ray; Diabetes Mellitus - drug therapy; General and cellular metabolism. Vitamins; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - pharmacology; Insulin - blood; Male; Medical sciences; Mice; Models, Chemical; Models, Molecular; Oxazolidinones - chemistry; Oxazolidinones - pharmacology; Pharmacology. Drug treatments; Rats; Rats, Wistar; Temperature; Thiazoles - chemistry; Thiazoles - pharmacology; Thiazolidinediones
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm010490l

Two novel classes of 2,4-thiazolidinediones and 2,4-oxazolidinediones with an ω-(azolylalkoxyphenyl)alkyl substituent at the 5-position were prepared and their antidiabetic effects were evaluated in two genetically obese and diabetic animal models, KKAy 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 α-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 KKAy 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 γ (EC50 = 8.87 nM).