Isoxazolidine-3,5-dione and noncyclic 1,3-dicarbonyl compounds as hypoglycemic agents.
Isoxazolidine-3,5-dione 2 (JTT-501), one of the cyclic malonic acid derivatives, was found to decrease blood glucose at an oral dose of 38 mg/kg/day in KKAy mice and is currently undergoing evaluation in phase II clinical trials. Further studies on a series of malonic acids and related compounds showed that the 1,3-dicarbonyl structure was important for insulin-sensitizing activity. Dimethyl malonate 10, which was selected as a successor for 2, was the optimum compound in a series of 1,3-dicarbonyl compounds and was more potent than the corresponding thiazolidine-2,4-dione 1.
Shinkai
H
H
Central Pharmaceutical Research Institute, JT Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
Onogi
S
S
Tanaka
M
M
Shibata
T
T
Iwao
M
M
Wakitani
K
K
Uchida
I
I
D016475:3T3 Cells; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D007328:Insulin / Q000502:physiology; D007555:Isoxazoles / Q000138:chemical synthesis / Q000494:pharmacology; D007739:L Cells; D008297:Male; D008314:Malonates / Q000138:chemical synthesis / Q000494:pharmacology; D051379:Mice; D010080:Oxazoles / Q000138:chemical synthesis / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D007555:Isoxazoles; D008314:Malonates; D010080:Oxazoles; D014280:Triglycerides; C112428:dimethyl 4-(2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy)benzylmalonate; C112329:JTT 501