Shinkai H, Onogi S, Tanaka M, Shibata T, Iwao M, Wakitani K, Uchida I
Central Pharmaceutical Research Institute, JT Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
J Med Chem. 1998 May 21;41(11):1927-33. doi: 10.1021/jm970771m.
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.
异恶唑烷-3,5-二酮2（JTT-501）是环状丙二酸衍生物之一，发现在KKAy小鼠中口服剂量为38mg/kg/天时可降低血糖，目前正在进行II期临床试验评估。对一系列丙二酸及相关化合物的进一步研究表明，1,3-二羰基结构对胰岛素增敏活性很重要。被选为2的后续药物的丙二酸二甲酯10是一系列1,3-二羰基化合物中的最佳化合物，且比相应的噻唑烷-2,4-二酮1更有效。
