Shinkai H, Ozeki H, Motomura T, Ohta T, Furukawa N, Uchida I
Central Pharmaceutical Research Institute, JT Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
J Med Chem. 1998 Dec 31;41(27):5420-8. doi: 10.1021/jm9804228.
During an investigation of drugs for improving the beta-cell response to glucose, we found that 4-cyclohexyl-4-oxobutyric acid selectively improved glucose-stimulated insulin release and glucose tolerance in both normal and diabetic rats. A series of 4-cycloalkyl-4-oxobutyric acids and related compounds were synthesized and evaluated for their effects on the glucose tolerance test and fasting euglycemia. This study elucidated the structural requirements for drug activity and determined that the optimum compound was 4-(trans-4-methylcyclohexyl)-4-oxobutyric acid 7 (JTT-608). This compound improved glucose tolerance from an oral dose of 3 mg/kg and did not change fasting euglycemia even at an oral dose of 30 mg/kg. Selective improvement of glucose-induced insulin secretion was observed in studies using neonatal streptozotocin rats (nSTZ rats) and perfused pancreases isolated from nSTZ rats.
在一项关于改善β细胞对葡萄糖反应的药物研究中，我们发现4-环己基-4-氧代丁酸能选择性地改善正常大鼠和糖尿病大鼠的葡萄糖刺激的胰岛素释放及糖耐量。合成了一系列4-环烷基-4-氧代丁酸及其相关化合物，并评估了它们对糖耐量试验和空腹血糖正常的影响。本研究阐明了药物活性的结构要求，并确定最佳化合物为4-(反式-4-甲基环己基)-4-氧代丁酸7（JTT-608）。该化合物口服剂量为3mg/kg时可改善糖耐量，即使口服剂量达30mg/kg也不会改变空腹血糖正常。在使用新生链脲佐菌素大鼠（nSTZ大鼠）以及从nSTZ大鼠分离出的灌注胰腺的研究中，观察到了葡萄糖诱导的胰岛素分泌的选择性改善。
