Pharmacology Research Labs, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tuskuba, Ibaraki 305-8585, Japan.
Eur J Pharmacol. 2010 Oct 25;645(1-3):185-91. doi: 10.1016/j.ejphar.2010.07.018. Epub 2010 Jul 23.
Recent evidence suggests that the forkhead transcription factor Foxo1 plays an important role in the regulation of glucose and triglyceride metabolism at the gene transcription level for glucose-6 phosphatase (G6Pase), phosphoenolpyruvate carboxykinase (PEPCK), and apolipoprotein C-III (apoC-III). Here, we report on the pharmacological effects of the novel Foxo1 inhibitor AS1708727, which we identified by compound screening. Chronic treatment of diabetic db/db mice with AS1708727 for four days significantly reduced blood glucose and triglyceride levels with decrease of gene expression levels of hepatic G6Pase, PEPCK, and apoC-III. No reports have yet examined the influence of Foxo1 inhibitors on these pharmacological effects. In this study, we newly identified a Foxo1 inhibitor compound capable of exerting both an anti-hypertriglyceridemic and anti-hyperglycemic effect. These effects were dependent on maintaining a stable blood concentration of AS1708727 and achieving a high rate of compound transition to the liver. We also investigated the action mechanism of AS1708727 on gluconeogenesis in vitro and in vivo. The compound inhibited gene expression of key gluconeogenic molecules and suppressed gluconeogenesis in Fao hepatocyte cells in vitro. Further, in the pyruvate challenge study using db/db mice in vivo, AS1708727 suppressed increases in blood glucose level by inhibiting gluconeogenic gene expression. These results indicate that the novel Foxo1 inhibitor AS1708727 may exert anti-diabetic and anti-hypertriglyceridemic effects by improving blood glucose and triglyceride metabolism at the gene expression level, and may represent a new class of drugs useful for treating type 2 diabetes mellitus and hypertriglyceridemia.
最近的证据表明，叉头转录因子 Foxo1 在葡萄糖-6-磷酸酶（G6Pase）、磷酸烯醇丙酮酸羧激酶（PEPCK）和载脂蛋白 C-III（apoC-III）的基因转录水平上对葡萄糖和甘油三酯代谢的调节起着重要作用。在这里，我们报告了通过化合物筛选鉴定的新型 Foxo1 抑制剂 AS1708727 的药理作用。用 AS1708727 对糖尿病 db/db 小鼠进行为期四天的慢性治疗，可显著降低血糖和甘油三酯水平，并降低肝 G6Pase、PEPCK 和 apoC-III 的基因表达水平。目前还没有报道研究 Foxo1 抑制剂对这些药理作用的影响。在这项研究中，我们新鉴定了一种能够发挥抗高甘油三酯血症和抗高血糖作用的 Foxo1 抑制剂化合物。这些作用依赖于维持 AS1708727 的稳定血药浓度和达到高化合物向肝脏转化的速率。我们还研究了 AS1708727 在体外和体内对糖异生的作用机制。该化合物抑制关键糖异生分子的基因表达，并在体外抑制 Fao 肝细胞中的糖异生。此外，在体内使用 db/db 小鼠进行的丙酮酸挑战研究中，AS1708727 通过抑制糖异生基因表达抑制血糖水平升高。这些结果表明，新型 Foxo1 抑制剂 AS1708727 通过改善基因表达水平的血糖和甘油三酯代谢，可能发挥抗糖尿病和抗高甘油三酯血症作用，可能代表一类用于治疗 2 型糖尿病和高甘油三酯血症的新型药物。
