Glucokinase (GK) activators are being developed for the treatment of type 2 diabetes mellitus (T2DM). However, existing GK activators have risks of hypoglycemia caused by over-activation of GK in islet cells and dyslipidemia caused by over-activation of intrahepatic GK. In the effort to mitigate risks of hypoglycemia and dyslipidemia while maintaining the promising efficacy of GK activator, we investigated a series of cycloalkyl-fused N-thiazol-2-yl-benzamides as tissue non-specific partial GK activators, which led to the identification of compound 72 that showed a good balance between in vitro potency and enzyme kinetic parameters, and protected β-cells from streptozotocin-induced apoptosis. Chronic treatment of compound 72 demonstrated its potent activity in regulation of glucose homeostasis and low risk of dyslipidemia with diabetic db/db mice in oral glucose tolerance test (OGTT). Moreover, acute treatment of compound 72 did not induce hypoglycemia in C57BL/6J mice even at 200 mg/kg via oral administration.

葡萄糖激酶（GK）激活剂正在开发中，用于治疗2型糖尿病（T2DM）。但是，现有的GK激活剂存在因胰岛细胞中G​​K过度激活而引起的低血糖症和因肝内GK过度激活而引起的血脂异常的风险。为了减轻低血糖和血脂异常的风险，同时又保持了GK激活剂的前景，我们研究了一系列环烷基稠合的N-噻唑-2-基-苯甲酰胺作为组织非特异性部分GK激活剂，从而鉴定了化合物72在体外效能和酶动力学参数之间显示出良好的平衡，并保护β细胞免受链脲佐菌素诱导的细胞凋亡。化合物72的慢性治疗在口服葡萄糖耐量试验（OGTT）中，证实了其对糖尿病db / db小鼠调节葡萄糖稳态和降低血脂异常风险的有效作用。此外，化合物的急性治疗72不通过口服给药诱导即使在200毫克/千克在C57BL / 6J小鼠的低血糖。