Discovery of cycloalkyl-fused N-thiazol-2-yl-benzamides as tissue non-specific glucokinase activators: Design, synthesis, and biological evaluation

• DOI: 10.1016/j.ejmech.2017.07.051
• Publication Date: 2017-07-25T08:01:26Z
• Authors: Zhengyu Wang; Xiaofan Shi; Huan Zhang; Liang Yu; Yanhua Cheng; Hefeng Zhang; Huibin Zhang; Jinpei Zhou; Jing Chen; Xu Shen; Wenhu Duan
• Keywords: Dyslipidemia; Glucokinase

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.