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

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

  • Eur J Med Chem. 2017 Oct 20:139:128-152. doi: 10.1016/j.ejmech.2017.07.051.
Zhengyu Wang 1,  Xiaofan Shi 2,  Huan Zhang 3,  Liang Yu 4,  Yanhua Cheng 1,  Hefeng Zhang 5,  Huibin Zhang 3,  Jinpei Zhou 6,  Jing Chen 7,  Xu Shen 4,  Wenhu Duan 8
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China.
  • 2 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China.
  • 3 Center of Drug Discovery, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing, Jiangsu 210009, PR China.
  • 4 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China.
  • 5 University of Chinese Academy of Sciences, Beijing 100049, PR China; Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China.
  • 6 Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China. Electronic address: jpzhou668@163.com.
  • 7 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China. Electronic address: jingchen@simm.ac.cn.
  • 8 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China. Electronic address: whduan@simm.ac.cn.
PMID: 28800453 DOI: 10.1016/j.ejmech.2017.07.051
Abstract

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.

Keywords

Dyslipidemia; Glucokinase activators; Hypoglycemia; N-Thiazol-2-yl-benzamides; Type 2 diabetes mellitus.

Figures