Design, Synthesis and Hypoglycemic Activity of Cyclopropane-Bearing C-Glucosides as Sodium-Glucose Cotransporter 2 Inhibitors

doi:10.6023/cjoc201508003

Chin. J. Org. Chem. ›› 2016, Vol. 36 ›› Issue (3): 604-612.DOI: 10.6023/cjoc201508003 Previous Articles Next Articles

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含环丙烷结构的C-葡萄糖苷类钠-葡萄糖共转运子2抑制剂的设计、合成与降血糖活性研究

史永恒^a, 周春梅^a, 张盼龙^a, 刘继平^a, 赵桂龙^b, 王玉丽^b

a 陕西中医药大学药学院咸阳 712046;
b 天津药物研究院有限公司天津市新药设计与发现重点实验室天津 300193

收稿日期:2015-08-05 修回日期:2015-11-01 发布日期:2015-11-06
通讯作者: 史永恒 E-mail:shiyongheng1986@aliyun.com
基金资助:
陕西省教育厅专项科研(No. 15JK1203)、国家自然科学基金(No. 21302141)和山东省自然科学基金(No. ZR2015BM028)资助项目.

Design, Synthesis and Hypoglycemic Activity of Cyclopropane-Bearing C-Glucosides as Sodium-Glucose Cotransporter 2 Inhibitors

Shi Yongheng^a, Zhou Chunmei^a, Zhang Panlong^a, Liu Jiping^a, Zhao Guilong^b, Wang Yuli^b

a College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang 712046;
b Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193

Received:2015-08-05 Revised:2015-11-01 Published:2015-11-06
Supported by:
Project supported by the Scientific Research Projects of Shaanxi Education Department (No. 15JK1203), the National Natural Science Fundation of China (No. 21302141) and the Natural Science Foundation of Shandong Province (No. ZR2015BM028).

1. Design, Synthesis and Hypoglycemic Activity of Cyclopropane-Bearing C-Glucosides as Sodium-Glucose Cotransporter 2 Inhibitors.PDF(6825KB)

Abstract

A novel series of cyclopropane-bearing C-glucosides were designed and synthesized as sodium-glucose cotransporter 2 (SGLT2) inhibitors starting from the substituted bromobenzoic acids. The reaction condition for the construction of the cyclopropane moiety was studied, and a more economical synthetic route was established. All the synthesized compounds were characterized by ¹H NMR and HR-MS. In vivo evaluation of these compounds by rat urinary glucose excretion (UGE) test revealed that all the synthesized seven cyclopropane-bearing C-glucosides 1a~1g exhibited potent hypoglycemic activity, among which (1S)-1-deoxy-1-{4-chloro-3-[1-(4-ethoxyphenyl)cyclopropyl-1-yl]-phenyl}-D-glucopyranose (1e) was the most potent one but still exhibited lower hypoglycemic activity to dapagliflozin, demonstrating that the cyclopropane moiety can not be well tolerated in dapagliflozin molecule and the position of the Cl atom in dapagliflozin is the best among the analogues.

Key words: cyclopropane, C-glucoside, SGLT2 inhibitor, synthesis, hypoglycemic activity

Cite this article

Shi Yongheng, Zhou Chunmei, Zhang Panlong, Liu Jiping, Zhao Guilong, Wang Yuli. Design, Synthesis and Hypoglycemic Activity of Cyclopropane-Bearing C-Glucosides as Sodium-Glucose Cotransporter 2 Inhibitors[J]. Chin. J. Org. Chem., 2016, 36(3): 604-612.

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含环丙烷结构的C-葡萄糖苷类钠-葡萄糖共转运子2抑制剂的设计、合成与降血糖活性研究

Design, Synthesis and Hypoglycemic Activity of Cyclopropane-Bearing C-Glucosides as Sodium-Glucose Cotransporter 2 Inhibitors

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