3-Oxodapagliflozin as a Potent and Highly Selective SGLT2 Inhibitor for the Treatment of Type 2 Diabetes

doi:10.1007/s40242-014-4043-9

高等学校化学研究 ›› 2014, Vol. 30 ›› Issue (5): 785-793.doi: 10.1007/s40242-014-4043-9

3-Oxodapagliflozin as a Potent and Highly Selective SGLT2 Inhibitor for the Treatment of Type 2 Diabetes

ZHANG Shuo^1,2, WANG Yuli², LIU Wei², XIE Yafei², LIU Yuqiang², XU Weiren², TANG Lida², WANG Jianwu¹, ZHAO Guilong²

1. School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, P. R. China;
2. Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, P. R. China

收稿日期:2014-02-11 修回日期:2014-04-09 出版日期:2014-10-01 发布日期:2014-04-21
通讯作者: ZHAO Guilong, WANG Jianwu E-mail:zhao_guilong@126.com;jwwang@sdu.edu.cn
基金资助:
Supported by the National Natural Science Foundation of China(No.21302141), the Key Projects of Tianjin Science and Technology Support Plan, China(No.10ZCKFSH01300) and the Tianjin Municipal Natural Science Foundation, China(No.14JCQNJC12900).

3-Oxodapagliflozin as a Potent and Highly Selective SGLT2 Inhibitor for the Treatment of Type 2 Diabetes

ZHANG Shuo^1,2, WANG Yuli², LIU Wei², XIE Yafei², LIU Yuqiang², XU Weiren², TANG Lida², WANG Jianwu¹, ZHAO Guilong²

1. School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, P. R. China;
2. Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, P. R. China

Received:2014-02-11 Revised:2014-04-09 Online:2014-10-01 Published:2014-04-21
Contact: ZHAO Guilong, WANG Jianwu E-mail:zhao_guilong@126.com;jwwang@sdu.edu.cn
Supported by:
Supported by the National Natural Science Foundation of China(No.21302141), the Key Projects of Tianjin Science and Technology Support Plan, China(No.10ZCKFSH01300) and the Tianjin Municipal Natural Science Foundation, China(No.14JCQNJC12900).

摘要/Abstract

摘要：

Structural modifications of 3-OH in the glucose moiety of dapagliflozin(1), an approved potent sodium-dependent glucose transporter 2(SGLT2) inhibitor, led to 3-oxodapagliflozin(16), a highly potent and more selective SGLT2 inhibitor[IC₅₀(hSGLT1)/IC₅₀(hSGLT2)=2851 for compound 16 vs. 843 for compound 1]. 3-Oxodapagliflozin(16) exhibited in vitro(IC₅₀=1.0 nmol/L against hSGLT2 for compound 16 vs. 1.3 nmol/L for compound 1) and in vivo activities comparable to those of dapagliflozin(1). The bioactivities of 3-oxodapagliflozin (16) warrant its further evaluation as a promising SGLT2 inhibitor for the treatment of type 2 diabetes.

关键词: SGLT2 inhibitor, Structure-activity relationship, Dapagliflozin

Abstract:

Key words: SGLT2 inhibitor, Structure-activity relationship, Dapagliflozin

ZHANG Shuo, WANG Yuli, LIU Wei, XIE Yafei, LIU Yuqiang, XU Weiren, TANG Lida, WANG Jianwu, ZHAO Guilong. 3-Oxodapagliflozin as a Potent and Highly Selective SGLT2 Inhibitor for the Treatment of Type 2 Diabetes[J]. 高等学校化学研究, 2014, 30(5): 785-793.

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3-Oxodapagliflozin as a Potent and Highly Selective SGLT2 Inhibitor for the Treatment of Type 2 Diabetes

3-Oxodapagliflozin as a Potent and Highly Selective SGLT2 Inhibitor for the Treatment of Type 2 Diabetes

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