Chemical Research in Chinese Universities ›› 2014, Vol. 30 ›› Issue (5): 785-793.doi: 10.1007/s40242-014-4043-9

Previous Articles     Next Articles

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

ZHANG Shuo1,2, WANG Yuli2, LIU Wei2, XIE Yafei2, LIU Yuqiang2, XU Weiren2, TANG Lida2, WANG Jianwu1, ZHAO Guilong2   

  1. 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).

Abstract:

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.

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