Design of SGLT2 Inhibitors for the Treatment of Type 2 Diabetes: A History Driven by Biology to Chemistry

Author(s): Wenqing Cai, Linlin Jiang, Yafei Xie, Yuqiang Liu, Wei Liu, Guilong Zhao

Journal Name: Medicinal Chemistry

Volume 11 , Issue 4 , 2015

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Abstract:

A brief history of the design of sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors is reviewed. The design of O-glucoside SGLT2 inhibitors by structural modification of phlorizin, a naturally occurring O-glucoside, in the early stage was a process mainly driven by biology with anticipation of improving SGLT2/SGLT1 selectivity and increasing metabolic stability. Discovery of dapagliflozin, a pioneering C-glucoside SGLT2 inhibitor developed by Bristol-Myers Squibb, represents an important milestone in this history. In the second stage, the design of C-glycoside SGLT2 inhibitors by modifications of the aglycone and glucose moiety of dapagliflozin, an original structural template for almost all C-glycoside SGLT2 inhibitors, was mainly driven by synthetic organic chemistry due to the challenge of designing dapagliflozin derivatives that are patentable, biologically active and synthetically accessible. Structure-activity relationships (SAR) of the SGLT2 inhibitors are also discussed.

Keywords: Drug design, C-glycoside, SGLT2 inhibitor, structure-activity relationship (SAR), type 2 diabetes.

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Article Details

VOLUME: 11
ISSUE: 4
Year: 2015
Published on: 29 April, 2015
Page: [317 - 328]
Pages: 12
DOI: 10.2174/1573406411666150105105529
Price: $65

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