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

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

Volume: 11 Issue: 4

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

Affiliation:

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

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.

Cite this article as:

Cai Wenqing, Jiang Linlin, Xie Yafei, Liu Yuqiang, Liu Wei and Zhao Guilong, Design of SGLT2 Inhibitors for the Treatment of Type 2 Diabetes: A History Driven by Biology to Chemistry, Medicinal Chemistry 2015; 11 (4) . https://dx.doi.org/10.2174/1573406411666150105105529