title: Design of SGLT2 Inhibitors for the Treatment of Type 2 Diabetes: A History Driven by Biology to Chemistry.
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.
authors.forename: Wenqing
authors.initials: W
authors.lastname: Cai
authors.forename: Linlin
authors.initials: L
authors.lastname: Jiang
authors.forename: Yafei
authors.initials: Y
authors.lastname: Xie
authors.forename: Yuqiang
authors.initials: Y
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, 308 An Shan Xi Dao, Nankai District, Tianjin 300193, P.R. China. zhao_guilong@126.com.
authors.forename: Guilong
authors.initials: G
authors.lastname: Zhao
mesh_terms: D001559:Benzhydryl Compounds / Q000138:chemical synthesis / Q000266:history / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015195:Drug Design; D055808:Drug Discovery / Q000266:history*; D005960:Glucosides / Q000138:chemical synthesis / Q000266:history / Q000627:therapeutic use; D006027:Glycosides; D049673:History, 20th Century; D049674:History, 21st Century; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000266:history* / Q000627:therapeutic use; D009005:Monosaccharides / Q000138:chemical synthesis / Q000266:history / Q000627:therapeutic use; D010695:Phlorhizin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000266:history / Q000627:therapeutic use; D051297:Sodium-Glucose Transporter 2 / Q000737:chemistry / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013329:Structure-Activity Relationship
chemical_list: D001559:Benzhydryl Compounds; C438934:C-glycoside; D005960:Glucosides; D006027:Glycosides; D007004:Hypoglycemic Agents; D009005:Monosaccharides; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C529054:dapagliflozin; D010695:Phlorhizin