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.
Publication types
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Historical Article
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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Benzhydryl Compounds / chemical synthesis
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Benzhydryl Compounds / history
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Benzhydryl Compounds / therapeutic use
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Diabetes Mellitus, Type 2 / drug therapy*
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Diabetes Mellitus, Type 2 / metabolism
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Diabetes Mellitus, Type 2 / pathology
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Drug Design
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Drug Discovery / history*
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Glucosides / chemical synthesis
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Glucosides / history
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Glucosides / therapeutic use
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Glycosides
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History, 20th Century
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History, 21st Century
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Humans
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Hypoglycemic Agents / chemical synthesis*
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Hypoglycemic Agents / history*
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Hypoglycemic Agents / therapeutic use
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Monosaccharides / chemical synthesis
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Monosaccharides / history
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Monosaccharides / therapeutic use
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Phlorhizin / analogs & derivatives
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Phlorhizin / chemical synthesis
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Phlorhizin / history
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Phlorhizin / therapeutic use
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Sodium-Glucose Transporter 2 / chemistry
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Sodium-Glucose Transporter 2 / metabolism
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Sodium-Glucose Transporter 2 Inhibitors*
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Structure-Activity Relationship
Substances
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Benzhydryl Compounds
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C-glycoside
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Glucosides
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Glycosides
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Hypoglycemic Agents
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Monosaccharides
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SLC5A2 protein, human
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Sodium-Glucose Transporter 2
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Sodium-Glucose Transporter 2 Inhibitors
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dapagliflozin
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Phlorhizin