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.
Medicinal 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.
Export Options
About this article
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
DOI https://dx.doi.org/10.2174/1573406411666150105105529 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
Call for Papers in Thematic Issues
Carbohydrates in Computational and Medicinal Chemistry
Carbohydrates are the most essential organic molecules and are involved in the maintenance of various physiological and metabolic processes in living organisms. Carbohydrate-based compounds have come to the attention of researchers because of their significant contributions to biological functions, such as cell development and cell proliferation, connections between several cells, ...read more
Recent Advances in the Medicinal Chemistry of Cancer
Scope of the Thematic Issue: Correlation between structure and function is one of the important aspects of the success of anti-cancer compounds associated with their structure-activity interactions, physiology, biochemical, molecular, and genetic processes. Overcoming these obstacles is key to obtaining further insights into developments in rational drug design, bioorganic chemistry, ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Third and Fourth Generation Fluoroquinolone Antibacterials: A Systematic Review of Safety and Toxicity Profiles
Current Drug Safety Phosphodiesterase 5 Inhibitors - Drug Design and Differentiation Based on Selectivity, Pharmacokinetic and Efficacy Profiles
Current Pharmaceutical Design Pegaptanib Sodium for the Treatment of Proliferative Diabetic Retinopathy and Diabetic Macular Edema
Current Diabetes Reviews Indoor Dust Levels of Perfluoroalkyl Substances (PFASs) and the Role of Ingestion as an Exposure Pathway: A Review
Current Organic Chemistry Associations of Plasma BACE1 Level and BACE1 C786G Gene Polymorphism with Cognitive Functions in Patients with Type 2 Diabetes: A Cross- Sectional Study
Current Alzheimer Research Diabetes and Obesity in Pregnancy: From Patients to Molecular Mechanisms
Current Vascular Pharmacology Exosomes and Exosomal microRNAs in Age-associated Stroke
Current Vascular Pharmacology Modifiable Midlife Risk Factors for Late-Life Cognitive Impairment and Dementia
Current Psychiatry Reviews Global View on Alzheimer’s Disease and Diabetes Mellitus: Threats, Risks and Treatment Alzheimer’s Disease and Diabetes Mellitus
Current Alzheimer Research Oxidation Inhibits Iron-Induced Blood Coagulation
Current Drug Targets Effects of Liver Diseases on Drug-metabolizing Enzymes: Implications for Drug Fate Alterations and Nano-therapeutic Openings
Current Medicinal Chemistry Oxidative Stress in Cardiovascular Disease: A New Avenue Toward Future Therapeutic Approaches
Recent Patents on Cardiovascular Drug Discovery The Complexity of Aging: Cancer Risk Among Elderly People and Infectious Risk Among Those with Cancer
Anti-Cancer Agents in Medicinal Chemistry Rho-Kinase and RGS-Containing RhoGEFs as Molecular Targets for the Treatment of Erectile Dysfunction
Current Pharmaceutical Design Polymorphism in Endothelin-1 Gene: An Overview
Current Clinical Pharmacology Anti-IL-1 β Therapies
Recent Patents on DNA & Gene Sequences Role of AGEs-RAGE System in Cardiovascular Disease
Current Pharmaceutical Design Placental Growth Hormone, Fetal Growth and the IGF Axis in Normal and Diabetic Pregnancy
Current Diabetes Reviews Editorial (Thematic Issue: New Therapeutic Targets in Clinical Medicine)
Current Pharmaceutical Design The Biology of the Peroxisome Proliferator-activated Receptor System in the Female Reproductive Tract
Current Pharmaceutical Design