Abstract
Sodium-glucose cotransporter 2 (SGLT2) is almost exclusively expressed in the proximal renal tubules. It is responsible for about 90% of the glucose reabsorption from tubular fluid. Selective inhibition of SGLT2 is expected to favor in the normalization of plasma glucose levels in T2DM patients through the prevention of renal glucose reabsorption and the promotion of glucose excretion from urine. Selective SGLT2 inhibitors have the merits to minimize the gastrointestinal side effects associated with SGLT1 inhibition, and selective SGLT2 inhibition may have a low risk of hypoglycemia. Since the C-aryl glucosides are metabolically more stable than the O-glucosides, numerous efforts have been made in the development of potent and selective C-aryl glucoside SGLT2 inhibitors, and a number of them are now used as anti-diabetes drugs in clinic or at various stages of clinical developments. Based on their structural features, in this review, these SGLT2 inhibitors are classified as three types: the phenyl/arylmethylphenyl C-glucosides, with an emphasis on the modifications on the proximal and/or the distal phenyl ring, and the spacer; the heteroarylmethylphenyl Cglucosides, with a replacement of the distal phenyl ring by a heterocycle like pyridazine, pyrimidine, thiophene and benzothiophene, thiazole, 1,3,4-thiadiazole, and triazolopyridinone; and the glucose-modified Caryl glucosides, including the glucose C-1 derived O-spiroketals, C-4 gem-difluoro analogues, C-5 and C-6 modified derivatives, dioxa-bicyclo[3.2.1]octane bridged ketals, the thioglucosides, and carbasugars. The structure-activity relationships (SARs) of each type along with their inhibitory potency against human SGLT2 and selectivity over human SGLT1 are discussed.
Keywords: Antidiabetic agents, C-aryl glucoside, diabetes, glucose, inhibitors, SGLT2, SGLT1, sodium-glucose cotransporter 2, type 2 diabetes mellitus, T2DM.
Current Medicinal Chemistry
Title:Recent Developments of C-Aryl Glucoside SGLT2 Inhibitors
Volume: 23 Issue: 8
Author(s): Yang Zhang and Zhao-Peng Liu
Affiliation:
Keywords: Antidiabetic agents, C-aryl glucoside, diabetes, glucose, inhibitors, SGLT2, SGLT1, sodium-glucose cotransporter 2, type 2 diabetes mellitus, T2DM.
Abstract: Sodium-glucose cotransporter 2 (SGLT2) is almost exclusively expressed in the proximal renal tubules. It is responsible for about 90% of the glucose reabsorption from tubular fluid. Selective inhibition of SGLT2 is expected to favor in the normalization of plasma glucose levels in T2DM patients through the prevention of renal glucose reabsorption and the promotion of glucose excretion from urine. Selective SGLT2 inhibitors have the merits to minimize the gastrointestinal side effects associated with SGLT1 inhibition, and selective SGLT2 inhibition may have a low risk of hypoglycemia. Since the C-aryl glucosides are metabolically more stable than the O-glucosides, numerous efforts have been made in the development of potent and selective C-aryl glucoside SGLT2 inhibitors, and a number of them are now used as anti-diabetes drugs in clinic or at various stages of clinical developments. Based on their structural features, in this review, these SGLT2 inhibitors are classified as three types: the phenyl/arylmethylphenyl C-glucosides, with an emphasis on the modifications on the proximal and/or the distal phenyl ring, and the spacer; the heteroarylmethylphenyl Cglucosides, with a replacement of the distal phenyl ring by a heterocycle like pyridazine, pyrimidine, thiophene and benzothiophene, thiazole, 1,3,4-thiadiazole, and triazolopyridinone; and the glucose-modified Caryl glucosides, including the glucose C-1 derived O-spiroketals, C-4 gem-difluoro analogues, C-5 and C-6 modified derivatives, dioxa-bicyclo[3.2.1]octane bridged ketals, the thioglucosides, and carbasugars. The structure-activity relationships (SARs) of each type along with their inhibitory potency against human SGLT2 and selectivity over human SGLT1 are discussed.
Export Options
About this article
Cite this article as:
Zhang Yang and Liu Zhao-Peng, Recent Developments of C-Aryl Glucoside SGLT2 Inhibitors, Current Medicinal Chemistry 2016; 23 (8) . https://dx.doi.org/10.2174/0929867323666160210125747
DOI https://dx.doi.org/10.2174/0929867323666160210125747 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...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
- Announcements
Related Articles
-
Surgical Complications of Hyperglycaemia
Current Diabetes Reviews Relations between GPR4 Expression, Microvascular Density (MVD) and Clinical Pathological Characteristics of Patients with Epithelial Ovarian Carcinoma (EOC)
Current Pharmaceutical Design Homeostasis and Compensatory Homeostasis: Bridging Western Medicine and Traditional Chinese Medicine
Current Cardiology Reviews Progress of Oral Insulin and Related Drug Delivery Systems and their Pharmacokinetics
Current Drug Metabolism New Antipsychotics and Schizophrenia: A Review on Efficacy and Side Effects
Current Medicinal Chemistry Local Cerebral Blood Flow is Preserved in Sepsis
Current Neurovascular Research Side Effects of Atypical Antipsychotic Drugs
Current Pharmaceutical Design Role of Ischemia Modified Albumin Serum Levels as an Oxidative Stress Marker in Children with Diabetic Ketoacidosis
Combinatorial Chemistry & High Throughput Screening Hyperglycemic Hyperosmolar State: A Pragmatic Approach to Properly Manage Sodium Derangements
Current Diabetes Reviews Somatostatin and its Analogs
Current Drug Targets The Central Nervous System as a Promising Target to Treat Diabetes Mellitus
Current Topics in Medicinal Chemistry Evolution of Antipsychotic Intervention in the Schizophrenic Psychosis
Current Drug Targets Surgical Esophageal Emergencies
Current Respiratory Medicine Reviews Effect of Fasting Ramadan in Diabetes Control Status - Application of Extensive Diabetes Education, Serum Creatinine with HbA1c Statistical ANOVA and Regression Models to Prevent Hypoglycemia
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Association Between Seizures and Diabetes Mellitus: A Comprehensive Review of Literature
Current Diabetes Reviews Sodium-glucose Cotransporter 2 Inhibitors and the Risk of Diabetic Ketoacidosis; from Pathophysiology to Clinical Practice
Cardiovascular & Hematological Disorders-Drug Targets The Complications of Bariatric Surgery Patients with Type 2 Diabetes in the World: A Systematic Review and Meta-Analysis
Current Diabetes Reviews Transporters at CNS Barrier Sites: Obstacles or Opportunities for Drug Delivery?
Current Pharmaceutical Design Sodium Glucose Cotransporter-2 Inhibitor Treatment and the Risk of Diabetic Ketoacidosis in Denmark: A Retrospective Cohort Study of Five Years of Use
Current Drug Safety Human Islet Transplantation: Current Status and Future Direction
Micro and Nanosystems