Discovery of 6-deoxydapagliflozin as a highly potent sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes.

Abstract

Systematic mono-deoxylation of the four hydroxyl groups in the glucose moiety in dapagliflozin led to the discovery of 6-deoxydapagliflozin 1 as a more active sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor (IC50 = 0.67 nM against human SGLT2 (hSGLT2) vs 1.16 nM for dapagliflozin). It exhibited more potent blood glucose inhibitory activity in rat oral glucose tolerance test and induced more urinary glucose in rat urinary glucose excretion test than its parent compound dapagliflozin.

• Authors: Lingyu Zhang, Yuli Wang, Huaqiang Xu, Yongheng Shi, Bingni Liu, Qunchao Wei, Weiren Xu, Lida Tang, Jianwu Wang, Guilong Zhao
• Journal: Medicinal chemistry (Shariqah (United Arab Emirates)) (Med Chem) Vol. 10 Issue 3 Pg. 304-17 (May 2014) ISSN: 1875-6638 [Electronic] Netherlands
• PMID: 24059684 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1,6-dideoxyglucopyranose
• Benzhydryl Compounds
• Blood Glucose
• Hypoglycemic Agents
• SLC5A2 protein, human
• Sodium-Glucose Transporter 2
• Sodium-Glucose Transporter 2 Inhibitors
• Deoxyglucose

Topics

• Animals
• Benzhydryl Compounds (administration & dosage, chemistry, pharmacology)
• Blood Glucose (drug effects)
• Deoxyglucose (administration & dosage, analogs & derivatives, chemistry, pharmacology)
• Diabetes Mellitus, Experimental (drug therapy)
• Diabetes Mellitus, Type 2 (drug therapy)
• Dose-Response Relationship, Drug
• Drug Discovery
• Glucose Tolerance Test
• Humans
• Hypoglycemic Agents (chemical synthesis, chemistry, pharmacology)
• Molecular Structure
• Rats
• Sodium-Glucose Transporter 2
• Sodium-Glucose Transporter 2 Inhibitors
• Structure-Activity Relationship