Identification of an oxime-containing C-glucosylarene as a potential inhibitor of sodium-dependent glucose co-transporter 2.

Abstract

Treatment of hyperglycemia with drugs that block renal glucose reabsorption via inhibition of sodium-dependent glucose cotransporter 2 (SGLT2) is a novel approach to diabetes management. In this study, twenty-seven aryl C-glycosides bearing a C=N/C-N linkage at the glucosyl C6 position were designed, synthesized and evaluated for their inhibitory activity against human SGLT2 (hSGLT2). Compounds with good hSGLT2 inhibition were further investigated to determine their selectivity over hSGLT1. Of these, five representative aryl C-glycosides were chosen for pharmacokinetic analysis. Oxime 2a was determined to have the most promising pharmacokinetic properties and was selected for in vivo glucosuria and plasma glucose level studies, which found it to exhibit comparable efficacy to dapagliflozin (1). Furthermore, 2a was not found to exhibit either significant cytotoxicity (CC50 > 50 μM) or human ether-a-go-go related gene (hERG) inhibition (2% inhibition at 10 μM). Taken together, these efforts culminated in the discovery of oxime 2a as a potential SGLT2 inhibitor.

• Authors: Mao-Chia Yuan, Teng-Kuang Yeh, Chiung-Tong Chen, Jen-Shin Song, Yu-Chen Huang, Tsung-Chih Hsieh, Chung-Yu Huang, Yu-Ling Huang, Min-Hsien Wang, Szu-Huei Wu, Chun-Hsu Yao, Yu-Sheng Chao, Jinq-Chyi Lee
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 143 Pg. 611-620 (Jan 01 2018) ISSN: 1768-3254 [Electronic] France
• PMID: 29216560 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Chemical References

• Benzhydryl Compounds
• Blood Glucose
• C-glucosylarene
• Glucosides
• Hypoglycemic Agents
• Monosaccharides
• Oximes
• SLC5A2 protein, human
• Sodium-Glucose Transporter 2
• Sodium-Glucose Transporter 2 Inhibitors
• dapagliflozin
• Glucose

Topics

• Administration, Intravenous
• Administration, Oral
• Animals
• Benzhydryl Compounds (administration & dosage, pharmacology)
• Blood Glucose (drug effects)
• Diabetes Mellitus, Experimental (drug therapy)
• Dose-Response Relationship, Drug
• Glucose (analysis)
• Glucosides (administration & dosage, pharmacology)
• Humans
• Hypoglycemic Agents (administration & dosage, chemistry, pharmacology)
• Molecular Structure
• Monosaccharides (chemistry, pharmacology)
• Oximes (administration & dosage, chemistry, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Sodium-Glucose Transporter 2
• Sodium-Glucose Transporter 2 Inhibitors
• Structure-Activity Relationship