Discovery of a Potent, Selective Renal Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor (HSK0935) for the Treatment of Type 2 Diabetes.

Abstract

A new class of potent and highly selective SGLT2 inhibitors is disclosed. Compound 31 (HSK0935) demonstrated excellent hSGLT2 inhibition of 1.3 nM and a high hSGLT1/hSGLT2 selectivity of 843-fold. It showed robust urinary glucose excretion in Sprague-Dawley (SD) rats and affected more urinary glucose excretion in Rhesus monkeys. Finally, an efficient synthetic route has been developed featuring a ring-closing cascade reaction to incorporate a double ketal 1-methoxy-6,8-dioxabicyclo[3.2.1]octane ring system.

• Authors: Yao Li, Zongjun Shi, Lei Chen, Suxin Zheng, Sheng Li, Bo Xu, Zhenhong Liu, Jianyu Liu, Chongyang Deng, Fei Ye
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 60 Issue 10 Pg. 4173-4184 (05 25 2017) ISSN: 1520-4804 [Electronic] United States
• PMID: 28447791 (Publication Type: Journal Article)

Chemical References

• Bridged Bicyclo Compounds, Heterocyclic
• Hypoglycemic Agents
• Sodium-Glucose Transporter 2
• Sodium-Glucose Transporter 2 Inhibitors
• Glucose

Topics

• Animals
• Bridged Bicyclo Compounds, Heterocyclic (chemistry, pharmacokinetics, pharmacology)
• CHO Cells
• Cricetulus
• Diabetes Mellitus, Type 2 (drug therapy, metabolism, urine)
• Glucose (analysis, metabolism)
• Glycosuria (chemically induced, metabolism)
• Humans
• Hypoglycemic Agents (chemistry, pharmacokinetics, pharmacology)
• Kidney (drug effects, metabolism)
• Macaca mulatta
• Male
• Mice, Inbred ICR
• Rats, Sprague-Dawley
• Sodium-Glucose Transporter 2 (metabolism)
• Sodium-Glucose Transporter 2 Inhibitors