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