Abstract
A series of C-glucosides with various heteroaromatics has been synthesized and its inhibitory activity toward SGLTs was evaluated. Upon screening several compounds, the benzothiophene derivative (14a) was found to have potent inhibitory activity against SGLT2 and good selectivity versus SGLT1. Through further optimization of 14a, a novel benzothiophene derivative (14h; ipragliflozin, ASP1941) was discovered as a highly potent and selective SGLT2 inhibitor that reduced blood glucose levels in a dose-dependent manner in diabetic models KK-A(y) mice and STZ rats.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Blood Glucose / drug effects*
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CHO Cells
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Cricetinae
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Diabetes Mellitus, Type 2
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Glucosides / chemical synthesis
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Glucosides / chemistry*
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Glucosides / pharmacokinetics
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Glucosides / pharmacology*
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Humans
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Hypoglycemic Agents / chemical synthesis
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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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Inhibitory Concentration 50
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Male
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Mice
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Molecular Structure
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Rats
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Rats, Sprague-Dawley
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Sodium-Glucose Transporter 2 Inhibitors*
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Thiophenes / chemical synthesis
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Thiophenes / chemistry*
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Thiophenes / pharmacokinetics
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Thiophenes / pharmacology*
Substances
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Blood Glucose
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Glucosides
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Hypoglycemic Agents
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Sodium-Glucose Transporter 2 Inhibitors
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Thiophenes
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ipragliflozin