Abstract
Canagliflozin (1), a novel inhibitor for sodium-dependent glucose cotransporter 2 (SGLT2), has been developed for the treatment of type 2 diabetes. To investigate the effect of replacement of the phenyl ring in 1 with heteroaromatics, C-glucosides 2 were designed, synthesized, and evaluated for their inhibitory activities against SGLT2. Of these, 3-pyridyl, 2-pyrimidyl or 5-membered heteroaryl substituted derivatives showed highly potent inhibitory activity against SGLT2, while 5-pyrimidyl substitution was associated with slightly reduced activity. In particular, 2g (TA-3404) had remarkable anti-hyperglycemic effects in high-fat diet fed KK (HF-KK) mice.
Keywords:
Canagliflozin; Glucoside; SGLT2 inhibitor; Thiophene; Type 2 diabetes.
Copyright © 2013 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Blood Glucose / analysis
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CHO Cells
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Canagliflozin
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Cell Line
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Cricetinae
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Cricetulus
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Diet, High-Fat
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Glucosides / chemical synthesis
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Glucosides / chemistry*
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Glucosides / pharmacokinetics
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Half-Life
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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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Male
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Mice
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Monosaccharides / chemical synthesis
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Monosaccharides / chemistry*
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Monosaccharides / pharmacokinetics
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Protein Binding
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Pyridines / chemical synthesis
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Pyridines / chemistry*
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Pyridines / pharmacokinetics
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Rats
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Rats, Sprague-Dawley
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Sodium-Glucose Transporter 1 / antagonists & inhibitors
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Sodium-Glucose Transporter 1 / genetics
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Sodium-Glucose Transporter 1 / metabolism
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Sodium-Glucose Transporter 2 / genetics
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Sodium-Glucose Transporter 2 / metabolism
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Sodium-Glucose Transporter 2 Inhibitors*
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Thiophenes / chemistry*
Substances
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Blood Glucose
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Glucosides
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Hypoglycemic Agents
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Monosaccharides
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Pyridines
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Sodium-Glucose Transporter 1
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Sodium-Glucose Transporter 2
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Sodium-Glucose Transporter 2 Inhibitors
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TA-3404
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Thiophenes
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Canagliflozin