Abstract
Novel C-aryl glucoside SGLT2 inhibitors containing 1,3,4-thiadiazole moieties were designed and synthesized. Among the compounds tested, biaryl-type compounds containing pyrazine 59, 2-furan 61, and 3-thiophene 71 showed the best in vitro inhibitory activities to date (IC(50) = 3.51-7.03 nM) against SGLT2. A selected compound 61, demonstrated reasonable blood glucose-lowering effects, indicating that the information obtained from the SAR studies in this 1,3,4-thiadiazolylmethylphenyl glucoside series might help to design more active SGLT2 inhibitors that are structurally related.
Copyright 2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Diabetic Nephropathies / drug therapy
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Drug Design
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Glucosides / chemical synthesis
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Glucosides / chemistry
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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 / pharmacology*
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Male
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Mice
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Mice, Inbred Strains
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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 / metabolism
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Sodium-Glucose Transporter 2 Inhibitors*
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Stereoisomerism
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Structure-Activity Relationship
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Thiadiazoles / chemical synthesis
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Thiadiazoles / chemistry
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Thiadiazoles / pharmacology*
Substances
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1,3,4-thiadiazolylmethylphenyl glucoside
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Glucosides
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Hypoglycemic Agents
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SLC5A2 protein, human
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Sodium-Glucose Transporter 2
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Sodium-Glucose Transporter 2 Inhibitors
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Thiadiazoles