Abstract
Sulfonylureido thiazoles were identified from a HTS campaign and optimized through a combination of structure-activity studies, X-ray crystallography and molecular modeling to yield potent inhibitors of fructose-1,6-bisphosphatase. Compound 12 showed favorable ADME properties, for example, F=70%, and a robust 32% glucose reduction in the acute db/db mouse model for Type-2 diabetes.
Copyright 2009 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Binding Sites
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Crystallography, X-Ray
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Diabetes Mellitus, Type 2 / drug therapy*
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Disease Models, Animal
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Fructose-Bisphosphatase / antagonists & inhibitors*
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Fructose-Bisphosphatase / metabolism
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High-Throughput Screening Assays
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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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Mice
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Structure-Activity Relationship
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Sulfonylurea Compounds / chemical synthesis
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Sulfonylurea Compounds / chemistry*
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Sulfonylurea Compounds / pharmacokinetics
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Thiazoles / chemical synthesis
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Thiazoles / chemistry*
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Thiazoles / pharmacokinetics
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Thiazoles / pharmacology
Substances
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Hypoglycemic Agents
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Sulfonylurea Compounds
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Thiazoles
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Fructose-Bisphosphatase