Abstract
The structure based drug design, synthesis and structure-activity relationship of a series of C6 sulfur linked triazolopyridine based p38 inhibitors are described. The metabolic deficiencies of this series were overcome through changes in the C6 linker from sulfur to methylene, which was predicted by molecular modeling to be bioisosteric. X-ray of the ethylene linked compound 61 confirmed the predicted binding orientation of the scaffold in the p38 enzyme.
Copyright 2009 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Benzamides / chemical synthesis
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Benzamides / chemistry*
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Benzamides / pharmacology
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Binding Sites
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Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis
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Bridged Bicyclo Compounds, Heterocyclic / chemistry*
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology
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Crystallography, X-Ray
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Drug Design
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Humans
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Microsomes, Liver / metabolism
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Models, Chemical
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Models, Molecular
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacology
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry*
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Pyrimidines / pharmacology
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Rats
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Structure-Activity Relationship
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Triazoles / chemical synthesis
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Triazoles / chemistry*
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Triazoles / pharmacology
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Benzamides
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Bridged Bicyclo Compounds, Heterocyclic
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Protein Kinase Inhibitors
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Pyrimidines
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Triazoles
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p38 Mitogen-Activated Protein Kinases