Abstract
We have identified a novel series of potent p38 MAP kinase inhibitors through structure-based design which due to their extended molecular architecture bind, in addition to the ATP site, to an allosteric pocket. In vitro ADME and in vivo PK studies show these compounds to have drug-like characteristics which could result in the development of an oral treatment for inflammatory conditions.
MeSH terms
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Adenosine Triphosphate / metabolism
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Allosteric Site
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Amides / chemical synthesis*
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Amides / chemistry
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Amides / pharmacokinetics
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Amides / pharmacology
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Animals
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Binding Sites
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Cells, Cultured
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Crystallography, X-Ray
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Drug Design*
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Humans
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Lipopolysaccharides / pharmacology
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Models, Molecular
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Molecular Structure
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Monocytes / cytology
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Monocytes / drug effects
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Phosphorylation / drug effects
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Protein Binding
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Protein Conformation
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology
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Rats
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Structure-Activity Relationship
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Tumor Necrosis Factor-alpha / metabolism
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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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Amides
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Lipopolysaccharides
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Protein Kinase Inhibitors
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Tumor Necrosis Factor-alpha
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Adenosine Triphosphate
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p38 Mitogen-Activated Protein Kinases