Abstract
Rational design, synthesis, and SAR studies of a novel class of benzothiazole based inhibitors of p38alpha MAP kinase are described. The issue of metabolic instability associated with vicinal phenyl, benzo[d]thiazol-6-yl oxazoles/imidazoles was addressed by the replacement of the central oxazole or imidazole ring with an aminopyrazole system. The proposed binding mode of this new class of p38alpha inhibitors was confirmed by X-ray crystallographic studies of a representative inhibitor (6a) bound to the p38alpha enzyme.
MeSH terms
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Animals
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Benzothiazoles / chemistry*
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Cells, Cultured / drug effects
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Cells, Cultured / enzymology
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Crystallography, X-Ray
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Humans
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Lipopolysaccharides / pharmacology
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Mice
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Microsomes / drug effects
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Microsomes / enzymology
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Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors*
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Mitogen-Activated Protein Kinase 14 / metabolism
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Molecular Structure
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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
Substances
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Benzothiazoles
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Lipopolysaccharides
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Protein Kinase Inhibitors
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Tumor Necrosis Factor-alpha
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Mitogen-Activated Protein Kinase 14
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benzothiazole