Abstract
Inhibition of c-Kit has the potential to treat mast cell associated fibrotic diseases. We report the discovery of several aminoquinazoline pyridones that are potent inhibitors of c-Kit with greater than 200-fold selectivity against KDR, p38, Lck, and Src. In vivo efficacy of pyridone 16 by dose-dependent inhibition of histamine release was demonstrated in a rodent pharmacodynamic model of mast cell activation.
MeSH terms
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Administration, Oral
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Animals
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Crystallography, X-Ray
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Histamine Release / drug effects
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Mast Cells / drug effects
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Mast Cells / metabolism
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Models, Molecular
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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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Proto-Oncogene Proteins c-kit / metabolism*
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Pyridones / chemical synthesis*
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Pyridones / pharmacokinetics
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Pyridones / pharmacology
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Quinazolines / chemical synthesis*
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Quinazolines / pharmacokinetics
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Quinazolines / pharmacology
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Rats
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Structure-Activity Relationship
Substances
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Protein Kinase Inhibitors
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Pyridones
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Quinazolines
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Proto-Oncogene Proteins c-kit