Abstract
The identification and evolution of a series of potent and selective p38 inhibitors is described. p38 inhibitors based on a N-benzyl pyridinone high-throughput screening hit were prepared and their SAR explored. Their design was guided by ligand bound co-crystals of p38alpha. These efforts resulted in the identification of 12r and 19 as orally active inhibitors of p38 with significant efficacy in both acute and chronic models of inflammation.
MeSH terms
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Administration, Oral
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Animals
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Anti-Inflammatory Agents / chemical synthesis
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Anti-Inflammatory Agents / chemistry*
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Anti-Inflammatory Agents / pharmacokinetics
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Binding Sites
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Catalytic Domain
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Crystallography, X-Ray
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Drug Discovery
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Humans
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JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
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JNK Mitogen-Activated Protein Kinases / metabolism
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Male
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Microsomes, Liver / metabolism
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacokinetics
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Pyridones / chemical synthesis
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Pyridones / chemistry*
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Pyridones / pharmacokinetics
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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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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Anti-Inflammatory Agents
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Protein Kinase Inhibitors
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Pyridones
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JNK Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases