Abstract
A novel structural class of p38alpha MAP kinase inhibitors has been identified via iterative SAR studies of a focused deck screen hit. Optimization of the lead series generated 6e, BMS-640994, a potent and selective p38alpha inhibitor that is orally efficacious in rodent models of acute and chronic inflammation.
MeSH terms
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Animals
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Arthritis / drug therapy
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Caco-2 Cells
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Cell Membrane Permeability / drug effects
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Cells, Cultured
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Crystallography, X-Ray
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Cytochrome P-450 Enzyme Inhibitors
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Cytochrome P-450 Enzyme System / metabolism
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Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
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Humans
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Lipopolysaccharides / pharmacology
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Male
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Mice
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Microsomes, Liver / drug effects
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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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Monocytes / cytology
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Monocytes / drug effects
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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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Rats, Inbred Lew
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Structure-Activity Relationship
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Thiazoles / chemical synthesis
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Thiazoles / pharmacokinetics
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Thiazoles / pharmacology*
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Tumor Necrosis Factor-alpha / metabolism
Substances
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BMS-640994
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Cytochrome P-450 Enzyme Inhibitors
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Ether-A-Go-Go Potassium Channels
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KCNH1 protein, human
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Lipopolysaccharides
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Protein Kinase Inhibitors
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Thiazoles
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Tumor Necrosis Factor-alpha
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Cytochrome P-450 Enzyme System
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Mitogen-Activated Protein Kinase 14