Abstract
2,6-Diamino-3,5-difluoropyridinyl substituted pyridinylimidazoles, -pyrroles, -oxazoles, -thiazoles and -triazoles have been identified as novel p38alpha inhibitors. Pyridinylimidazole 11 potently inhibited LPS-induced TNFalpha in mice, showed good efficacy in the established rat adjuvant (ED(50): 10 mg/kg po b.i.d.) and collagen induced arthritis (ED(50): 5 mg/kg po b.i.d.) with disease modifying properties based on histological analysis of the joints.
MeSH terms
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Animals
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Arthritis, Experimental / drug therapy
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Arthritis, Experimental / pathology
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology*
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Enzyme Inhibitors / therapeutic use
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Humans
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Lipopolysaccharides / pharmacology
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Mice
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Mitogen-Activated Protein Kinases / antagonists & inhibitors*
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Mitogen-Activated Protein Kinases / metabolism
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Molecular Structure
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Pyridones / chemistry*
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Pyridones / pharmacology*
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Pyridones / therapeutic use
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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
Substances
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Enzyme Inhibitors
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Lipopolysaccharides
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Pyridones
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Tumor Necrosis Factor-alpha
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases