Abstract
Quinolinones and naphthyridinones with C7 N-t-butyl piperidine substituents were found to be potent p38 MAP kinase inhibitors. These compounds significantly suppress TNF-alpha release in both cellular and LPS-stimulated whole blood assays. They also displayed excellent PK profiles across three animal species. Quinolinone at 10 mpk showed comparable oral efficacy to that of dexamethasone at 1 mpk in a murine collagen-induced arthritis model.
MeSH terms
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Animals
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Arthritis, Experimental
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Collagen / chemistry
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Dexamethasone / chemistry
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Dogs
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Enzyme Inhibitors / pharmacology*
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Haplorhini
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Humans
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Inhibitory Concentration 50
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Lipopolysaccharides / metabolism
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Mice
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Models, Chemical
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Naphthyridines / chemistry*
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Piperidines / chemistry*
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Quinolones / chemistry*
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Rats
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Time Factors
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / chemistry
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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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Enzyme Inhibitors
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Lipopolysaccharides
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Naphthyridines
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Piperidines
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Quinolones
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Tumor Necrosis Factor-alpha
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piperidine
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Dexamethasone
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Collagen
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p38 Mitogen-Activated Protein Kinases