Abstract
We have synthesized a series of C7-piperidine- and 4-aminopiperidine-substituted naphthyridinones, quinolinones, and dihydroquinazolinones that are highly potent inhibitors of both p38MAP kinase activity and TNF-alpha release. The 4-aminopentamethylpiperidine naphthyridinone 5, which was designed to block metabolism at major 'hot spots', combined excellent inhibitory potency with good oral bioavailability in the rat.
MeSH terms
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Animals
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Anti-Infective Agents / chemical synthesis*
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Anti-Infective Agents / pharmacology*
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Area Under Curve
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Biological Availability
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Dogs
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacology*
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Half-Life
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Macaca mulatta
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Mitogen-Activated Protein Kinases / antagonists & inhibitors*
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Naphthyridines / chemical synthesis*
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Naphthyridines / pharmacology*
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Piperidines / chemical synthesis*
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Piperidines / pharmacology*
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Quinazolines / chemical synthesis*
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Quinazolines / pharmacology*
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Quinolones / chemical synthesis*
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Quinolones / pharmacology*
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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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Anti-Infective Agents
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Enzyme Inhibitors
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Naphthyridines
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Piperidines
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Quinazolines
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Quinolones
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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