Abstract
The development of potent, orally bioavailable (in rat) and selective dihydroquinazolinone inhibitors of p38alpha MAP kinase is described. These analogues are hybrids of a pyridinylimidazole p38alpha inhibitor reported by Merck Research Laboratories and VX-745. Optimization of the C-5 phenyl and the C-7 piperidinyl substituents led to the identification of 15i which gave excellent suppression of TNF-alpha production in LPS-stimulated whole blood (IC(50)=10nM) and good oral exposure in rats (F=68%, AUCn PO=0.58 microM h).
MeSH terms
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Animals
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Area Under Curve
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Biological Availability
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Drug Design
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology*
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In Vitro Techniques
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Microsomes, Liver / drug effects
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Microsomes, Liver / metabolism
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Mitogen-Activated Protein Kinases / antagonists & inhibitors*
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Models, Molecular
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Molecular Conformation
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Monocytes / drug effects
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Monocytes / metabolism
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Quinazolines / chemical synthesis*
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Quinazolines / pharmacology*
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Rats
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Structure-Activity Relationship
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / biosynthesis
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p38 Mitogen-Activated Protein Kinases
Substances
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Enzyme Inhibitors
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Quinazolines
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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