Abstract
A series of polysubstituted pyridin-4-yl imidazole inhibitors of p38 MAP (mitogen-activated protein) kinase was prepared as small molecular anticytokine agents and drug candidates for the treatment of chronic inflammatory diseases. The contribution of substituents at the pyridinyl and imidazole moiety to selective inhibition of p38 without concomitant cytochrome P450 interaction was evaluated. Placement of a 1-phenylethyl (7e, p38: IC(50) 0.38 microM) or acetyl substituent at the exocyclic nitrogen of several 2-aminopyridine imidazoles led to the identification of potent p38 inhibitors which exceeded the starting lead ML 3375 (p38: IC(50) 0.63 microM) in potency. A preliminary modeling study related the enhanced bioactivity of 7e to a novel interaction between its 1-phenylethylamino side chain and a hydrophobic pocket close to the linker region of p38. The most active p38 inhibitors in this series maintained their efficacy in functional PBMC (peripheral blood mononuclear cells) and whole blood assays. Moreover, cytochrome P450 interaction, which has been linked to the liver toxicity observed for model p38 inhibitors, was very efficiently reduced through introduction of a tetramethylpiperidine substituent at the 1 position of the imidazole nucleus. Combination of both structural features provided 14c (p38: 0.34 microM, inhibition of CYP1A2 0%, 2C9 2.6%, 2C19 7.6% at 10 microM), which was selected for further development.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aminopyridines / chemical synthesis*
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Aminopyridines / chemistry
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Aminopyridines / pharmacology
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Chronic Disease
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Cytochrome P-450 Enzyme System / blood
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Cytochrome P-450 Enzyme System / metabolism*
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Cytokines / antagonists & inhibitors*
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Humans
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Imidazoles / chemical synthesis*
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Imidazoles / chemistry
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Imidazoles / pharmacology
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Interleukin-1 / antagonists & inhibitors
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Isoenzymes / metabolism
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Leukocytes, Mononuclear / drug effects
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Leukocytes, Mononuclear / metabolism
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Liver / enzymology*
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Models, Molecular
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Pyridines / chemical synthesis*
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Pyridines / chemistry
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Pyridines / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases
Substances
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Aminopyridines
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Anti-Inflammatory Agents, Non-Steroidal
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Cytokines
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Enzyme Inhibitors
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Imidazoles
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Interleukin-1
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Isoenzymes
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N-(4-(5-(4-fluorophenyl)-2-methylsulfanyl-3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-imidazol-4-yl)pyridin-2-yl)acetamide
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Pyridines
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Tumor Necrosis Factor-alpha
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Cytochrome P-450 Enzyme System
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases