Abstract
In search of antiinflammatory drugs with a new mechanism of action, U0126 was found to functionally antagonize AP-1 transcriptional activity via noncompetitive inhibition of the dual specificity kinase MEK with an IC50 of 0.07 microM for MEK 1 and 0.06 microM for MEK 2. U0126 can undergo isomerization and cyclization reactions to form a variety of products, both chemically and in vivo, all of which exhibit less affinity for MEK and lower inhibition of AP-1 activity than parent, U0126.
MeSH terms
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Animals
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Anti-Inflammatory Agents / chemistry
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Anti-Inflammatory Agents / pharmacokinetics
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Anti-Inflammatory Agents / pharmacology
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Biotransformation
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Butadienes / chemistry*
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Butadienes / pharmacokinetics
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Butadienes / pharmacology
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Cyclization
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology
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NF-kappa B / antagonists & inhibitors
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Nitriles / chemistry*
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Nitriles / pharmacokinetics
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Nitriles / pharmacology
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Rats
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Transcription Factor AP-1 / antagonists & inhibitors
Substances
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Anti-Inflammatory Agents
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Butadienes
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Enzyme Inhibitors
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NF-kappa B
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Nitriles
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Transcription Factor AP-1
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U 0126
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Protein Serine-Threonine Kinases