Abstract
Employing phenylmalonitrile dianion chemistry, a large number of analogues of MEK inhibitor lead SH053 (IC(50)=140 nM) were rapidly synthesized leading to single digit nM inhibitors, displaying submicromolar AP-1 transcription inhibition in COS-7 cells. Compound 41, exhibiting a MEK IC(50)=12 nM showed ip activity in a TPA-induced ear edema model with an ED(50)=5 mg/kg.
MeSH terms
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Animals
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Butadienes / chemical synthesis*
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COS Cells
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Chemistry, Pharmaceutical / methods*
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Chlorocebus aethiops
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Enzyme Inhibitors / chemical synthesis*
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Nitriles / chemical synthesis*
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Structure-Activity Relationship
Substances
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Butadienes
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Enzyme Inhibitors
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Nitriles
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U 0126
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Mitogen-Activated Protein Kinase Kinases