Abstract
A new series of MEK1 inhibitors, the 4-anilino-5-carboxamido-2-pyridones, were designed and synthesized using a combination of medicinal chemistry, computational chemistry, and structural elucidation. The effect of variation in the carboxamide side chain, substitution on the pyridone nitrogen, and replacement of the 4'-iodide were all investigated. This study afforded several compounds which were either equipotent or more potent than the clinical candidate CI-1040 (1) in an isolated enzyme assay, as well as murine colon carcinoma (C26) cells, as measured by suppression of phosphorylated ERK substrate. Most notably, pyridone 27 was found to be more potent than 1 in vitro and produced a 100% response rate at a lower dose than 1, when tested for in vivo efficacy in animals bearing C26 tumors.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amides / chemical synthesis*
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Amides / chemistry
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Amides / pharmacology
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Aniline Compounds / chemical synthesis*
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Aniline Compounds / chemistry
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Aniline Compounds / pharmacology
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Benzamides / pharmacology
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Cell Line, Tumor
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Drug Screening Assays, Antitumor
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Extracellular Signal-Regulated MAP Kinases / metabolism
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MAP Kinase Kinase 1 / antagonists & inhibitors*
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MAP Kinase Kinase 1 / chemistry
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MAP Kinase Kinase 2 / antagonists & inhibitors*
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MAP Kinase Kinase 2 / chemistry
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Male
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Mice
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Models, Molecular
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Neoplasm Transplantation
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Phosphorylation
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Pyridones / chemical synthesis*
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Pyridones / chemistry
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Pyridones / pharmacology
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Rats
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Structure-Activity Relationship
Substances
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2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
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4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide
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Amides
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Aniline Compounds
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Antineoplastic Agents
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Benzamides
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Pyridones
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Extracellular Signal-Regulated MAP Kinases
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MAP Kinase Kinase 1
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MAP Kinase Kinase 2