Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 50, Issue 21, Pages 5090-5102Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm0704548
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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 supression of phosphorylated ERK, substrate. Most notably, pyridone 27 was found to be more potent than I 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.
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