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4-Anilino-5-carboxamido-2-pyridone Derivatives as Noncompetitive Inhibitors of Mitogen-Activated Protein Kinase Kinase

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journal contribution
posted on 18.10.2007, 00:00 by Julie A. Spicer, Gordon W. Rewcastle, Michael D. Kaufman, Shannon L. Black, Mark S. Plummer, William A. Denny, John Quin, Aurash B. Shahripour, Stephen D. Barrett, Christopher E. Whitehead, Jared B. J. Milbank, Jeffrey F. Ohren, Richard C. Gowan, Charles Omer, Heidi S. Camp, Nadia Esmaeil, Kelley Moore, Judith S. Sebolt-Leopold, Sally Pryzbranowski, Ronald L. Merriman, Daniel F. Ortwine, Joseph S. Warmus, Cathlin M. Flamme, Alexander G. Pavlovsky, Haile Tecle
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 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.