4-Anilino-5-carboxamido-2-pyridone Derivatives as Noncompetitive Inhibitors of Mitogen-Activated Protein Kinase Kinase
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- 作者：Julie A. Spicer ; Gordon W. Rewcastle ; Michael D. Kaufman ; Shannon L. Black ; Mark S. Plummer ; William A. Denny ; John Quin ; III ; Aurash B. Shahripour ; Stephen D. Barrett ; Christopher E. Whitehead ; Jared
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：October 18, 2007
- 年：2007
- 卷：50
- 期：21
- 页码：5090 - 5102
- 全文大小：487K
- 年卷期：v.50,no.21(October 18, 2007)
- ISSN：1520-4804
文摘
A new series of MEK1 inhibitors, the 4-anilino-5-carboxamido-2-pyridones, were designed and synthesizedusing a combination of medicinal chemistry, computational chemistry, and structural elucidation. The effectof variation in the carboxamide side chain, substitution on the pyridone nitrogen, and replacement of the4'-iodide were all investigated. This study afforded several compounds which were either equipotent ormore potent than the clinical candidate CI-1040 (1) in an isolated enzyme assay, as well as murine coloncarcinoma (C26) cells, as measured by supression of phosphorylated ERK substrate. Most notably, pyridone27 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.