4-苯胺基-5-羧酰胺基-2-吡啶酮衍生物作为丝裂原活化蛋白激酶激酶的非竞争性抑制剂
4-anilino-5-carboxamido-2-pyridone derivatives as noncompetitive inhibitors of mitogen-activated protein kinase kinase.
作者信息
Spicer Julie A, Rewcastle Gordon W, Kaufman Michael D, Black Shannon L, Plummer Mark S, Denny William A, Quin John, Shahripour Aurash B, Barrett Stephen D, Whitehead Christopher E, Milbank Jared B J, Ohren Jeffrey F, Gowan Richard C, Omer Charles, Camp Heidi S, Esmaeil Nadia, Moore Kelley, Sebolt-Leopold Judith S, Pryzbranowski Sally, Merriman Ronald L, Ortwine Daniel F, Warmus Joseph S, Flamme Cathlin M, Pavlovsky Alexander G, Tecle Haile
机构信息
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
出版信息
J Med Chem. 2007 Oct 18;50(21):5090-102. doi: 10.1021/jm0704548. Epub 2007 Sep 19.
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.
利用药物化学、计算化学和结构解析相结合的方法，设计并合成了一系列新型MEK1抑制剂，即4-苯胺基-5-羧酰胺基-2-吡啶酮。研究了羧酰胺侧链变化、吡啶酮氮上的取代以及4'-碘化物的取代对其的影响。在一项分离酶测定中，以及在小鼠结肠癌（C26）细胞中，通过抑制磷酸化ERK底物测定，该研究得到了几种与临床候选药物CI-1040（1）效力相当或更强的化合物。最值得注意的是，吡啶酮27在体外比1更有效，并且在对携带C26肿瘤的动物进行体内疗效测试时，在比1更低的剂量下产生了100%的反应率。
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