Optimizing the Physicochemical Properties of Raf/MEK Inhibitors by Nitrogen Scanning
Optimizing the Physicochemical Properties of Raf/MEK Inhibitors by Nitrogen Scanning
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DOI：
10.1021/ml400379x
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发表时间：
2014-04-01
影响因子：
4.2
通讯作者：
Iikura, Hitoshi
中科院分区：
文献类型：
--
作者：
Aoki, Toshihiro;Hyohdoh, Ikumi;Iikura, Hitoshi
通过应用氮扫描，在我们的先导化合物11 a和13 g中用氮原子取代芳环上的碳原子（氮取代），得到一组化合物，其不仅改善了溶解度，而且改善了代谢稳定性。还检测到氮取代后对衍生物与其靶蛋白和脱靶蛋白（Raf/MEK、CYP和hERG通道）之间相互作用的影响，其中大多数导致相互作用减弱。在鉴定保持对HCT 116细胞生长和Raf/MEK的抑制活性的位置后，选择化合物I（CH 5126766/RO 5126766）作为临床化合物。目前正在进行针对实体癌的I期临床试验。
Substituting a carbon atom with a nitrogen atom (nitrogen substitution) on an aromatic ring in our leads 1 la and 13g by applying nitrogen scanning afforded a set of compounds that improved not only the solubility but also the metabolic stability. The impact after nitrogen substitution on interactions between a derivative and its on- and off-target proteins (Raf/MEK, CYPs, and hERG channel) was also detected, most of them contributing to weaker interactions. After identifying the positions that kept inhibitory activity on HCT116 cell growth and Raf/MEK, compound I (CH5126766/RO5126766) was selected as a clinical compound. A phase I clinical trial is ongoing for solid cancers.