Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
Bioorg Med Chem Lett. 2010 Mar 1;20(5):1779-82. doi: 10.1016/j.bmcl.2010.01.005. Epub 2010 Jan 11.
This Letter describes the one pot synthesis of tertiary carbinamine 3 and related analogs of brain penetrant BACE-1 inhibitors via the alkylation of the Schiff base intermediate 2. The methodology developed for this study provided a convenient and rapid means to explore the P1 region of these types of inhibitors, where the P1 group is installed in the final step using a one-pot two-step protocol. Further SAR studies led to the identification of 10 which is twofold more potent in vitro as compared to the lead compound. This inhibitor was characterized in a cisterna magna ported rhesus monkey model, where significant lowering of CSF Abeta40 was observed.
这封信件描述了通过席夫碱中间体 2 的烷基化反应一锅法合成叔碳胺 3 和相关穿透脑的 BACE-1 抑制剂类似物。本研究中开发的方法为探索这类抑制剂的 P1 区域提供了一种方便快捷的手段，其中 P1 基团在最后一步使用一锅两步法进行安装。进一步的 SAR 研究确定了化合物 10，其体外活性比先导化合物高两倍。该抑制剂在经小脑延髓池给药的恒河猴模型中进行了特征描述，其中观察到 CSF Abeta40 显著降低。
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