Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA.
Bioorg Med Chem Lett. 2011 Jul 1;21(13):3992-6. doi: 10.1016/j.bmcl.2011.05.007. Epub 2011 May 8.
In the course of a β-site APP-cleaving enzyme 1 (BACE1) inhibitor discovery project an in situ synthesis/screening protocol was employed to prepare 120 triazole-linked reduced amide isostere inhibitors. Among these compounds, four showed modest (single digit micromolar) BACE1 inhibition. Our ligand design was based on a potent reduced amide isostere 1, wherein the P(2) amide moiety was replaced with an anti-1,2,3-triazole unit. Unfortunately, this replacement resulted in a 1000-fold decrease in potency. Docking studies of triazole-linked reduced amide isostere A3Z10 and potent oxadiazole-linked tertiary carbinamine 2a with BACE1 suggests that the docking poses of A3Z10 and 2a in the active sites are quite similar, with one exception. In the docked structures the placement of the protonated amine that engages D228 differs considerably between 2a and A3Z10. This difference could account for the lower BACE1 inhibition potency of A3Z10 and related compounds relative to 2a.
在 β-位点 APP 裂解酶 1（BACE1）抑制剂的发现项目过程中，采用了原位合成/筛选方案来制备 120 个三唑连接的还原酰胺等排体抑制剂。在这些化合物中，有四个表现出中等（个位数微摩尔）的 BACE1 抑制活性。我们的配体设计基于一种有效的还原酰胺等排体 1，其中 P(2)酰胺部分被反式-1,2,3-三唑单元取代。不幸的是，这种取代导致了 1000 倍的效力下降。用 BACE1 对三唑连接的还原酰胺等排体 A3Z10 和有效噁二唑连接的叔碳胺 2a 进行对接研究表明，A3Z10 和 2a 在活性部位的对接构象非常相似，只有一个例外。在对接结构中，与 D228 结合的质子化胺的位置在 2a 和 A3Z10 之间有很大的不同。这种差异可能导致 A3Z10 和相关化合物的 BACE1 抑制活性相对较低。
