大环 BACE 抑制剂：从微摩尔级别的命中物到纳摩尔级别的先导化合物的优化。
Macrocyclic BACE inhibitors: Optimization of a micromolar hit to nanomolar leads.
机构信息
Research and Early Development, Johnson & Johnson Pharmaceutical Research & Development, LLC, Spring House, PA 19477-0776, USA.
出版信息
Bioorg Med Chem Lett. 2010 May 15;20(10):3158-60. doi: 10.1016/j.bmcl.2010.03.097. Epub 2010 Mar 30.
PMID:20399652
Abstract
We have identified macrocyclic inhibitors of the aspartic protease BACE, implicated in the etiology of Alzheimer's disease. An X-ray structure of screening hit 1 in the BACE active site revealed a hairpin conformation suggesting that constrained macrocyclic derivatives may also bind there. Several of the analogs we prepared were >100x more potent than 1, such as 7 (5 nM K(i)).
摘要
我们已经鉴定出天冬氨酸蛋白酶 BACE 的大环抑制剂，该酶与阿尔茨海默病的病因有关。筛选命中化合物 1 在 BACE 活性部位的 X 射线结构显示出发夹构象，表明约束性大环衍生物也可能在那里结合。我们制备的几种类似物比 1 强 100 倍以上，例如 7（5 nM K(i)）。
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