期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 27, 期 11, 页码 2432-2438出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2017.04.011
关键词
BACE-1; beta-Secretase; Alzheimer's disease; Memapsin 2; Protease inhibitors
资金
- National Institutes of Health
- Purdue University Office of the Executive Vice President for Research
- Purdue Center for Cancer Research through NIH [P30CA023168]
- Argonne National Laboratory [DE-AC02-06CH11357]
We report the design and synthesis of a series of BACE1 inhibitors incorporating mono- and bicyclic 6 substituted 2-oxopiperazines as novel P1' and P2' ligands and isophthalamide derivative as P2-P3 ligands. Among mono-substituted 2-oxopiperazines, inhibitor 5a with N-benzyl-2-oxopiperazine and isophthalamide showed potent BACE1 inhibitory activity (K-i = 2 nM). Inhibitor 5g, with N-benzyl-2-oxopiperazine and substituted indole-derived P2-ligand showed a reduction in potency. The X-ray crystal structure of 5g-bound BACE1 was determined and used to design a set of disubstituted 2-oxopiperazines and bicyclic derivatives that were subsequently investigated. Inhibitor 6j with an oxazolidinone derivative showed a BACE1 inhibitory activity of 23 nM and cellular EC50 of 80 nM. (C) 2017 Elsevier Ltd. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据