期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 22, 期 14, 页码 4640-4644出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2012.05.089
关键词
Alzheimer's disease; beta-Secretase; BACE1; BACE1 inhibitor
资金
- MEXT (Ministry of Education, Culture, Sports, Science and Technology), Japan [21249007, 23590137]
- Grants-in-Aid for Scientific Research [23590137, 21249007] Funding Source: KAKEN
Recently, we reported substrate-based pentapeptidic BACE1 inhibitors possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. These inhibitors showed potent inhibitory activities in enzymatic and cell assays. We also designed and synthesized non-peptidic and small-sized inhibitors possessing a heterocyclic scaffold at the P-2 position. By studying the structure-activity relationship of these inhibitors, we found that the sigma-pi interaction of an inhibitor with the BACE1-Arg235 side chain played a key role in the inhibition mechanism. Hence, we optimized the inhibitors with a focus on their P-2 regions. In this Letter, a series of novel BACE1 inhibitors possessing a 5-nitroisophthalic scaffold at the P-2 position are described along with the results of the related structure-activity relationship study. These small-sized inhibitors are expected improved membrane permeability and bioavailability. (C) 2012 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