期刊
CURRENT ALZHEIMER RESEARCH
卷 7, 期 3, 页码 207-209出版社
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/156720510791050920
关键词
Protease; amyloid; inhibitors; drug discovery
资金
- NINDS NIH HHS [R01 NS041355, R01 NS041355-01, NS41355, R01 NS041355-08] Funding Source: Medline
Overwhelming evidence supports a central role for the amyloid beta-peptide (A beta) in the pathogenesis of Alzheimer's disease (AD), and the proteases that produce A beta from its precursor protein APP are top targets for therapeutic intervention. Considerable effort has focused on targeting gamma-secretase, which generates the C-terminus of A beta; however, gamma-secretase inhibitors cause serious toxicities due to interference with the Notch signaling pathway. We have been working toward compounds that directly alter gamma-secretase activity to reduce A beta production without affecting the proteolysis of Notch. Using purified enzyme and substrate, we have shown that gamma-secretase can be selectively inhibited in this way by naphthyl-substituted gamma-aminoketones and gamma-aminoalcohols. These early hits, however, suffered from chemical instability and/or poor potency. Iterative design, synthesis and evaluation have led to the discovery of Notch-sparing gamma-secretase inhibitors with substantially increased potencies in biochemical and cellular assays. These compounds are of low molecular weight and are under evaluation for drug-like properties. The discovery and development of these compounds will be discussed.
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