Discovery of notch-sparing gamma-secretase inhibitors.
Discovery of notch-sparing gamma-secretase inhibitors.
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DOI：
10.2174/156720510791050920
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发表时间：
2010-05
影响因子：
2.1
通讯作者：
Wolfe MS
中科院分区：
文献类型：
--
作者：
Augelli-Szafran CE;Wei HX;Lu D;Zhang J;Gu Y;Yang T;Osenkowski P;Ye W;Wolfe MS
Overwhelming evidence supports a central role for the amyloid β-peptide (Aβ) in the pathogenesis of Alzheimer’s disease (AD), and the proteases that produce Aβ from its precursor protein APP are top targets for therapeutic intervention. Considerable effort has focused on targeting γ-secretase, which generates the C-terminus of Aβ; however, γ-secretase inhibitors cause serious toxicities due to interference with the Notch signaling pathway. We have been working toward compounds that directly alter γ-secretase activity to reduce Aβ production without affecting the proteolysis of Notch. Using purified enzyme and substrate, we have shown that γ-secretase can be selectively inhibited in this way by naphthyl-substituted γ-aminoketones and γ-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 γ-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.
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