Abstract
Overwhelming evidence supports a central role for the amyloid β-peptide (Aβ) in the pathogenesis of Alzheimers 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.
Keywords: Protease, amyloid, inhibitors, drug discovery
Current Alzheimer Research
Title: Discovery of Notch-Sparing γ-Secretase Inhibitors
Volume: 7 Issue: 3
Author(s): C.E. Augelli-Szafran, H.-X. Wei, D. Lu, J. Zhang, Y. Gu, T. Yang, P. Osenkowski, W. Ye and M.S. Wolfe
Affiliation:
Keywords: Protease, amyloid, inhibitors, drug discovery
Abstract: Overwhelming evidence supports a central role for the amyloid β-peptide (Aβ) in the pathogenesis of Alzheimers 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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Cite this article as:
Augelli-Szafran C.E., Wei H.-X., Lu D., Zhang J., Gu Y., Yang T., Osenkowski P., Ye W. and Wolfe M.S., Discovery of Notch-Sparing γ-Secretase Inhibitors, Current Alzheimer Research 2010; 7 (3) . https://dx.doi.org/10.2174/156720510791050920
DOI https://dx.doi.org/10.2174/156720510791050920 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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