Discovery of notch-sparing γ-secretase inhibitors

C. E. Augelli-Szafran, H. X. Wei, D. Lu, J. Zhang, Y. Gu, T. Yang, P. Osenkowski, W. Ye, M. S. Wolfe

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)207-209
Number of pages3
JournalCurrent Alzheimer research
Issue number3
StatePublished - May 2010
Externally publishedYes


  • Amyloid
  • Drug discovery
  • Inhibitors
  • Protease

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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