Discovery of notch-sparing gamma-secretase inhibitors

Overwhelming evidence supports a central role for the amyloid beta-peptide (Abeta) in the pathogenesis of Alzheimer's disease (AD), and the proteases that produce Abeta 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 Abeta; 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 Abeta 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.