Discovery of Notch-Sparing γ-Secretase Inhibitors

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.