γ-Secretase Modulators

γ-Secretase is responsible for the final cut of the amyloid β-peptide (Aβ) precursor (APP) to produce the Aβ peptide implicated the pathogenesis of Alzheimer's disease (AD). Thus, this protease is a top target for the development of AD therapeutics. γ-Secretase is a complex of four different integral membrane proteins, with the multi-pass presenilin being the catalytic component of a novel intramembrane-cleaving aspartyl protease. γ-Secretase cleaves other substrates besides APP, the most notorious being the Notch receptor that is required for many cell differentiation events. Because proteolysis of Notch by γ-secretase is essential for Notch signaling, interference with this process by γ-secretase inhibitors can cause severe toxicities. Thus, the potential of &ggr-secretase as therapeutic target likely depends on the ability to selectively inhibit Aβ production without hindering Notch proteolysis. The discovery of compounds capable of such allosteric modulation of the protease activity has revived γ-secretase as an attractive target. Structural modification of these &ggr- secretase modulators through medicinal chemistry should lead to in vivo active agents suitable for clinical trials.