γ-Secretase Inhibition and Modulation for Alzheimer's Disease

γ-Secretase is a multi-protein complex that proteolyzes the transmembrane region of the amyloid β-peptide (Aβ) precursor (APP), producing the Aβ peptide implicated in the pathogenesis of Alzheimer's disease (AD). This protease has been a top target for AD, and various inhibitors have been identified, including transition-state analogue inhibitors that interact with the active site, helical peptides that interact with the initial substrate docking site, and other less peptidelike, more drug-like compounds. Although one γ-secretase inhibitor has advanced into late-phase clinical trials, concerns about inhibiting this protease remain. The protease complex cleaves a number of other substrates, and in vivo toxicities observed with γ-secretase inhibitors are apparently due to blocking one particularly important substrate, the Notch receptor. Thus, the potential of γ-secretase as therapeutic target likely depends on the ability to selectively inhibit Aβ production without hindering Notch proteolysis (i.e., modulation rather than inhibition). The discovery of γ-secretase modulators has revived γ-secretase as an attractive target and has so far resulted in one compound in late-phase clinical trials. The identification of other modulators in a variety of structural classes raise the hope that more promising agents will soon be in the pipeline.