Gamma-secretase inhibition and modulation for Alzheimer's disease.

Gamma-secretase is a multi-protein complex that proteolyzes the transmembrane region of the amyloid beta-peptide (Abeta) precursor (APP), producing the Abeta 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 peptide-like, more drug-like compounds. Although one gamma-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 gamma-secretase inhibitors are apparently due to blocking one particularly important substrate, the Notch receptor. Thus, the potential of gamma-secretase as therapeutic target likely depends on the ability to selectively inhibit Abeta production without hindering Notch proteolysis (i.e., modulation rather than inhibition). The discovery of gamma-secretase modulators has revived gamma-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.