Advances in gamma-secretase modulation.

Inhibition of the production of insoluble amyloid-Beta (ABeta) is a widely pursued strategy for the treatment of Alzheimer's disease (AD). The final step in the generation of ABeta from the amyloid precursor protein (APP) involves cleavage by gamma-secretase, and gamma-secretase inhibitors (GSIs) have been shown to reduce the amyloid burden in animal models of AD. Unfortunately, GSIs also cause inhibition of the cleavage of other gamma-secretase substrates, including Notch, while the co-inhibition of Notch processing by GSIs in animal studies was observed to result in a gamut of side effects. A new class of compounds, known as gamma-secretase modulators (GSMs), inhibit the amyloidogenic function of gamma-secretase without interfering in the processing of Notch and other substrates. While the exact reason for the selectivity of these agents remains unclear, they are thought to intervene at an allosteric site on gamma-secretase and cause a shift of the preferred APP cleavage site so that shorter, more soluble peptides (eg, ABeta(38)) are produced instead of the highly insoluble ABeta(42). This review describes the history of the discovery of GSMs and the current medicinal chemistry efforts aimed at providing clinically useful GSM compounds.