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[摘要]：We present an integrated approach to identify and optimize a novel class of gamma-secretase modulators (GSMs) with a unique pharmacological profile. Our strategy included (i) virtual screening through application of a recently developed protocol (PhAST), (ii) synthetic chemistry to discover structure-activity relationships, and (iii) detailed in vitro pharmacological characterization. GSMs are promising agents for treatment or prevention of Alzheimer's disease. They modulate the gamma-secretase product spectrum (i.e., amyloid-beta (A beta) peptides of different length) and induce a shift from toxic A beta 42 to shorter A beta species such as A beta 38 with no or minimal effect on the overall rate of gamma-secretase cleavage. We describe the identification of a series of 4-hydroxypyridin-2-one derivatives, which display a novel type of gamma-secretase modulation with equipotent inhibition of A beta 42 and A beta 38 peptide species. |
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