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ACS Chem Biol. 2012 Sep 21;7(9):1488-95. Epub 2012 Jul 2.

Discovery of γ-secretase modulators with a novel activity profile by text-based virtual screening.

Author information

1
Department of Neuropathology, Heinrich-Heine-University, D-40225 Duesseldorf, Germany.

Abstract

We present an integrated approach to identify and optimize a novel class of γ-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 γ-secretase product spectrum (i.e., amyloid-β (Aβ) peptides of different length) and induce a shift from toxic Aβ42 to shorter Aβ species such as Aβ38 with no or minimal effect on the overall rate of γ-secretase cleavage. We describe the identification of a series of 4-hydroxypyridin-2-one derivatives, which display a novel type of γ-secretase modulation with equipotent inhibition of Aβ42 and Aβ38 peptide species.

PMID:
22725102
DOI:
10.1021/cb3001952
[Indexed for MEDLINE]

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