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Discovery of γ-Secretase Modulators with a Novel Activity Profile by Text-Based Virtual Screening
journal contribution
posted on 2012-09-21, 00:00 authored by Heiko Zettl, Julia Ness, Volker Hähnke, Dirk Beher, Thorsten Jumpertz, Arman Saric, Karlheinz Baumann, Claus U. Pietrzik, Bruno Bulic, Gisbert Schneider, Sascha WeggenWe 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.