Discovery of γ-Secretase Modulators with a Novel Activity Profile by Text-Based Virtual Screening Heiko Zettl Julia Ness Volker Hähnke Dirk Beher Thorsten Jumpertz Arman Saric Karlheinz Baumann Claus U. Pietrzik Bruno Bulic Gisbert Schneider Sascha Weggen 10.1021/cb3001952.s001 https://acs.figshare.com/articles/journal_contribution/Discovery_of_Secretase_Modulators_with_a_Novel_Activity_Profile_by_Text_Based_Virtual_Screening/2484271 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 <i>in vitro</i> pharmacological characterization. GSMs are promising agents for treatment or prevention of Alzheimer’s disease. They modulate the γ-secretase product spectrum (<i>i.e</i>., 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. 2012-09-21 00:00:00 β species novel type β42 GSM secretase novel class Novel Activity Profile β38 peptide species