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