Article

Discovery of γ-Secretase Modulators with a Novel Activity Profile by Text-Based Virtual Screening.

Department of Neuropathology, Heinrich-Heine-University , D-40225 Duesseldorf, Germany.
ACS Chemical Biology (impact factor: 6.45). 06/2012; 7(9):1488-95. DOI:10.1021/cb3001952
Source: PubMed

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.

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Keywords

Alzheimer's disease
 
Aβ38 peptide species
 
developed protocol
 
equipotent inhibition
 
induce
 
integrated approach
 
minimal effect
 
novel class
 
novel type
 
shorter Aβ species
 
structure-activity relationships
 
unique pharmacological profile
 
vitro pharmacological characterization
 
γ-secretase modulators
 
γ-secretase product spectrum