6533b835fe1ef96bd12a0119
RESEARCH PRODUCT
Discovery of γ-secretase modulators with a novel activity profile by text-based virtual screening.
Sascha WeggenBruno BulicClaus U. PietrzikJulia NessHeiko ZettlVolker HähnkeThorsten JumpertzGisbert SchneiderDirk BeherKarlheinz BaumannArman Saricsubject
PyridinesPyridonesMolecular Sequence DataPeptideComputational biologyCHO CellsBiochemistryStructure-Activity RelationshipAlzheimer DiseaseCricetinaeAnimalsHumansγ secretaseAmino Acid Sequencechemistry.chemical_classificationVirtual screeningActivity profileAmyloid beta-PeptidesChemistryGeneral MedicineIntegrated approachIn vitroMinimal effectDrug DesignMolecular MedicineAmyloid Precursor Protein Secretasesdescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2012-06-26 | ACS chemical biology |