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Zettl H.,ETH Zurich | Ness J.,Heinrich Heine University Dusseldorf | Hahnke V.,ETH Zurich | Beher D.,Global Research and Early Development | And 7 more authors.
ACS Chemical Biology | Year: 2012

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. © 2012 American Chemical Society. Source


Busch M.,Global Research and Early Development | Thoma H.B.,Global Research and Early Development | Kober I.,Global Research and Early Development
Journal of Biomolecular Screening | Year: 2013

An explanation for randomly occurring spikes on microplates in fluorescence-based assays employing shorter-wavelength readouts is presented. It is demonstrated that lint originating from standard (white cotton) lab coats is most likely to be responsible for such artifacts in assays applying wavelengths at 380 nm excitation and 450 nm emission. The fluorescence properties of this lint are discussed and compared with those of optical brighteners. An alternative to the use of cotton-based lab coats is presented, which led to a reduction of spikes in a high-throughput screening campaign by 90%. © 2013 Society for Laboratory Automation and Screening. Source


Saric A.,Merck Serono SA | Brugge L.Z.,Global Research and Early Development | Muller-Pompalla D.,Global Research and Early Development | Rysiok T.,Global Research and Early Development | And 6 more authors.
Journal of Biomolecular Screening | Year: 2013

β-Site amyloid precursor protein cleaving enzyme-1 (BACE-1) is a transmembrane aspartic protease that mediates the initial cleavage of the amyloid precursor protein (APP), leading to the generation of amyloid-β (Aβ) peptides that are thought to be causative of Alzheimer's disease (AD). Consequently, inhibition of BACE-1 is an attractive therapeutic approach for the treatment of AD. In general, in vitro biochemical assays to monitor BACE-1 activity have used the extracellular domain of the protein that contains the catalytic active site. This form of BACE-1 is catalytically active at acidic pH and cleaves APP-based peptide substrates at the β-site. However, this form of BACE-1 does not mimic the natural physiology of BACE-1 and shows minimal activity at pH 6.0, which is more representative of the pH within the intracellular compartments where BACE-1 resides. Moreover, high-throughput screens with recombinant BACE-1 at pH 4.5 have failed to identify tractable leads for drug discovery, and hence, BACE-1 inhibitor development has adopted a rational drug design approach. Here we describe the development and validation of a novel membrane assay comprising full-length BACE-1 with measurable activity at pH 6.0, which could be used for the identification of novel inhibitors of BACE-1. © 2012 Society for Laboratory Automation and Screening. Source

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