Gene mutation defends against Alzheimer's disease.

Nature (Impact Factor: 42.35). 07/2012; 487(7406):153. DOI: 10.1038/487153a
Source: PubMed

ABSTRACT Rare genetic variant suggests a cause and treatment for cognitive

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    ABSTRACT: Beta-secretase (BACE1), the enzyme responsible for the first and rate-limiting step in the production of amyloid-beta peptides, is an attractive target for the treatment of Alzheimer's disease. In this study, we report the application of the de novo fragment-based molecular design program SPROUT to the discovery of a series of non-peptide BACE1 inhibitors based upon a biphenylacetamide scaffold. The binding affinity of molecules based upon this designed molecular scaffold was increased following the synthesis of a library of optimized ligands whose structures were refined using the recently developed SPROUT-HitOpt software. Although a number of inhibitors were found to exhibit cellular toxicity, one compound in the series was found to have useful BACE1 inhibitory activity in a cellular assay with minimal cellular toxicity.
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