Discovery of Biphenylacetamide-Derived Inhibitors of BACE1 Using de Novo Structure-Based Molecular Design

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• 作者：N. Yi Mok ; James Chadwick ; Katherine A. B. Kellett ; Eva Casas-Arce ; Nigel M. Hooper ; A. Peter Johnson ; Colin W. G. Fishwick
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：March 14, 2013
• 年：2013
• 卷：56
• 期：5
• 页码：1843-1852
• 全文大小：515K
• 年卷期：v.56,no.5(March 14, 2013)
• ISSN：1520-4804

文摘

尾-Secretase (BACE1), the enzyme responsible for the first and rate-limiting step in the production of amyloid-尾 peptides, is an attractive target for the treatment of Alzheimer鈥檚 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 nonpeptide BACE1 inhibitors based upon a biphenylacetamide scaffold. The binding affinity of molecules based upon this designed molecular scaffold was increased from an initial BACE1 IC₅₀ of 323 渭M to 27 渭M 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. This work demonstrates the power of an in silico fragment-based molecular design approach in the discovery of novel BACE1 inhibitors.