Structure guided P1鈥?modifications of HEA derived 尾-secretase inhibitors for the treatment of Alzheimer鈥檚 disease

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• 作者：Holger Monenschein^c ; ^&dagger ; ; Daniel B. Horne^a ; ^{dhorne@amgen.com} ; Michael D. Bartberger^b ; Stephen A. Hitchcock^c ; ^&dagger ; ; Thomas T. Nguyen^a ; Vinod F. Patel^d ; ^&dagger ; ; Lewis D. Pennington^a ; Wenge Zhong^a
• 关键词：A尾 amyloid ; Alzheimer&rsquo ; s disease ; Aspartyl protease ; 尾-secretase ; BACE inhibitors ; Hydroxyethylene derivatives ; Protease inhibitors
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：1 June, 2012
• 卷：22
• 期：11
• 页码：3607-3611
• 文件大小：886 K

摘要

The synthesis and SAR of a series of BACE-1 hydroxyethyl amine inhibitors containing substitutions on a spirocyclobutyl moiety is described. Selectivity against cathepsin D, a related aspartyl protease with potential off target toxicity, and improved microsomal stability is exemplified.