A Potent and Orally Efficacious, Hydroxyethylamine-Based Inhibitor of 尾-Secretase

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• 作者：Matthew R. Kaller ; Scott S. Harried ; Brian Albrecht ; Patricia Amarante ; Safura Babu-Khan ; Michael D. Bartberger ; James Brown ; Ryan Brown ; Kui Chen ; Yuan Cheng ; Martin Citron ; Michael D. Croghan ; Russell Graceffa ; Dean Hickman ; Ted Judd ; Chuck Kriemen ; Daniel La ; Vivian Li ; Patricia Lopez ; Yi Luo ; Craig Masse ; Holger Monenschein ; Thomas Nguyen ; Lewis D. Pennington ; Tisha San Miguel ; E. Allen Sickmier ; Robert C. Wahl ; Matthew M. Weiss ; Paul H. Wen ; Toni Williamson ; Stephen Wood ; May Xue ; Bryant Yang ; Jianhua Zhang ; Vinod Patel ; Wenge Zhong ; Stephen Hitchcock
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：November 8, 2012
• 年：2012
• 卷：3
• 期：11
• 页码：886-891
• 全文大小：334K
• 年卷期：v.3,no.11(November 8, 2012)
• ISSN：1948-5875

文摘

尾-Secretase inhibitors are potentially disease-modifying treatments for Alzheimer's disease. Previous efforts in our laboratory have resulted in hydroxyethylamine-derived inhibitors such as 1 with low nanomolar potency against 尾-site amyloid precursor protein cleaving enzyme (BACE). When dosed intravenously, compound 1 was also shown to significantly reduce A尾₄₀ levels in plasma, brain, and cerebral spinal fluid. Herein, we report further optimizations that led to the discovery of inhibitor 16 as a novel, potent, and orally efficacious BACE inhibitor.

Keywords:

尾-site amyloid precursor protein cleaving enzyme (BACE); Alzheimer's disease (AD); hydroxyethylamine (HEA) isostere