Design and Preparation of a Potent Series of Hydroxyethylamine Containing 尾-Secretase Inhibitors That Demonstrate Robust Reduction of Central 尾-Amyloid

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• 作者：Matthew M. Weiss ; Toni Williamson ; Safura Babu-Khan ; Michael D. Bartberger ; James Brown ; Kui Chen ; Yuan Cheng ; Martin Citron ; Michael D. Croghan ; Thomas A. Dineen ; Joel Esmay ; Russell F. Graceffa ; Scott S. Harried ; Dean Hickman ; Stephen A. Hitchcock ; Daniel B. Horne ; Hongbing Huang ; Ronke Imbeah-Ampiah ; Ted Judd ; Matthew R. Kaller ; Charles R. Kreiman ; Daniel S. La ; Vivian Li ; Patricia Lopez ; Steven Louie ; Holger Monenschein ; Thomas T. Nguyen ; Lewis D. Pennington ; Claire Rattan ; Tisha San Miguel ; E.Allen Sickmier ; Robert C. Wahl ; Paul H. Wen ; Stephen Wood ; Qiufen Xue ; Bryant H. Yang ; Vinod F. Patel ; Wenge Zhong
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 8, 2012
• 年：2012
• 卷：55
• 期：21
• 页码：9009-9024
• 全文大小：529K
• 年卷期：v.55,no.21(November 8, 2012)
• ISSN：1520-4804

文摘

A series of potent hydroxyethyl amine (HEA) derived inhibitors of 尾-site APP cleaving enzyme (BACE1) was optimized to address suboptimal pharmacokinetics and poor CNS partitioning. This work identified a series of benzodioxolane analogues that possessed improved metabolic stability and increased oral bioavailability. Subsequent efforts focused on improving CNS exposure by limiting susceptibility to Pgp-mediated efflux and identified an inhibitor which demonstrated robust and sustained reduction of CNS 尾-amyloid (A尾) in Sprague鈥揇awley rats following oral administration.