Design and Synthesis of Potent, Orally Efficacious Hydroxyethylamine Derived 尾-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors
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- 作者：Thomas A. Dineen ; Matthew M. Weiss ; Toni Williamson ; Paul Acton ; Safura Babu-Khan ; Michael D. Bartberger ; James Brown ; Kui Chen ; Yuan Cheng ; Martin Citron ; Michael D. Croghan ; Robert T. Dunn ; II ; 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 ; Tisha San Miguel ; E. Allen Sickmier ; Hugo M. Vargas ; Robert C. Wahl ; Paul H. Wen ; Douglas A. Whittington ; 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：9025-9044
- 全文大小：577K
- 年卷期：v.55,no.21(November 8, 2012)
- ISSN：1520-4804
文摘
We have previously shown that hydroxyethylamines can be potent inhibitors of the BACE1 enzyme and that the generation of BACE1 inhibitors with CYP 3A4 inhibitory activities in this scaffold affords compounds (e.g., 1) with sufficient bioavailability and pharmacokinetic profiles to reduce central amyloid-尾 peptide (A尾) levels in wild-type rats following oral dosing. In this article, we describe further modifications of the P1-phenyl ring of the hydroxyethylamine series to afford potent, dual BACE1/CYP 3A4 inhibitors which demonstrate improved penetration into the CNS. Several of these compounds caused robust reduction of A尾 levels in rat CSF and brain following oral dosing, and compound 37 exhibited an improved cardiovascular safety profile relative to 1.