Inhibitors of 尾-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1): Identification of (S)-7-(2-Fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5鈥?i>H-spiro[chromeno[2,3-b]py

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• 作者：Thomas A. Dineen ; Kui Chen ; Alan C. Cheng ; Katayoun Derakhchan ; Oleg Epstein ; Joel Esmay ; Dean Hickman ; Chuck E. Kreiman ; Isaac E. Marx ; Robert C. Wahl ; Paul H. Wen ; Matthew M. Weiss ; Douglas A. Whittington ; Stephen Wood ; Robert T. Fremeau ; Jr. ; Ryan D. White ; Vinod F. Patel
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：December 11, 2014
• 年：2014
• 卷：57
• 期：23
• 页码：9811-9831
• 全文大小：690K
• ISSN：1520-4804

文摘

We have previously shown that the aminooxazoline xanthene scaffold can generate potent and orally efficacious BACE1 inhibitors although certain of these compounds exhibited potential hERG liabilities. In this article, we describe 4-aza substitution on the xanthene core as a means to increase BACE1 potency while reducing hERG binding affinity. Further optimization of the P3 and P2鈥?side chains resulted in the identification of 42 (AMG-8718), a compound with a balanced profile of BACE1 potency, hERG binding affinity, and Pgp recognition. This compound produced robust and sustained reductions of CSF and brain A尾 levels in a rat pharmacodynamic model and exhibited significantly reduced potential for QTc elongation in a cardiovascular safety model.