| Literature DB >> 25613679 |
Jian Jeffrey Chen1, Qingyian Liu2, Chester Yuan2, Vijay Gore2, Patricia Lopez2, Vu Ma2, Albert Amegadzie2, Wenyuan Qian2, Ted C Judd2, Ana E Minatti2, James Brown2, Yuan Cheng2, May Xue2, Wenge Zhong2, Thomas A Dineen3, Oleg Epstein3, Jason Human3, Charles Kreiman3, Isaac Marx3, Matthew M Weiss3, Stephen A Hitchcock2, Timothy S Powers2, Kui Chen4, Paul H Wen5, Douglas A Whittington6, Alan C Cheng6, Michael D Bartberger7, Dean Hickman8, Jonathan A Werner9, Hugo M Vargas9, Nancy E Everds9, Steven L Vonderfecht9, Robert T Dunn9, Stephen Wood5, Robert T Fremeau5, Ryan D White3, Vinod F Patel3.
Abstract
The β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is one of the most hotly pursued targets for the treatment of Alzheimer's disease. We used a structure- and property-based drug design approach to identify 2-aminooxazoline 3-azaxanthenes as potent BACE1 inhibitors which significantly reduced CSF and brain Aβ levels in a rat pharmacodynamic model. Compared to the initial lead 2, compound 28 exhibited reduced potential for QTc prolongation in a non-human primate cardiovascular safety model.Entities:
Keywords: 3-Azaxanthene; Alzheimer’s disease (AD); Aminooxazoline; Amyloid; Aβ peptides; Xanthene; β-Secretase (BACE1)
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Year: 2015 PMID： 25613679 DOI： 10.1016/j.bmcl.2014.12.092
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823