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An Orally Available BACE1 Inhibitor That Affords Robust CNS Aβ Reduction without Cardiovascular Liabilities

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journal contribution
posted on 12.02.2015, 00:00 by Yuan Cheng, James Brown, Ted C. Judd, Patricia Lopez, Wenyuan Qian, Timothy S. Powers, Jian Jeffrey Chen, Michael D. Bartberger, Kui Chen, Robert T. Dunn, Oleg Epstein, Robert T. Fremeau, Scott Harried, Dean Hickman, Stephen A. Hitchcock, Yi Luo, Ana Elena Minatti, Vinod F. Patel, Hugo M. Vargas, Robert C. Wahl, Matthew M. Weiss, Paul H. Wen, Ryan D. White, Douglas A. Whittington, Xiao Mei Zheng, Stephen Wood
BACE1 inhibition to prevent Aβ peptide formation is considered to be a potential route to a disease-modifying treatment for Alzheimer’s disease. Previous efforts in our laboratory using a combined structure- and property-based approach have resulted in the identification of aminooxazoline xanthenes as potent BACE1 inhibitors. Herein, we report further optimization leading to the discovery of inhibitor 15 as an orally available and highly efficacious BACE1 inhibitor that robustly reduces CSF and brain Aβ levels in both rats and nonhuman primates. In addition, compound 15 exhibited low activity on the hERG ion channel and was well tolerated in an integrated cardiovascular safety model.