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

作者：Cheng Yuan^*; Brown James; Judd Ted C; Lopez Patricia; Qian Wenyuan; Powers Timothy S; Chen Jian Jeffrey; Bartberger Michael D; Chen Kui; Dunn Robert T II; Epstein Oleg; Fremeau Robert T Jr; Harried Scott; Hickman Dean; Hitchcock Stephen A; Luo Yi; Minatti Ana Elena; Patel Vinod F; Vargas Hugo M; Wahl Robert C; Weiss Matthew M; Wen Paul H; White Ryan D; Whittington Douglas A; Zheng Xiao Mei; Wood Stephen

来源：ACS Medicinal Chemistry Letters, 2015, 6(2): 210-215.

DOI：10.1021/ml500458t

• beta-site amyloid precursor protein cleaving enzyme 1 (BACE1)
• Alzheimer's disease (AD)
• A beta
• aminooxazoline
• xanthene

BACE1 inhibition to prevent A beta 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 A beta 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.

• 出版日期2015-2