Development of 2-aminooxazoline 3-azaxanthenes as orally efficacious β-secretase inhibitors for the potential treatment of Alzheimer’s disease

• Published in: Bioorganic & medicinal chemistry letters Vol. 25; no. 4; pp. 767 - 774
• Main Authors: Chen, Jian Jeffrey, Liu, Qingyian, Yuan, Chester, Gore, Vijay, Lopez, Patricia, Ma, Vu, Amegadzie, Albert, Qian, Wenyuan, Judd, Ted C., Minatti, Ana E., Brown, James, Cheng, Yuan, Xue, May, Zhong, Wenge, Dineen, Thomas A., Epstein, Oleg, Human, Jason, Kreiman, Charles, Marx, Isaac, Weiss, Matthew M., Hitchcock, Stephen A., Powers, Timothy S., Chen, Kui, Wen, Paul H., Whittington, Douglas A., Cheng, Alan C., Bartberger, Michael D., Hickman, Dean, Werner, Jonathan A., Vargas, Hugo M., Everds, Nancy E., Vonderfecht, Steven L., Dunn, Robert T., Wood, Stephen, Fremeau, Robert T., White, Ryan D., Patel, Vinod F.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.02.2015; Elsevier
• Subjects: 3-Azaxanthene; Alzheimer Disease - drug therapy; Alzheimer’s disease (AD); Aminooxazoline; Amyloid; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Animals; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aβ peptides; Cell Line; Chemistry; Chemistry, Medicinal; Chemistry, Organic; HEK293 Cells; Humans; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Physical Sciences; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Rats; Science & Technology; Xanthene; Xanthenes - chemical synthesis; Xanthenes - chemistry; Xanthenes - pharmacology; β-Secretase (BACE1); Alzheimer’s disease (AD); Aminooxazoline; 3-Azaxanthene; Amyloid; β-Secretase (BACE1); Xanthene; Aβ peptides; ENZYME BACE1 INHIBITORS; DESIGN; SERIES; HYPOTHESIS; Alzheimer's disease (AD); AMYLOID PRECURSOR PROTEIN; beta-Secretase (BACE1); A beta peptides
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2014.12.092

[Display omitted] 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.