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

[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 inhibitor...

Ausführliche Beschreibung

Gespeichert in:

Bibliographische Detailangaben
Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2015-02, Vol.25 (4), p.767-774
Hauptverfasser:	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:	Artikel
Sprache:	eng
Schlagworte:	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 HEK293 Cells Humans Protease Inhibitors - chemical synthesis Protease Inhibitors - chemistry Protease Inhibitors - pharmacology Rats Xanthene Xanthenes - chemical synthesis Xanthenes - chemistry Xanthenes - pharmacology β-Secretase (BACE1)
Online-Zugang:	Volltext
Tags:	Tag hinzufügen Keine Tags, Fügen Sie den ersten Tag hinzu!

Beschreibung
Zusammenfassung:	[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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2014.12.092