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Development of 2-aminooxazoline 3-azaxanthenes as orally efficacious β-secretase inhibitors for the potential treatment of Alzheimer's disease.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2015 Feb 15; Vol. 25 (4), pp. 767-74. Date of Electronic Publication: 2015 Jan 08. - Publication Year :
- 2015
-
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.<br /> (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Subjects :
- Alzheimer Disease drug therapy
Animals
Cell Line
HEK293 Cells
Humans
Protease Inhibitors chemical synthesis
Rats
Xanthenes chemical synthesis
Amyloid Precursor Protein Secretases antagonists & inhibitors
Aspartic Acid Endopeptidases antagonists & inhibitors
Protease Inhibitors chemistry
Protease Inhibitors pharmacology
Xanthenes chemistry
Xanthenes pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 25
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 25613679
- Full Text :
- https://doi.org/10.1016/j.bmcl.2014.12.092