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Discovery of amino-1,4-oxazines as potent BACE-1 inhibitors.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2018 Jul 01; Vol. 28 (12), pp. 2195-2200. Date of Electronic Publication: 2018 May 03. - Publication Year :
- 2018
-
Abstract
- New amino-1,4-oxazine derived BACE-1 inhibitors were explored and various synthetic routes developed. The binding mode of the inhibitors was elucidated by co-crystallization of 4 with BACE-1 and X-ray analysis. Subsequent optimization led to inhibitors with low double digit nanomolar activity in a biochemical and single digit nanomolar potency in a cellular assays. To assess the inhibitors for their permeation properties and potential to cross the blood-brain-barrier a MDR1-MDCK cell model was successfully applied. Compound 8a confirmed the in vitro results by dose-dependently reducing Aβ levels in mice in an acute treatment regimen.<br /> (Copyright © 2018. Published by Elsevier Ltd.)
- Subjects :
- Amyloid Precursor Protein Secretases metabolism
Animals
Aspartic Acid Endopeptidases metabolism
Dogs
Dose-Response Relationship, Drug
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors chemistry
Madin Darby Canine Kidney Cells drug effects
Mice
Models, Molecular
Molecular Conformation
Oxazines chemical synthesis
Oxazines chemistry
Structure-Activity Relationship
Amyloid Precursor Protein Secretases antagonists & inhibitors
Aspartic Acid Endopeptidases antagonists & inhibitors
Drug Discovery
Enzyme Inhibitors pharmacology
Oxazines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 28
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 29764741
- Full Text :
- https://doi.org/10.1016/j.bmcl.2018.05.003