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Synthesis of the Potent, Selective, and Efficacious β-Secretase (BACE1) Inhibitor NB-360.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2021 Apr 22; Vol. 64 (8), pp. 4677-4696. Date of Electronic Publication: 2021 Apr 12. - Publication Year :
- 2021
-
Abstract
- Starting from lead compound 4 , the 1,4-oxazine headgroup was optimized to improve potency and brain penetration. Focusing at the 6-position of the 5-amino-1,4-oxazine, the insertion of a Me and a CF <subscript>3</subscript> group delivered an excellent pharmacological profile with a p K <subscript>a</subscript> of 7.1 and a very low P-gp efflux ratio enabling high central nervous system (CNS) penetration and exposure. Various synthetic routes to access BACE1 inhibitors bearing a 5-amino-6-methyl-6-(trifluoromethyl)-1,4-oxazine headgroup were investigated. Subsequent optimization of the P3 fragment provided the highly potent N -(3-((3 R ,6 R )-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2 H -1,4-oxazin-3-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide 54 ( NB-360 ), able to reduce significantly A β levels in mice, rats, and dogs in acute and chronic treatment regimens.
- Subjects :
- Alzheimer Disease drug therapy
Amyloid Precursor Protein Secretases antagonists & inhibitors
Amyloid beta-Peptides metabolism
Animals
Aspartic Acid Endopeptidases antagonists & inhibitors
Aspartic Acid Endopeptidases metabolism
Binding Sites
Brain metabolism
Crystallography, X-Ray
Dogs
Enzyme Inhibitors metabolism
Enzyme Inhibitors therapeutic use
Half-Life
Humans
Mice
Molecular Dynamics Simulation
Oxazines chemistry
Picolinic Acids pharmacokinetics
Picolinic Acids therapeutic use
Rats
Structure-Activity Relationship
Thiazines pharmacokinetics
Thiazines therapeutic use
Amyloid Precursor Protein Secretases metabolism
Enzyme Inhibitors chemical synthesis
Picolinic Acids chemical synthesis
Thiazines chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 64
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 33844524
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.0c02143