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 CF3 group delivered an excellent pharmacological profile with a pKa 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-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide 54 (NB-360), able to reduce significantly Aβ levels in mice, rats, and dogs in acute and chronic treatment regimens.
MeSH terms
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Alzheimer Disease / drug therapy
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Amyloid Precursor Protein Secretases / antagonists & inhibitors
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Amyloid Precursor Protein Secretases / metabolism*
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Amyloid beta-Peptides / metabolism
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Animals
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Aspartic Acid Endopeptidases / antagonists & inhibitors
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Aspartic Acid Endopeptidases / metabolism
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Binding Sites
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Brain / metabolism
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Crystallography, X-Ray
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Dogs
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / therapeutic use
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Half-Life
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Humans
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Mice
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Molecular Dynamics Simulation
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Oxazines / chemistry
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Picolinic Acids / chemical synthesis*
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Picolinic Acids / pharmacokinetics
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Picolinic Acids / therapeutic use
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Rats
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Structure-Activity Relationship
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Thiazines / chemical synthesis*
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Thiazines / pharmacokinetics
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Thiazines / therapeutic use
Substances
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Amyloid beta-Peptides
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Enzyme Inhibitors
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NB-360
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Oxazines
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Picolinic Acids
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Thiazines
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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BACE2 protein, human
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BACE1 protein, human