Abstract
An extensive fluorine scan of 1,3-oxazines revealed the power of fluorine(s) to lower the pKa and thereby dramatically change the pharmacological profile of this class of BACE1 inhibitors. The CF3 substituted oxazine 89, a potent and highly brain penetrant BACE1 inhibitor, was able to reduce significantly CSF Aβ40 and 42 in rats at oral doses as low as 1 mg/kg. The effect was long lasting, showing a significant reduction of Aβ40 and 42 even after 24 h. In contrast to 89, compound 1b lacking the CF3 group was virtually inactive in vivo.
MeSH terms
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Alzheimer Disease / drug therapy*
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Animals
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Aspartic Acid Endopeptidases / antagonists & inhibitors*
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Brain Chemistry
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology*
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Enzyme Inhibitors / therapeutic use
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Female
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Fluorine / chemistry
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Humans
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Indicators and Reagents
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Models, Molecular
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Oxazines / chemical synthesis
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Oxazines / pharmacology
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Rats
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Rats, Wistar
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Structure-Activity Relationship
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X-Ray Diffraction
Substances
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Enzyme Inhibitors
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Indicators and Reagents
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Oxazines
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Fluorine
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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Bace1 protein, mouse
Associated data
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PDB/3ZLQ
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PDB/3ZMG
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PDB/4J0P
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PDB/4J0T
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PDB/4J0V
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PDB/4J0Y
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PDB/4J0Z
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PDB/4J17
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PDB/4J1C
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PDB/4J1E
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PDB/4J1F
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PDB/4J1H
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PDB/4J1I
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PDB/4J1K