Abstract
1,4-Oxazines are presented, which show good in vitro inhibition in enzymatic and cellular BACE1 assays. We describe lead optimization focused on reducing the amidine pKa while optimizing interactions in the BACE1 active site. Our strategy permitted modulation of properties such as permeation and especially P-glycoprotein efflux. This led to compounds which were orally bioavailable, centrally active, and which demonstrated robust lowering of brain and CSF Aβ levels, respectively, in mouse and dog models. The amyloid lowering potential of these molecules makes them valuable leads in the search for new BACE1 inhibitors for the treatment of Alzheimer's disease.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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Alzheimer Disease / drug therapy
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Alzheimer Disease / metabolism
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Amyloid beta-Peptides / antagonists & inhibitors
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Amyloid beta-Peptides / cerebrospinal fluid
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Animals
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Aspartic Acid Endopeptidases / antagonists & inhibitors*
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Biological Availability
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Blood Proteins / metabolism
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Blood-Brain Barrier
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Brain / metabolism*
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Cell Line, Tumor
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Cytochrome P-450 Enzyme Inhibitors / chemical synthesis
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Cytochrome P-450 Enzyme Inhibitors / pharmacology
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Dogs
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Drug Design
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Female
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Humans
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Male
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Mice
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Models, Molecular
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Oxazines / chemical synthesis*
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Oxazines / pharmacokinetics
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Oxazines / pharmacology*
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Protein Binding
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Amyloid beta-Peptides
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Blood Proteins
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Cytochrome P-450 Enzyme Inhibitors
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Oxazines
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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Bace1 protein, mouse