Abstract
In previous studies, the introduction of electron withdrawing groups to 1,4-oxazine BACE1 inhibitors reduced the p Ka of the amidine group, resulting in compound 2 that showed excellent in vivo efficacy, lowering Aβ levels in brain and CSF. However, a suboptimal cardiovascular safety margin, based on QTc prolongation, prevented further progression. Further optimization resulted in the replacement of the 2-fluoro substituent by a CF3-group, which reduced hERG inhibition. This has led to compound 3, with an improved cardiovascular safety margin and sufficiently safe in GLP toxicity studies to progress into clinical trials.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Intravenous
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Administration, Oral
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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 / cerebrospinal fluid
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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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Biological Availability
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Cardiovascular Diseases / chemically induced
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Chemical and Drug Induced Liver Injury / etiology
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Dogs
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Drug Evaluation, Preclinical / methods
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Drug Stability
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ERG1 Potassium Channel / metabolism
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Guinea Pigs
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Humans
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Male
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Mice, Inbred Strains
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Oxazines / chemistry
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Peptide Fragments / cerebrospinal fluid
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Protease Inhibitors / administration & dosage
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Protease Inhibitors / adverse effects
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Protease Inhibitors / chemistry*
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Protease Inhibitors / pharmacology*
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Rats, Sprague-Dawley
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Structure-Activity Relationship
Substances
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Amyloid beta-Peptides
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ERG1 Potassium Channel
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KCNH2 protein, human
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Oxazines
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Peptide Fragments
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Protease Inhibitors
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amyloid beta-protein (1-42)
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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BACE1 protein, human