Abstract
A series of potent hydroxyethyl amine (HEA) derived inhibitors of β-site APP cleaving enzyme (BACE1) was optimized to address suboptimal pharmacokinetics and poor CNS partitioning. This work identified a series of benzodioxolane analogues that possessed improved metabolic stability and increased oral bioavailability. Subsequent efforts focused on improving CNS exposure by limiting susceptibility to Pgp-mediated efflux and identified an inhibitor which demonstrated robust and sustained reduction of CNS β-amyloid (Aβ) in Sprague-Dawley rats following oral administration.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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Administration, Oral
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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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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Biological Availability
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Brain / drug effects*
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Brain / metabolism
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Crystallography, X-Ray
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Dioxolanes / chemical synthesis*
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Dioxolanes / pharmacokinetics
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Dioxolanes / pharmacology
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Dogs
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Drug Design
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Ethylamines / chemical synthesis*
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Ethylamines / pharmacokinetics
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Ethylamines / pharmacology
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Humans
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Macaca mulatta
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Male
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Microsomes, Liver / metabolism
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Models, Molecular
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Peptide Fragments / metabolism*
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Protein Conformation
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Protein Transport
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Rats
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Rats, Sprague-Dawley
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Stereoisomerism
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Structure-Activity Relationship
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Amyloid beta-Peptides
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Dioxolanes
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Ethylamines
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Peptide Fragments
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amyloid beta-protein (1-40)
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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BACE1 protein, human