Abstract
In this Letter, we describe our efforts to design HEA BACE-1 inhibitors that are highly permeable coupled with negligible levels of permeability-glycoprotein activity. These efforts culminate in producing 16 which lowers Αβ by 28% and 32% in the cortex and CSF, respectively, in the preclinical wild type Hartley guinea pig animal model when dosed orally at 30mpk BID for 2.5days.
Copyright © 2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Alkylation
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Alzheimer Disease
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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 / metabolism
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Cell Line
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Dogs
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Drug Design
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Ethylamines / chemical synthesis*
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Ethylamines / pharmacology*
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Guinea Pigs
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Humans
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Indicators and Reagents
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Protease Inhibitors / chemical synthesis*
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Protease Inhibitors / pharmacokinetics
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Protease Inhibitors / pharmacology*
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Protein Binding
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Structure-Activity Relationship
Substances
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Ethylamines
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Indicators and Reagents
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Protease Inhibitors
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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BACE1 protein, human