Abstract
We previously reported potent BACE1 inhibitors KMI-420 and KMI-570 possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. Acidic moieties at the P(1)(') and P(4) positions of KMI inhibitors are thought to be unfavorable in terms of membrane permeability across the blood-brain barrier. Herein, we replaced acidic moieties at the P(4) position with hydrogen bond accepting groups and acidic moieties at the P(1)(') position with less acidic and similar molecular-size moieties (carboxylic acid or tetrazole bioisosteres). These inhibitors exhibited improved BACE1 inhibitory activities and a thorough quantitative structure-activity relationship study was performed.
(c) 2010 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Aspartic Acid Endopeptidases / antagonists & inhibitors*
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Carboxylic Acids / chemistry
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Crystallography, X-Ray
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Drug Design*
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Enzyme Inhibitors* / chemical synthesis
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Enzyme Inhibitors* / chemistry
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Enzyme Inhibitors* / pharmacology
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Humans
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Hydrogen Bonding
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Hydrogen-Ion Concentration
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Inhibitory Concentration 50
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Models, Molecular
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Molecular Structure
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Oligopeptides / chemical synthesis*
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Oligopeptides / chemistry
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Oligopeptides / pharmacology*
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Thiazoles / chemistry
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Triazoles / chemistry
Substances
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Carboxylic Acids
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Enzyme Inhibitors
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KMI-420
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KMI-570
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Oligopeptides
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Thiazoles
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Triazoles
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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BACE1 protein, human