Abstract
We have reported potent peptidic and non-peptidic BACE1 inhibitors with a hydroxymethylcarbonyl (HMC) isostere as a substrate transition-state mimic. However, our potent inhibitors possess a tetrazole ring at the P1' position. It is desirable that central nervous system (CNS) drugs do not possess an acidic moiety. In this study, we synthesized non-acidic BACE1 inhibitors with heterocyclic derivatives at the P1' position. KMI-1764 (27) exhibited potent inhibitory activity (IC50=27nM). Interestingly, these non-acidic inhibitors tended to follow the quantitative structure-activity relationship (QSAR) equation and interacted with BACE1-Arg235 in the binding model.
Keywords:
Alzheimer’s disease; Hydroxymethylcarbonyl isostere; Non-acidic inhibitor; Quantitative structure–activity relationship; β-Secretase.
Copyright © 2013 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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Amyloid Precursor Protein Secretases / genetics
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Amyloid Precursor Protein Secretases / metabolism
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Aspartic Acid Endopeptidases / antagonists & inhibitors*
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Aspartic Acid Endopeptidases / genetics
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Aspartic Acid Endopeptidases / metabolism
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Benzamides / chemical synthesis
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Benzamides / chemistry*
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Benzamides / metabolism
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Heterocyclic Compounds / chemical synthesis
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Heterocyclic Compounds / chemistry*
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Heterocyclic Compounds / metabolism
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Humans
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Hydrogen Bonding
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Protease Inhibitors / chemical synthesis
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Protease Inhibitors / chemistry*
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Protease Inhibitors / metabolism
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Protein Binding
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Quantitative Structure-Activity Relationship
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Recombinant Proteins / biosynthesis
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Thiadiazoles / chemical synthesis
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Thiadiazoles / chemistry*
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Thiadiazoles / metabolism
Substances
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Benzamides
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Heterocyclic Compounds
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N1-(4-(5-bromo-1,3,4-thiadiazol-2-ylamino)-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-5-(N-methylmethanesulfonamido)-N3-(1-phenylethyl)isophthalamide
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Protease Inhibitors
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Recombinant Proteins
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Thiadiazoles
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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BACE1 protein, human