Abstract
We have identified macrocyclic inhibitors of the aspartic protease BACE, implicated in the etiology of Alzheimer's disease. An X-ray structure of screening hit 1 in the BACE active site revealed a hairpin conformation suggesting that constrained macrocyclic derivatives may also bind there. Several of the analogs we prepared were >100x more potent than 1, such as 7 (5 nM K(i)).
Copyright 2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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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 / metabolism
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Binding Sites
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Computer Simulation
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Humans
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Macrocyclic Compounds / chemical synthesis
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Macrocyclic Compounds / chemistry*
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Macrocyclic Compounds / pharmacology
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Protease Inhibitors / chemical synthesis
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Protease Inhibitors / chemistry*
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Protease Inhibitors / pharmacology
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Quinazolines / chemical synthesis
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Quinazolines / chemistry*
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Quinazolines / pharmacology
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Structure-Activity Relationship
Substances
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Macrocyclic Compounds
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Protease Inhibitors
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Quinazolines
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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BACE1 protein, human