Abstract
Structure-based design, synthesis, and biological evaluation of a series of dihydroquinazoline-derived β-secretase inhibitors incorporating thiazole and pyrazole-derived P2-ligands are described. We have identified inhibitor 4f which has shown potent enzyme inhibitory (K(i)=13 nM) and cellular (IC(50)=21 nM in neuroblastoma cells) assays. A model of 4f was created based upon the X-ray structure of 3a-bound β-secretase. The model suggested possible interactions in the active site.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Alzheimer Disease / drug therapy
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Alzheimer Disease / enzymology
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Amyloid Precursor Protein Secretases / chemistry
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Amyloid Precursor Protein Secretases / metabolism
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Catalytic Domain
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Cell Line, Tumor
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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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Models, Molecular
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Pyrazoles / chemical synthesis
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Pyrazoles / chemistry
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Pyrazoles / 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
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Thiazoles / chemical synthesis
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Thiazoles / chemistry
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Thiazoles / pharmacology
Substances
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Enzyme Inhibitors
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Pyrazoles
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Quinazolines
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Thiazoles
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pyrazole
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Amyloid Precursor Protein Secretases