Abstract
Efforts were dedicated to develop potent and brain penetrant prolylcarboxypeptidase (PrCP) inhibitors by replacing the amide group of original leads 1 and 2 with heterocycles. Aminopyrimidines including compound 32a were identified to display good PrCP inhibitory activity (32a, IC(50)=43 nM) and impressive ability to penetrate brain in mice (brain/plasma ratio: 1.4).
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Amides / chemistry
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Amines / chemical synthesis*
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Amines / chemistry
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Amines / pharmacology
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Animals
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Brain / drug effects*
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Brain / enzymology
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Carboxypeptidases / antagonists & inhibitors*
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Drug Discovery*
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Enzyme Activation / drug effects
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Enzyme Inhibitors* / chemical synthesis
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Enzyme Inhibitors* / pharmacology
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Heterocyclic Compounds / chemical synthesis*
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Heterocyclic Compounds / chemistry
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Heterocyclic Compounds / pharmacology*
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Inhibitory Concentration 50
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Mice
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Molecular Structure
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Structure-Activity Relationship
Substances
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Amides
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Amines
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Enzyme Inhibitors
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Heterocyclic Compounds
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Carboxypeptidases
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lysosomal Pro-X carboxypeptidase