Abstract
A design for the selective release of drug molecules in the liver was tested, involving the attachment of a representative active agent by an ester linkage to various 2-substituted 5-aminovaleric acid carbamates. The anticipated pathway of carboxylesterase-1-mediated carbamate cleavage followed by lactamization and drug release was frustrated by unexpectedly high sensitivity of the ester linkage toward hydrolysis by carboxylesterase-2 and other microsomal components.
Keywords:
Carboxylesterase; Cleavable linkers; Drug targeting; Liver targeting.
Copyright © 2014 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acids, Neutral / chemical synthesis
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Amino Acids, Neutral / chemistry
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Amino Acids, Neutral / pharmacology*
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Carbamates / chemical synthesis
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Carbamates / chemistry
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Carbamates / pharmacology*
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Carboxylesterase / antagonists & inhibitors*
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Carboxylesterase / metabolism
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Carboxylic Ester Hydrolases / antagonists & inhibitors*
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Carboxylic Ester Hydrolases / metabolism
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Dose-Response Relationship, Drug
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Drug Design*
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Humans
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Liver / drug effects*
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Liver / enzymology
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Molecular Structure
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Structure-Activity Relationship
Substances
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Amino Acids, Neutral
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Carbamates
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5-aminovaleric acid
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Carboxylic Ester Hydrolases
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CES1 protein, human
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CES2 protein, human
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Carboxylesterase