Abstract
Fluorination of metabolic hotspots in a molecule is a common medicinal chemistry strategy to improve in vivo half-life and exposure and, generally, this strategy offers significant benefits. Here, we report the application of this strategy to a series of poly-ADP ribose glycohydrolase (PARG) inhibitors, resulting in unexpected in vivo toxicity which was attributed to this single-atom modification.
Keywords:
Animal welfare; Ataxia; Toxicophore.
Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Animals
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Cyclopropanes / administration & dosage
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Cyclopropanes / chemistry
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Cyclopropanes / pharmacokinetics
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Cyclopropanes / pharmacology*
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Glycoside Hydrolases / administration & dosage
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Glycoside Hydrolases / chemistry
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Glycoside Hydrolases / pharmacokinetics
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Glycoside Hydrolases / toxicity*
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Half-Life
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Humans
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Mice
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Microsomes, Liver / drug effects*
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Microsomes, Liver / metabolism
Substances
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Cyclopropanes
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Glycoside Hydrolases
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poly ADP-ribose glycohydrolase