Abstract
Inhibition of intestinal carboxylesterases may allow modification of the pharmacokinetics/pharmacodynamic profile of existing drugs by altering half-life or toxicity. Since previously identified diarylethane-1,2-dione inhibitors are decidedly hydrophobic, a modified dione scaffold was designed and elaborated into a >300 member library, which was subsequently screened to establish the SAR for esterase inhibition. This allowed the identification of single digit nanomolar hiCE inhibitors that showed improvement in selectivity and measured solubility.
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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Acetylcholinesterase / chemistry
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Butyrylcholinesterase / chemistry
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Carboxylesterase / antagonists & inhibitors*
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Cholinesterase Inhibitors / chemical synthesis*
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Cholinesterase Inhibitors / chemistry
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Glyoxal / analogs & derivatives*
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Glyoxal / chemical synthesis*
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Glyoxal / chemistry
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Humans
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Pyridines / chemical synthesis*
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Pyridines / chemistry
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Small Molecule Libraries
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Structure-Activity Relationship
Substances
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Cholinesterase Inhibitors
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Pyridines
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Small Molecule Libraries
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Glyoxal
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Carboxylesterase
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Acetylcholinesterase
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Butyrylcholinesterase