Abstract
In this paper, we describe the synthesis of (+)-(1R( *),2R( *))-2-[(1S( *))-1-amino-1-carboxy-2-(9H-xanthen-9-yl)-ethyl]-1-fluorocyclopropanecarboxylic acid (+)-16a, a compound, that is, fluorinated at the alpha position of the carboxylic acid in the cyclopropane ring of a group II mGluRs antagonist, 1 (LY341495), using a previously reported stereoselective cyclopropanation reaction. The fluorinated compound (+)-16a exhibited almost the same affinity (IC(50)=3.49 nM) for mGluR2 as 1 but had a superior pharmacokinetic profile. Furthermore, a marked elevation of the plasma levels of (+)-16a was observed following the administration of a prodrug, (+)-17.
MeSH terms
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Animals
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Crystallography, X-Ray
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Liver / drug effects
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Liver / metabolism
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Male
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Models, Molecular
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Molecular Structure
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Prodrugs / chemical synthesis
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Prodrugs / chemistry
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Prodrugs / pharmacology
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Protein Binding
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Rats
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Receptors, Metabotropic Glutamate / antagonists & inhibitors*
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Receptors, Metabotropic Glutamate / metabolism
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Structure-Activity Relationship
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Xanthenes / chemical synthesis*
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Xanthenes / chemistry
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Xanthenes / pharmacology*
Substances
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2-(1-amino-1-carboxy-2-(9H-xanthen-9-yl)-ethyl)-1-fluorocyclopropanecarboxylic acid, 6-heptyl ester
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2-(1-amino-1-carboxy-2-(9H-xanthen-9-yl)ethyl)-1-fluorocyclopropanecarboxylic acid
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Prodrugs
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Receptors, Metabotropic Glutamate
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Xanthenes
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metabotropic glutamate receptor 2