Abstract
Two representative glutamate carboxypeptidase II (GCP II) inhibitors, 2-(hydroxypentafluorophenylmethyl-phosphinoylmethyl)pentanedioic acid 2 and 2-(3-mercaptopropyl)pentanedioic acid 3, were synthesized in high optical purities (>97%ee). The two enantiomers of 2 were prepared from previously reported chiral intermediates, (R)- and (S)-2-(hydroxyphosphinoylmethyl)pentanedioic acid benzyl esters 8. The synthesis of (R)- and (S)-3 involves the hydrolysis of (R)- and (S)-3-(2-oxo-tetrahydro-thiopyran-3-yl)propionic acids, (R)- and (S)-11, the corresponding optically pure thiolactones delivered by chiral chromatographic separation of the racemic 11. GCP II inhibitory assay revealed that (S)-2 is 40-fold more potent than (R)-2. In contrast, both enantiomers of 3 inhibited GCP II with nearly equal potency. The efficacy observed in subsequent animal studies with these enantiomers correlated well with the inhibitory potency in a GCP II assay.
MeSH terms
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Analgesics / chemical synthesis
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Analgesics / chemistry
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Analgesics / pharmacology
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Animals
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Brain Ischemia / metabolism
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Cerebral Cortex / drug effects
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Cerebral Cortex / metabolism
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Constriction, Pathologic / complications
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Crystallography, X-Ray
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Glutamate Carboxypeptidase II / antagonists & inhibitors*
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Glutamate Carboxypeptidase II / chemistry
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Glutarates / chemical synthesis*
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Glutarates / chemistry
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Glutarates / pharmacology
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Infarction, Middle Cerebral Artery / drug therapy
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L-Lactate Dehydrogenase / metabolism
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Molecular Structure
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Neuroprotective Agents / chemical synthesis
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / pharmacology
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Pain / drug therapy
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Pain / etiology
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Peripheral Nervous System Diseases / drug therapy
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Peripheral Nervous System Diseases / etiology
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Phosphinic Acids / chemical synthesis*
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Phosphinic Acids / chemistry
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Phosphinic Acids / pharmacology
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Rats
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Stereoisomerism
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Structure-Activity Relationship
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Sulfhydryl Compounds / chemical synthesis*
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Sulfhydryl Compounds / chemistry
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Sulfhydryl Compounds / pharmacology
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Tissue Culture Techniques
Substances
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2-(3-mercaptopropyl)pentanedioic acid
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2-(hydroxypentafluorophenylmethylphosphinoylmethyl)pentanedioic acid
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Analgesics
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Glutarates
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Neuroprotective Agents
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Phosphinic Acids
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Sulfhydryl Compounds
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L-Lactate Dehydrogenase
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Glutamate Carboxypeptidase II