Enantiospecificity of glutamate carboxypeptidase II inhibition

J Med Chem. 2005 Apr 7;48(7):2319-24. doi: 10.1021/jm049258g.

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

  • Analgesics / chemical synthesis
  • Analgesics / chemistry
  • Analgesics / pharmacology
  • Animals
  • Brain Ischemia / metabolism
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Constriction, Pathologic / complications
  • Crystallography, X-Ray
  • Glutamate Carboxypeptidase II / antagonists & inhibitors*
  • Glutamate Carboxypeptidase II / chemistry
  • Glutarates / chemical synthesis*
  • Glutarates / chemistry
  • Glutarates / pharmacology
  • Infarction, Middle Cerebral Artery / drug therapy
  • L-Lactate Dehydrogenase / metabolism
  • Molecular Structure
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology
  • Pain / drug therapy
  • Pain / etiology
  • Peripheral Nervous System Diseases / drug therapy
  • Peripheral Nervous System Diseases / etiology
  • Phosphinic Acids / chemical synthesis*
  • Phosphinic Acids / chemistry
  • Phosphinic Acids / pharmacology
  • Rats
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfhydryl Compounds / chemical synthesis*
  • Sulfhydryl Compounds / chemistry
  • Sulfhydryl Compounds / pharmacology
  • Tissue Culture Techniques

Substances

  • 2-(3-mercaptopropyl)pentanedioic acid
  • 2-(hydroxypentafluorophenylmethylphosphinoylmethyl)pentanedioic acid
  • Analgesics
  • Glutarates
  • Neuroprotective Agents
  • Phosphinic Acids
  • Sulfhydryl Compounds
  • L-Lactate Dehydrogenase
  • Glutamate Carboxypeptidase II