gpi-5693 and Infarction--Middle-Cerebral-Artery

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.

Topics: Analgesics; Animals; Brain Ischemia; Cerebral Cortex; Constriction, Pathologic; Crystallography, X-Ray; Glutamate Carboxypeptidase II; Glutarates; Infarction, Middle Cerebral Artery; L-Lactate Dehydrogenase; Molecular Structure; Neuroprotective Agents; Pain; Peripheral Nervous System Diseases; Phosphinic Acids; Rats; Stereoisomerism; Structure-Activity Relationship; Sulfhydryl Compounds; Tissue Culture Techniques