gpi-5693 and Brain-Ischemia

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

A series of hydroxamic acids has been prepared as potential inhibitors of glutamate carboxypeptidase II (GCP II). Compounds based on a P1' residue (primed-side inhibitors) were more potent than those based on a P1 group (unprimed-side inhibitors). Inhibitory potency of the primed-side GCP II inhibitors was found to be dependent on the number of methylene units between the hydroxamate group and pentanedioic acid. Succinyl hydroxamic acid derivative, 2-(hydroxycarbamoylmethyl)pentanedioic acid, is the most potent GCP II inhibitor with an IC(50) value of 220nM. The comparison of the results to those of other classes of GCP II inhibitors as well as hydroxamate-based MMP inhibitors provides further insight into the structure-activity relationships of GCP II inhibition.

Topics: Aeromonas; Brain Ischemia; Crystallography, X-Ray; Dose-Response Relationship, Drug; Glutamate Carboxypeptidase II; Hydroxamic Acids; Indicators and Reagents; Protease Inhibitors; Stereoisomerism; Structure-Activity Relationship