Document Report Card

ID: ALA1143563

Journal: J Med Chem

Title: Enantiospecificity of glutamate carboxypeptidase II inhibition.

Authors: Tsukamoto T, Majer P, Vitharana D, Ni C, Hin B, Lu XC, Thomas AG, Wozniak KM, Calvin DC, Wu Y, Slusher BS, Scarpetti D, Bonneville GW.

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.

CiteXplore: 15801825

DOI: 10.1021/jm049258g