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Enantiospecificity of glutamate carboxypeptidase II inhibition.

Research paper by Takashi T Tsukamoto, Pavel P Majer, Dilrukshi D Vitharana, Chiyou C Ni, Bunda B Hin, Xi-Chun M XC Lu, Ajit G AG Thomas, Krystyna M KM Wozniak, David C DC Calvin, Ying Y Wu, Barbara S BS Slusher, David D Scarpetti, George W GW Bonneville

Indexed on: 02 Apr '05Published on: 02 Apr '05Published in: Journal of Medicinal Chemistry



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.

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