Enantiospecificity of glutamate carboxypeptidase II inhibition

Takashi Tsukamoto, Pavel Majer, Dilrukshi Vitharana, Chiyou Ni, Bunda Hin, Xi Chun M Lu, Ajit G. Thomas, Krystyna M. Wozniak, David C. Calvin, Ying Wu, Barbara Slusher, David Scarpetti, George W. Bonneville

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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-(hydroxyphosphinoyl-methyl) 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.

Original languageEnglish (US)
Pages (from-to)2319-2324
Number of pages6
JournalJournal of Medicinal Chemistry
Volume48
Issue number7
DOIs
StatePublished - Apr 7 2005
Externally publishedYes

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ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Tsukamoto, T., Majer, P., Vitharana, D., Ni, C., Hin, B., Lu, X. C. M., Thomas, A. G., Wozniak, K. M., Calvin, D. C., Wu, Y., Slusher, B., Scarpetti, D., & Bonneville, G. W. (2005). Enantiospecificity of glutamate carboxypeptidase II inhibition. Journal of Medicinal Chemistry, 48(7), 2319-2324. https://doi.org/10.1021/jm049258g