Synthesis and biological evaluation of thiol-based inhibitors of glutamate carboxypeptidase II: Discovery of an orally active GCP II inhibitor

Pavel Majer, Paul F. Jackson, Greg Delahanty, Brian S. Grella, Yao Sen Ko, Weixing Li, Qun Liu, Keith M. Maclin, Jana Poláková, Kathryn A. Shaffer, Doris Stoermer, Dilrukshi Vitharana, Eric Yanjun Wang, Anthony Zakrzewski, Camilo Rojas, Barbara S. Slusher, Krystyna M. Wozniak, Eric Burak, Tharin Limsakun, Takashi Tsukamoto

Research output: Contribution to journalArticle

Abstract

A series of 2-(thioalkyl)pentanedioic acids were synthesized and evaluated as inhibitors of glutamate carboxypeptidase II (GCP II, EC 3.4.17.21). The inhibitory potency of these thiol-based compounds against GCP II was found to be dependent on the number of methylene units between the thiol group and pentanedioic acid. A comparison of the SAR of the thiol-based inhibitors to that of the phosphonate-based inhibitors provides insight into the role of each of the two zinc-binding groups in GCP II inhibition. The most potent thiol-based inhibitor, 2-(3-mercaptopropyl)pentanedioic acid (IC50 = 90 nM), was found to be orally bioavailable in rats and exhibited efficacy in an animal model of neuropathic pain following oral administration.

Original languageEnglish (US)
Pages (from-to)1989-1996
Number of pages8
JournalJournal of medicinal chemistry
Volume46
Issue number10
DOIs
StatePublished - May 8 2003
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Majer, P., Jackson, P. F., Delahanty, G., Grella, B. S., Ko, Y. S., Li, W., Liu, Q., Maclin, K. M., Poláková, J., Shaffer, K. A., Stoermer, D., Vitharana, D., Yanjun Wang, E., Zakrzewski, A., Rojas, C., Slusher, B. S., Wozniak, K. M., Burak, E., Limsakun, T., & Tsukamoto, T. (2003). Synthesis and biological evaluation of thiol-based inhibitors of glutamate carboxypeptidase II: Discovery of an orally active GCP II inhibitor. Journal of medicinal chemistry, 46(10), 1989-1996. https://doi.org/10.1021/jm020515w