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 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

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Glutamate Carboxypeptidase II
Sulfhydryl Compounds
Organophosphonates
Acids
Neuralgia
Inhibitory Concentration 50
Oral Administration
Zinc
Rats
Animals
Animal Models

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Synthesis and biological evaluation of thiol-based inhibitors of glutamate carboxypeptidase II : Discovery of an orally active GCP II inhibitor. / Majer, Pavel; Jackson, Paul F.; Delahanty, Greg; Grella, Brian S.; Ko, Yao Sen; Li, Weixing; Liu, Qun; Maclin, Keith M.; Poláková, Jana; Shaffer, Kathryn A.; Stoermer, Doris; Vitharana, Dilrukshi; Yanjun Wang, Eric; Zakrzewski, Anthony; Rojas, Camilo; Slusher, Barbara; Wozniak, Krystyna M.; Burak, Eric; Limsakun, Tharin; Tsukamoto, Takashi.

In: Journal of Medicinal Chemistry, Vol. 46, No. 10, 08.05.2003, p. 1989-1996.

Research output: Contribution to journalArticle

Majer, P, Jackson, PF, Delahanty, G, Grella, BS, Ko, YS, Li, W, Liu, Q, Maclin, KM, Poláková, J, Shaffer, KA, Stoermer, D, Vitharana, D, Yanjun Wang, E, Zakrzewski, A, Rojas, C, Slusher, B, Wozniak, KM, 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, vol. 46, no. 10, pp. 1989-1996. https://doi.org/10.1021/jm020515w
Majer, Pavel ; Jackson, Paul F. ; Delahanty, Greg ; Grella, Brian S. ; Ko, Yao Sen ; Li, Weixing ; Liu, Qun ; Maclin, Keith M. ; Poláková, Jana ; Shaffer, Kathryn A. ; Stoermer, Doris ; Vitharana, Dilrukshi ; Yanjun Wang, Eric ; Zakrzewski, Anthony ; Rojas, Camilo ; Slusher, Barbara ; Wozniak, Krystyna M. ; Burak, Eric ; Limsakun, Tharin ; Tsukamoto, Takashi. / Synthesis and biological evaluation of thiol-based inhibitors of glutamate carboxypeptidase II : Discovery of an orally active GCP II inhibitor. In: Journal of Medicinal Chemistry. 2003 ; Vol. 46, No. 10. pp. 1989-1996.
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