Synthesis and biological evaluation of hydroxamate-based inhibitors of glutamate carboxypeptidase II

Doris Stoermer, Qun Liu, Monicia R. Hall, Juliet M. Flanary, Ajit G. Thomas, Camilo Rojas, Barbara S. Slusher, Takashi Tsukamoto

Research output: Contribution to journalArticle

Abstract

A series of hydroxamic acids has been prepared as potential inhibitors of glutamate carboxypeptidase II (GCP II). Compounds based on a P1′ residue (primed-side inhibitors) were more potent than those based on a P1 group (unprimed-side inhibitors). Inhibitory potency of the primed-side GCP II inhibitors was found to be dependent on the number of methylene units between the hydroxamate group and pentanedioic acid. Succinyl hydroxamic acid derivative, 2-(hydroxycarbamoylmethyl)pentanedioic acid, is the most potent GCP II inhibitor with an IC50 value of 220 nM. The comparison of the results to those of other classes of GCP II inhibitors as well as hydroxamate-based MMP inhibitors provides further insight into the structure-activity relationships of GCP II inhibition.

Original languageEnglish (US)
Pages (from-to)2097-2100
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume13
Issue number13
DOIs
StatePublished - Jul 7 2003
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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