Design, synthesis, and pharmacological evaluation of glutamate carboxypeptidase II (GCPII) inhibitors based on thioalkylbenzoic acid scaffolds

Doris Stoermer, Dilrukshi Vitharana, Niyada Hin, Greg Delahanty, Bridget Duvall, Dana V. Ferraris, Brian S. Grella, Randall Hoover, Camilo Rojas, Megan K. Shanholtz, Kyle P. Smith, Marigo Stathis, Ying Wu, Krystyna M. Wozniak, Barbara S. Slusher, Takashi Tsukamoto

Research output: Contribution to journalArticlepeer-review

Abstract

A series of thiol-based glutamate carboxypeptidase II (GCPII) inhibitors have been synthesized with either a 3-(mercaptomethyl)benzoic acid or 2-(2-mercaptoethyl)benzoic acid scaffold. Potent inhibitors were identified from each of the two scaffolds with IC 50 values in the single-digit nanomolar range, including 2-(3-carboxybenzyloxy)-5-(mercaptomethyl)benzoic acid 27c and 3-(2-mercaptoethyl)biphenyl-2,3'-dicarboxylicacid 35c. Compound 35c was found to be metabolically stable and selective over a number of targets related to glutamate-mediated neurotransmission. Furthermore, compound 35c was found to be orally available in rats and exhibited efficacy in an animal model of neuropathic pain following oral administration.

Original languageEnglish (US)
Pages (from-to)5922-5932
Number of pages11
JournalJournal of medicinal chemistry
Volume55
Issue number12
DOIs
StatePublished - Jun 28 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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