δ-thiolactones as prodrugs of thiol-based glutamate carboxypeptidase II (GCPII) inhibitors

Dana V. Ferraris, Pavel Majer, Chiyou Ni, C. Ethan Slusher, Rana Rais, Ying Wu, Krystyna M. Wozniak, Jesse Alt, Camilo Rojas, Barbara S. Slusher, Takashi Tsukamoto

Research output: Contribution to journalArticlepeer-review

Abstract

δ-Thiolactones derived from thiol-based glutamate carboxypeptidase II (GCPII) inhibitors were evaluated as prodrugs. In rat liver microsomes, 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA, 1) was gradually produced from 3-(2-oxotetrahydrothiopyran-3-yl)propionic acid (5), a thiolactone derived from 1. Compound 1 was detected in plasma at concentrations well above its IC 50 for GCPII following oral administration of 5 in rats. Consistent with the oral plasma pharmacokinetics, thiolactone 5 exhibited efficacy in a rat model of neuropathic pain following oral administration.

Original languageEnglish (US)
Pages (from-to)243-247
Number of pages5
JournalJournal of medicinal chemistry
Volume57
Issue number1
DOIs
StatePublished - Jan 9 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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