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

J Med Chem. 2014 Jan 9;57(1):243-7. doi: 10.1021/jm401703a. Epub 2013 Dec 27.

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 IC50 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Glutamate Carboxypeptidase II / antagonists & inhibitors*
  • Lactones / chemical synthesis*
  • Lactones / pharmacology
  • Lactones / therapeutic use
  • Microsomes, Liver / metabolism
  • Neuralgia / drug therapy
  • Prodrugs / chemical synthesis*
  • Rats

Substances

  • Enzyme Inhibitors
  • Lactones
  • Prodrugs
  • Glutamate Carboxypeptidase II