title: δ-Thiolactones as prodrugs of thiol-based glutamate carboxypeptidase II (GCPII) inhibitors.
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.
authors.affiliation: Brain Science Institute and ‡Department of Neurology, Johns Hopkins University , Baltimore, Maryland 21205, United States.
authors.forename: Dana V
authors.initials: DV
authors.lastname: Ferraris
authors.forename: Pavel
authors.initials: P
authors.lastname: Majer
authors.forename: Chiyou
authors.initials: C
authors.lastname: Ni
authors.forename: C Ethan
authors.initials: CE
authors.lastname: Slusher
authors.forename: Rana
authors.initials: R
authors.lastname: Rais
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.forename: Krystyna M
authors.initials: KM
authors.lastname: Wozniak
authors.forename: Jesse
authors.initials: J
authors.lastname: Alt
authors.forename: Camilo
authors.initials: C
authors.lastname: Rojas
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Slusher
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsukamoto
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors*; D007783:Lactones / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D008862:Microsomes, Liver / Q000378:metabolism; D009437:Neuralgia / Q000188:drug therapy; D011355:Prodrugs / Q000138:chemical synthesis*; D051381:Rats
chemical_list: D004791:Enzyme Inhibitors; D007783:Lactones; D011355:Prodrugs; D043425:Glutamate Carboxypeptidase II