δ‑Thiolactones as Prodrugs of Thiol-Based Glutamate Carboxypeptidase II (GCPII) Inhibitors

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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2014-01, Vol.57 (1), p.243-247
Main Authors: Ferraris, Dana V, Majer, Pavel, Ni, Chiyou, Slusher, C. Ethan, Rais, Rana, Wu, Ying, Wozniak, Krystyna M, Alt, Jesse, Rojas, Camilo, Slusher, Barbara S, Tsukamoto, Takashi
Format: Article
Language:English
Subjects:
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
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm401703a