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

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：January 9, 2014
• 年：2014
• 卷：57
• 期：1
• 页码：243-247
• 全文大小：248K
• ISSN：1520-4804

文摘

未-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.