δ-Thiolactones as Prodrugs of Thiol-Based Glutamate Carboxypeptidase II (GCPII) Inhibitors
δ-Thiolactones as Prodrugs of Thiol-Based Glutamate Carboxypeptidase II (GCPII) Inhibitors
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DOI：
10.1021/jm401703a
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发表时间：
2014-01-09
影响因子：
7.3
通讯作者：
Tsukamoto, Takashi
中科院分区：
文献类型：
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作者：
Ferraris, Dana V.;Majer, Pavel;Tsukamoto, Takashi
将衍生自硫醇基谷氨酸羧肽酶II（GCPII）抑制剂的δ-硫代内酯作为前药进行评价。在大鼠肝微粒体中，2-（3-巯基丙基）戊二酸（2-MPPA，1）逐渐由3-（2-氧代四氢噻喃-3-基）丙酸（5）产生，3-（2-氧代四氢噻喃-3-基）丙酸是一种硫代内酯，由1衍生而来。在大鼠中口服给药5后，在血浆中检测到浓度远高于其对GCPII的IC 50的化合物1。与口服血浆药代动力学一致，硫内酯5在口服给药后的神经性疼痛大鼠模型中表现出疗效。
delta-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.