Nitrosothiol esters of diclofenac: Synthesis and pharmacological characterization as gastrointestinal-sparing prodrugs
Nitrosothiol esters of diclofenac: Synthesis and pharmacological characterization as gastrointestinal-sparing prodrugs
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DOI：
10.1021/jm000178w
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发表时间：
2000-10-19
影响因子：
7.3
通讯作者：
Tam, SW
中科院分区：
文献类型：
--
作者：
Bandarage, UK;Chen, LQ;Tam, SW
尽管双氯芬酸被广泛使用，但其具有非甾体类抗炎药（NSAID）常见的胃肠道负担，可通过同时给予胃肠道细胞保护剂（如一氧化氮（NO））来减轻。一系列新的双氯芬酸酯含有亚硝基硫醇（-S-NO）部分作为一个NO供体功能已被合成和评价在体内的生物利用度，药理活性，和胃刺激。所有的S-NO-双氯芬酸衍生物作为口服生物可利用的前药，在小鼠口服给药后15分钟内在血浆中产生显著水平的双氯芬酸。在等摩尔口服剂量下，S-NO-双氯芬酸衍生物（20 a-21 b）在角叉菜胶诱导的爪水肿试验和小鼠苯基苯醌诱导的扭体试验中分别显示出与双氯芬酸相当的大鼠镇痛和镇痛活性。所有测试的S-NO-双氯芬酸衍生物（20 a-21 b）都是胃保护性的，因为与由高等摩尔剂量的双氯芬酸在大鼠中引起的胃损伤相比，它们引起的胃损伤显著较少。双氯芬酸的亚硝基硫醇酯是一类新型的NO供体化合物，具有作为非甾体类抗炎药的治疗潜力，并具有增强的胃安全性。
Despite its widespread use, diclofenac has gastrointestinal liabilities common to nonsteroidal antiinflammatory drugs (NSAIDs) that might be reduced by concomitant administration of a gastrointestinal cytoprotectant such as nitric oxide (NO). A series of novel diclofenac esters containing a nitrosothiol (-S-NO) moiety as a NO donor functionality has been synthesized and evaluated in vivo for bioavailability, pharmacological activity, and gastric irritation. All S-NO-diclofenac derivatives acted as orally bioavailable prodrugs, producing significant levels of diclofenac in plasma within 15 min after oral administration to mice. At equimolar oral doses, S-NO-diclofenac derivatives (20a-21b) displayed rat antiinflammatory and analgesic activities comparable to those of diclofenac in the carrageenan-induced paw edema test and the mouse phenylbenzoquinone-induced writhing test, respectively. All tested S-NO-diclofenac derivatives (20a-21b) were gastric-sparing in that they elicited markedly fewer stomach lesions as compared to the stomach lesions caused by a high equimolar dose of diclofenac in the rat. Nitrosothiol esters of diclofenac comprise a novel class of NO-donating compounds having therapeutic potential as nonsteroidal antiinflammatory agents with an enhanced gastric safety profile.