Novel nonsteroidal antiinflammatory drugs possessing a nitric oxide donor diazen-1-ium-1,2-diolate moiety:: Design, synthesis, biological evaluation, and nitric oxide release studies
Novel nonsteroidal antiinflammatory drugs possessing a nitric oxide donor diazen-1-ium-1,2-diolate moiety:: Design, synthesis, biological evaluation, and nitric oxide release studies
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DOI：
10.1021/jm050211k
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发表时间：
2005-06-16
影响因子：
7.3
通讯作者：
Knaus, EE
中科院分区：
文献类型：
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作者：
Velázquez, C;Rao, PNP;Knaus, EE
一组新型的混合一氧化氮释放非甾体抗炎药（(NO)-N-中心点-NSAID），具有 1-(吡咯烷-1-基)diazen-1-ium-1,2-二醇 (11, 13, 15) 或 1-(N,N-二甲氨基)diazen-1-ium-1,2-二醇 (12,14,16) 部分，通过合成了传统 NSAID 阿司匹林、布洛芬和吲哚美辛的羧酸基团的一碳亚甲基间隔基。尽管这些酯前药 (11-16) 均未表现出对 COX-1 和 COX-2 同工酶的体外环氧合酶 (COX) 抑制活性 (IC50 > 100 μM)，但所有化合物 (11-16) 均显着减少角叉菜胶诱导的大鼠爪水肿。在这方面，酯前药11-16显示出与母体药物阿司匹林、布洛芬和吲哚美辛同等的体内抗炎活性。所有化合物在与 pH 7.4 的磷酸盐缓冲溶液（14-16% 范围）或猪肝酯酶（16-19% 范围）孵育后均释放一氧化氮，但当这些酯前药与豚鼠血清一起孵育时，释放的 (NO)-N-中心点的百分比高达六倍（93%）。这些孵育研究表明，(NO)-N-中心点和母体 NSAID 均会在体内被非特异性血清酯酶裂解后释放。 (NO)-N-中心点阿司匹林前药同时释放阿司匹林和一氧化氮，构成了预防性预防血栓形成和不良心血管事件（例如中风和心肌梗塞）的潜在有益特性。体内溃疡指数 (UI) 测定中获得的数据表明，对于这组酯前药，特别是 (NO)-N-中心点状阿司匹林 (11, 12) 和 (NO)-N-中心点状布洛芬 (13, 14)，与母体药物阿司匹林（UI 57，250 mg/kg 口服剂量）、布洛芬（UI 45， 250 mg/kg 口服剂量），或等效剂量的吲哚美辛（UI = 34，30 mg/kg 口服剂量）。因此，这些具有diazen-1-ium-1,2-二醇部分的混合(NO)-N-中心点-NSAID前药代表了合理设计具有降低胃溃疡发生性的抗炎药物的新方法。
A novel group of hybrid nitric oxide-releasing nonsteroidal antiinflammatory drugs ((NO)-N-center dot-NSAIDs) possessing a 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (11, 13, 15) or 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate (12,14,16) moiety attached via a one-carbon methylene spacer to the carboxylic acid group of the traditional NSAIDs aspirin, ibuprofen, and indomethacin were synthesized. Although none of these ester prodrugs (11-16) exhibited in vitro cyclooxygenase (COX) inhibitory activity against the COX-1 and COX-2 isozymes (IC50 > 100 mu M), all of the compounds (11-16) significantly decreased carrageenan-induced rat paw edema. In this regard, the ester prodrugs 11-16 showed equipotent antiinflammatory activities in vivo to that of the parent drugs aspirin, ibuprofen, and indomethacin. All of the compounds released nitric oxide upon incubation with either phosphate buffer solution at pH 7.4 (14-16% range) or porcine liver esterase (16-19% range), but the percentage of (NO)-N-center dot released was up to sixfold higher (93%) when these ester prodrugs were incubated with guinea pig serum. These incubation studies suggest that both (NO)-N-center dot and the parent NSAID would be released upon in vivo cleavage by nonspecific serum esterases. The simultaneous release of aspirin and nitric oxide from the (NO)-N-center dot-aspirin prodrugs constitutes a potentially beneficial property for the prophylactic prevention of thrombus formation and adverse cardiovascular events such as stroke and myocardial infarction. The data acquired in an in vivo ulcer index (UI) assay showed that for this group of ester prodrugs, particularly the (NO)-N-center dot-aspirins (11, 12) and (NO)-N-center dot-ibuprofens (13, 14), no lesions were observed (UI 0) when compared to the parent drugs aspirin (UI 57, 250 mg/kg po dose), ibuprofen (UI 45, 250 mg/kg po dose), or indomethacin (UI = 34, 30 mg/kg po dose) at equivalent doses. Accordingly, these hybrid (NO)-N-center dot-NSAID prodrugs possessing a diazen-1-ium-1,2-diolate moiety, represent a new approach for the rational design of antiinflammatory drugs with reduced gastric ulcerogenicity.