O2-Acetoxymethyl-protected diazeniumdiolate-based NSAIDs (NONO-NSAIDs):: Synthesis, nitric oxide release, and biological evaluation studies
O2-Acetoxymethyl-protected diazeniumdiolate-based NSAIDs (NONO-NSAIDs):: Synthesis, nitric oxide release, and biological evaluation studies
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DOI：
10.1016/j.bmc.2007.05.009
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发表时间：
2007-07-15
影响因子：
3.5
通讯作者：
Knaus, Edward E.
中科院分区：
文献类型：
--
作者：
Velazquez, Carlos A.;Rao, P. N. Praveen;Knaus, Edward E.
通过将阿司匹林、布洛芬或吲哚美辛的羧酸基团与o -2-乙酰氧基甲基1-[N-（2-羟乙基）-N-甲基胺]二氮苯二酸酯酯化，合成了一类新的o -2-乙酰氧基甲基保护的非甾体抗炎前体药（NONO-NSAIDs）。由此产生的一氧化氮(NO) -N-center点)释放高活性化合物(7 - 9)没有表现出体外对COX-1环氧合酶(COX)的抑制活性,COX - 2同功酶(IC50S > 100μM),相比之下,高活性化合物7和8显著降低carrageenan-induced老鼠爪子水肿表现增强体内抗炎活动(ID50 = 552和174亩摩尔/公斤)相对于父母的非甾体抗炎药阿司匹林(ID50 = 714亩摩尔/公斤)和布洛芬(ID50 = 326亩摩尔/公斤)。猪肝酯酶介导的前药7-9 （2 mol (NO)-N-center dot/mol）释放速率（0.6-6.5 min）明显高于未加酶催化的前药（40-48 h约1 mol (NO)-N-center dot/mol）。这些孵育研究表明(NO)- n -中心点和母体NSAID在体内被酯酶激活（水解）后都会释放。在体内溃疡指数（UI）测定中获得的数据显示，在等摩尔剂量下，nono -阿司匹林（UI = 0.8）、nono -吲哚美辛（UI = 1.3），特别是nono -布洛芬（UI = 0）与母体药物阿司匹林（UI = 57）、布洛芬（UI = 46）或吲哚美辛（UI = 34）相比，溃疡致生性显著降低。从nono -阿司匹林(7)前药中释放阿司匹林和(NO)- n -中心点对预防血栓形成和不良心血管事件（如中风和心肌梗死）具有潜在的有益特性。Elsevier Ltd.出版。
A novel group of O-2-acetoxymethyl-protected diazeniumdiolate-based non-steroidal anti-inflammatory prodrugs (NONO-NSAIDs) were synthesized by esterifying the carboxylate group of aspirin, ibuprofen, or indomethacin with O-2-acetoxymethyl 1-[N-(2-hydroxyethyl)-N-methylamino]diazeniumdiolate. The resulting nitric oxide ((NO)-N-center dot)-releasing prodrugs (7-9) did not exhibit in vitro cyclooxygenase (COX) inhibitory activity against the COX-1 and COX-2 isozymes (IC50S > 100 mu M), In contrast, prodrugs 7 and 8 significantly decreased carrageenan-induced rat paw edema showing enhanced in vivo anti-inflammatory activities (ID50's = 552 and 174 mu mol/kg, respectively) relative to those of the parent NSAIDs aspirin (ID50 = 714 mu mol/kg) and ibuprofen (ID50 = 326 mu mol/kg). The rate of porcine liver esterase-mediated (NO)-N-center dot release from prodrugs 7-9 (2 mol of (NO)-N-center dot/mol of test compound in 0.6-6.5 min) was substantially higher compared to that observed without enzymatic catalysis (about 1 mol of (NO)-N-center dot/mol of test compound in 40-48 h). These incubation studies suggest that both (NO)-N-center dot and the parent NSAID would be released upon in vivo activation (hydrolysis) by esterases. Data acquired in an in vivo ulcer index (UI) assay showed that NONO-aspirin (UI = 0.8), NONO-indomethacin (UI = 1.3), and particularly NONO-ibuprofen (UI = 0) were significantly less ulcerogenic compared to the parent drugs aspirin (UI = 57), ibuprofen (UI = 46) or indomethacin (UI = 34) at equimolar doses. The release of aspirin and (NO)-N-center dot from the NONO-aspirin (7) prodrug constitutes a potentially beneficial property for the prophylactic prevention of thrombus formation and adverse cardiovascular events such as stroke and myocardial infarction. Published by Elsevier Ltd.