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取代苯甲酰胍与曲美他嗪偶联物的合成及对Na+/H+交换器-1的抑制活性

Synthesis and Na+/H+ exchanger 1 inhibitory activity of substituted benzoylguanidine-trimetazidine conjugates

  • 摘要: 为了寻找对心肌缺血再灌注损伤具有保护作用的药物,并探索不同基团修饰对苯甲酰胍与曲美他嗪偶联物活性的影响,将苯甲酰胍的4位通过亚甲基与曲美他嗪进行偶联,并在苯环的3位引入不同的取代苯甲酰胺基,设计合成了12个未见文献报道的目标化合物。其结构经过IR,1H NMR和MS确证。体外血小板肿胀模型(PSA)试验结果表明,化合物 9b和9c 抑制Na+/H+交换器-1(NHE1)的IC50分别为2.55和2.80 nmol/L,其活性是卡立泊来德(IC50=12.1 nmol/L)的4.7和4.3倍。

     

    Abstract: In order to search for drugs with protective effects against myocardial ischemic-reperfusion injury,and study the structure-activity relationship of benzoylguanidine derivatives,a novel series of 4-4-(2,3,4-trimethoxybenzyl)piperazin-1-yl-methyl and 4-1-4-(2,3,4-trimethoxy -benzyl)piperazin-1-yl-ethyl benzoylguanidine derivatives were designed and synthesized,and their structures were characterized by MS,IR,1H NMR.Na+/H+ exchanger 1 (NHE1) inhibitory activity of twelve target compounds was evaluated in a rat platelet swelling assay.Among all the tested compounds,the IC50 values of compounds 9b and 9c were 4.7 and 4.3 times more potent than cariporide(IC50=12.1 nmol/L),respectively.

     

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