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有机化学 ›› 2008, Vol. 28 ›› Issue (12): 2142-2148. 上一篇    下一篇

研究论文

4-[4-(2,3,4-三甲氧基苄基)哌嗪-1-基甲基]苯甲酰胍类化合物的合成 及其Na＋/H＋交换器1抑制活性

姜向敏a; 杜 萍a; 徐云根*,a ; 张 迪a ; 龚国清b ; 尤启冬a   

  1. (a中国药科大学药物化学教研室 南京 210009)
    (b中国药科大学药理学教研室 南京 210009)
  • 收稿日期:2008-07-15 修回日期:2008-09-27 发布日期:2008-12-28
  • 通讯作者: 徐云根

Synthesis and Na＋/H＋ Exchanger 1 Inhibitory Activity of 4-[4-(2,3,4- Trimethoxy-benzyl)-piperazin-1-ylmethyl]benzoylguanidine Derivatives

JIANG, Xiang-Min a; DU, Pinga; XU, Yun-Gen*,a ; ZHANG, Dia;
GONG, Guo-Qingb; YOU, Qi-Donga
  

  1. (a Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009)
    (b Department of Pharmacology, China Pharmaceutical University, Nanjing 210009)
  • Received:2008-07-15 Revised:2008-09-27 Published:2008-12-28
  • Contact: XU, Yun-Gen

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为了寻找对心肌缺血再灌注损伤具有保护作用的药物, 以苯甲酰胍为母核, 在其苯环的4位引入4-(2,3,4-三甲氧基苄基)哌嗪-1-甲基, 3位引入不同的取代苯甲酰胺基, 设计并合成了12个未见文献报道的目标化合物. 其结构经MS, IR, 1H NMR和元素分析确证. 体外血小板肿胀模型(PSA)试验结果表明, 大部分目标化合物显示出较好的Na＋/H＋交换器1 (NHE1)抑制作用, 其中化合物7g和7l抑制NHE1的IC50值分别为3.72和3.53 nmol•L－1, 是卡立泊来德(IC50＝12.1 nmol•L－1)的3.2和3.4倍.

关键词: 苯甲酰胍衍生物, 缺血再灌注损伤, Na＋/H＋交换器1抑制活性, 合成

In order to search for drugs with protective effect against myocardial ischemic-reperfusion injury, a novel series of 4-[4-(2,3,4-trimethoxy-benzyl)-piperazin-1-ylmethyl]benzoylguanidine derivatives were designed and synthesized from methyl 4-methyl-3-nitrobenzoate via bromination, substitution, reduction, acylation, hydrolyzation and condensation, and their structures were characterized by MS, IR, 1H NMR techniques and elemental analysis. Na＋/H＋exchanger 1 (NHE1) inhibitory activity of twelve compounds 7 was evaluated in a rat platelet swelling assay, and the results show that most of the tested compounds possess NHE1 inhibitory effects, among which, the IC50 values of compounds 7g and 7l are 3.72 and 3.53 nmol•L－1 respectively, making them 3.2 and 3.4 times respectively more potent than cariporide (IC50＝12.1 nmol• L－1).

Key words: ischemia-reperfusion injury, benzoylguanidine derivative, Na＋/H＋exchanger 1 inhibitory activity, synthesis