具有NO供体的N-苯基-1H-吡咯羧酸结构化合物的设计,合成及抗高血压活性研究  

Design,Synthesis and Evaluation of Antihypertensive Activity of Novel Nitric Oxide-Releasing N-Phenyl-1H-Pyrrole Derivatives

作　　者：张艳春[1] 姚和权[2] 周金培[2] 吴晓明[2] 徐进宜[2] 

机构地区：[1]安徽中医药大学药学院,安徽省中医药科学院药物化学研究所,合肥230038 [2]中国药科大学药物化学教研室,南京210009

出　　处：《中国药学杂志》2015年第24期2160-2165,共6页Chinese Pharmaceutical Journal

摘　　要：目的合成并研究具有NO供体N-苯基-1H吡咯羧酸结构化合物的抗高血压活性。方法通过将AT1受体拮抗剂厄贝沙坦的关键结构与苯联吡咯连接,设计并合成了化合物4。同时以化合物4与NO供体结合,合成10个新化合物（IN 1~IN10）。采用体外NO释放量,以及对血管紧张素Ⅱ（AngⅡ）诱导的大鼠胸主动脉环的舒张作用的实验测定目标化合物活性。结果设计的目标化合物均表现出与氯沙坦相似的作用模式,且呈一定的剂量相关性。同时NO释放量与血管舒张活性正相关。其中化合物IN9血管紧张素Ⅱ（AngⅡ）诱导的大鼠胸主动脉环的舒张作用的活性明显优于阳性药氯沙坦。结论化合物IN9有望作为先导化合物,开发其心血管系统保护活性。OBJECTIVE To synthesize and evaluate of antihypertensive activity of novel nitric oxide-releasing N-phenyl-1H-pyrrole derivatives. METHODS By connecting key structural elements present in an AT1 receptor antagonist irbesartan with N-phenyl-1H-pyrrole carboxylic acid,a novel AT1 antagonist compound 4 was designed and synthesized,and a series of novel NO-donating derivatives（ IN 1- 10） were obtained by introducing NO donor. The amount of NO production in vitro of the target compounds were determined by Greiss assay. And the antagonism of Ang II induced vascular contraction assay was used to value the inhibition rate. RESULTS The antagonism of Ang Ⅱ induced vascular contraction assay indicated that the novel compound exhibited similar activity as losartan. The NO derivative,compound IN9,found to release the maximum amount of NO during the NO releasing assay,was more potent than the lead compound 4 and positive control losartan. CONCLUSION These date indicate that the improved activities of these hybrid molecules contribute to the NO donor and the protection ability of NO donor make them promising candidates as antihypertensive agents.

关 键 词：N-苯基-1H-吡咯羧酸 NO供体 AT1受体拮抗剂 抗高血压 

分 类 号：R286.24[医药卫生—中药学]