N-苯基-1H-吡咯取代的双苯并咪唑类衍生物的合成及其AT_1受体拮抗活性研究

Synthesis and Biological Activity Evaluation of AT_1 Angiotensin Ⅱ Receptor Antagonists of Dibenzimidazoles with N-Phenyl-1 H-Pyrrole

目的:寻找活性强、作用时间长的新型非肽类AT1受体拮抗剂。方法:以替米沙坦(telmisartan)为原型物,根据分子-受体结合模型的研究结果对其进行结构优化:运用生物电子等排原理,用苯基吡咯代替联苯结构,在此基础上将羧基与四氮唑两种酸性基团的作用进行比较;改变苯并咪唑2-位亲脂性侧链的长度;在苯基吡咯5-位引入吸电子取代基,共设计了3类结构新颖的N-苯基-1H-吡咯取代的双苯并咪唑类衍生物,并完成了12个目标化合物的合成。通过测定目标化合物抑制AⅡ诱导的兔胸主动脉环收缩的能力评价了其对AT1受体的拮抗活性。结果:目标化合物均未见文献报道,其结构经MS、IR1、H NMR和元素分析确证,其中化合物Ⅰd的AT1受体拮抗活性大于先导物替米沙坦。结论:Ⅰd具有进一步的研究价值。

AIM:To search for the novel angiotensin Ⅱ(A Ⅱ)AT_(1) receptor antagonists with high potency and long duration.METHODS:By use of telmisartan, a potent non-peptide AT_(1) receptor antagonist,as a lead compound and the optimized results of ligand-receptor complex modelling,N-phenylpyrrole with an acid group spacer was compared to the biphenyl bearing an acid group spacer which might provide optimal stereo electronic characteristics.Therefore,12 dibenzimidazoles bearing N-phenyl-1H-pyrrole moiety were designed and synthesized by the replacement of the biphenyl tetrazole with N-phenyl-1H-pyrrole-2-tetrazole and replacement of the tetrazole group with a carboxylic acid moiety,meanwhile introducing different substitutes at the positions-2 of the dibenzimidazole ring and the pyrrole ring.On the other hand,their biological activities were evaluated for antagonism of AⅡ-induced contractions in the rabbit thoracic rings.RESULTS:None of the target compounds has been reported and their structures were identified by IR,(()^(1)H NMR),MS spectra and elemental analysis. And the biological activities were evaluated for antagonism of A Ⅱ-induced contractions in the rabbit thoracic aortic rings.The results of preliminary pharmacological tests showed that compound Ⅰd was more potent than telmisartan.CONCLUSION:Ⅰd is worthy to be intensively investigated further.