4,5-二氢-1,2,4-三唑-5-酮类化合物的设计 合成及生物活性  

Design,synthesis and activity study of 4,5-dihydro-1,2,4-triazol-5-one derivatives

作　　者：徐进宜[1] 魏臻[1] 曾翼[1] 华维一[1] 吴晓明[1] 王秋娟[2] 张静[2] 

机构地区：[1]中国药科大学药物化学教研室,210009 [2]中国药科大学生理学教研室,210009

出　　处：《中国药物与临床》2005年第12期887-891,共5页Chinese Remedies & Clinics

基　　金：国家自然科学基金资助项目(30371688);教育部科技研究重点基金资助项目(03089)

摘　　要：目的设计合成新型的非肽类血管紧张素Ⅱ(AⅡ)AT1受体拮抗剂,评价其抑制AⅡ诱发的兔主动脉收缩反应的生物活性。方法在对已上市及正在临床研究阶段的AT1受体拮抗剂进行了结构参数和定量构效关系研究的基础上,以4,5-二氢-1,2,4-三唑-5-酮为核心,运用生物电子等排及结构拼合原理等药物设计方法,设计并合成了16个联苯羧基、联苯四氮唑、联苯磺酰胺基取代的三唑啉酮类衍生物,测定了它们对AⅡ引起的兔胸主动脉收缩幅度影响的IC50值。结果所有目标化合物均未见文献报道,本实验对其结构经过IR,1HNMR、MS和元素分析作出确证。通过测试目标化合物抑制AⅡ诱导的兔动脉环收缩的能力,评价了其AⅡ受体抗拮活性。结果表明,所合成的化合物均有不同程度的AT1受体拮抗活性,化合物10c,10d,12b和14d抑制兔主动脉环收缩能力IC50值大于阳性对照药伊贝沙坦(irbesartan),具有进一步的研究意义。结论所设计三唑啉酮类化合物大多具有较好的AT1受体拮抗活性,联苯侧链上酸性取代基的活性强弱为-CN4H>-COOH>-SO2NH2>-SO2NHR,这一结果为进一步研究提供了参考信息。Objective To design and synthesize the novel nonpeptide angiotensin Ⅱ （AⅡ）type 1 （AT1） receptor antagonists with high potency, and to assay their activities of inhibiting AⅡ-induced contraction in a rabbit＇s aortic ring preparation. Methods Based on the analysis of the quantitative structure-activity relationships（QSAR） of fortytwo new compounds reported in literatures as AT1 receptor antagonists,the modification of known AT1 receptor antagonists was studied by using the principle of bioisosterism and hybridization. With 4,5-dihydro-1,2,4-triazol-5- one as the eore,a series of triazolinone derivatives with substituting groups of biphenyl-2-tetrazole,biphenyl-2- earboxylie acid or biphenyl sulfonamide were designed and synthesized. The IC50 value of antagonistic activity of these compounds was assessed by the ability of inhibiting AⅡ induced contraction of rabbit＇s aortic ring. Results AⅡ target compounds were thus far unreported;this trial confirmed their structure by IR,^1HNMR,MS spectrum and elemental analysis.Preliminary pharmacological tests showed that all the target compounds exhibited certain antagonistic activity to AT1 receptor,among them,the IC50 value of the compounds 10e, 10d, 12b and 14d was comparable to that of the positive drug irbesartan （8.8×10^9 mol/L）,that of the most potent compound 10d was 1.0×10^-9 mol/L. Conclusion The author revealed the preliminary SAR of the bioisosteric replacement,which should supply valuable information,enabling us to design more potent AT1 antagonists.

关 键 词：血管紧张素Ⅱ1型受体拮抗剂 设计研究 4 5-二氢-1 2 4-三唑-5-酮 

分 类 号：R914[医药卫生—药物化学]