非甾体抗炎药ML4000的合成及生物活性研究  

Synthesis and biological activity of the non-steroidal anti-inflammatory drug ML4000

作　　者：郑志超[1] 梅林雨[2] 高晶[2] 罗振福[2] 孙有光[1] 

机构地区：[1]天津理工大学化学化工学院,天津300191 [2]天津药物研究院,天津300193

出　　处：《中国新药杂志》2011年第2期173-176,190,共5页Chinese Journal of New Drugs

基　　金：天津市2008年度科技计划项目(08ZCKFSH00700)

摘　　要：目的:合成非甾体抗炎药ML4000并研究其生物活性。方法:ML4000以环氧合酶(COX)和5-脂氧合酶(5-LOX)双重抑制剂利克飞龙(licofelone,ML3000)为先导化合物,结构上链接了1个一氧化氮(NO)供体;通过灌胃给药,观察ML4000在动物体内的初步代谢、抗炎活性、胃肠道作用以及血清和胃黏膜NO水平。结果:ML4000经IR,MS,1H NMR,13C NMR以及元素分析等确证结构;大鼠灌胃ML4000(10 mg.kg-1)0.25 h后,即可测到ML4000代谢为ML3000;ML4000抗炎活性与ML3000相当;连续14 d灌胃(60mg.kg-1,qd),未见大鼠胃肠道出血;灌胃给药(60 mg.kg-1)1 h后大鼠血清和胃黏膜NO量显著增加。结论:合成的ML4000具有较强的抗炎作用,胃肠道耐受性好,并能够释放出NO。Objective： To synthesize the non-steroidal anti-inflammatory drug（NSAID） ML4000 and evaluate its biological activity.Methods： Licofelone,a balanced inhibitor of cyclooxygenase（COX） and 5-lipoxygenase（5-LOX）,covalently bound to one NO-donating moiety to produce ML4000.The metabolism of ML4000 in vivo,the anti-inflammatory activity,and the effects on gastrointestinal tract（GI）,and NO level in the serum and gastric mucosa were determineed.Results： ML4000 structure was confirmed by IR,MS,1H NMR,13C NMR and elemental analysis.In rats,the metabolite ML3000 was detected 0.25h after oral administration of 10mg·kg-1 ML4000.ML4000 was equipotent to ML3000 in anti-inflammatory activity.No gastrointestinal bleeding and ulcers were found in rats after treatment with 60mg·kg-1,qd ML4000 for consecutive 14 days.Significant increase of NO in the serum and gastric mucosa was found 1 h after oral ML4000 60mg·kg-1.Conclusion： The synthesized ML4000 has satisfactory anti-inflammatory activity,gastrointestinal tolerability and significant NO releasing activity.

关 键 词：非甾体抗炎药 一氧化氮供体 利克飞龙 合成 生物活性 

分 类 号：R971.1[医药卫生—药品] R575.6[医药卫生—药学]