非甾体抗炎药ml4000的合成及生物活性研究[1]

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1、ChineseJournalofNewDrugs2011,20(2)实验研究非甾体抗炎药ML4000的合成及生物活性研究12221郑志超,梅林雨,高
晶,罗振福,孙有光(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)

[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

2、的初步代谢、抗炎活性、胃肠道作用以及血清和胃黏膜113NO水平。结果:ML4000经IR,MS,HNMR,CNMR以及元素分析等确证结构;大鼠灌胃ML4000(10mg-1kg)0.25h后,即可测到ML4000代谢为ML3000;ML4000抗炎活性与ML3000相当;连续14d灌胃(60-1-1mgkg,qd),未见大鼠胃肠道出血;灌胃给药(60mgkg)1h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。[关键词]
非甾体抗炎药;一氧化氮供体;利克飞龙;合

3、成;生物活性+[中图分类号]R971.1;R575.6
[文献标志码]A
[文章编号]1003-3734(2011)02-0173-05Synthesisandbiologicalactivityofthenon
steroidalanti
inflammatorydrugML400012221ZHENGZhi
chao,MEILin
yu,GAOJing,LUOZhen
fu,SUNYou
guang(1CollegeofChemistryandChemicalEngineering,TianjinUniversityofTec

4、hnology,Tianjin300191,China;2TianjinInstituteofPharmaceuticalResearch,Tianjin300193,China)[Abstract]
Objective:Tosynthesizethenon
steroidalanti
inflammatorydrug(NSAID)ML4000andevalu
ateitsbiologicalactivity.Methods:Licofelone,abalancedinhibitorofcyclooxygenase(COX)and

5、5
lipoxygenase(5
LOX),covalentlyboundtooneNO
donatingmoietytoproduceML4000.ThemetabolismofML4000invivo,theanti
inflammatoryactivity,andtheeffectsongastrointestinaltract(GI),andNOlevelintheserumandgastric113mucosaweredetermineed.Results:ML4000structurewasconfirmedbyIR,

6、MS,HNMR,CNMRandelemen
-1talanalysis.Inrats,themetaboliteML3000wasdetected0.25hafteroraladministrationof10mgkgML4000.ML4000wasequipotenttoML3000inanti
inflammatoryactivity.Nogastrointestinalbleedingandulcerswerefound-1inratsaftertreatmentwith60mgkg,qdML4000forconsecu

7、tive14days.SignificantincreaseofNOintheser
-1umandgastricmucosawasfound1hafteroralML400060mgkg.Conclusion:ThesynthesizedML4000hassatisfactoryanti
inflammatoryactivity,gastrointestinaltolerabilityandsignificantNOreleasingactivity.[Keywords]
non
steroidalanti
inflammat

8、orydrugs(NSAIDs);NOdonor;licofelone;synthesis;biologicalactivity

非甾体抗炎药(non
steroidalanti
inflammatorytis,OA)、类风湿关节炎(rheuma