4，5-二芳基噁唑类非甾体抗炎药物的设计、合成及其生物活性的研究
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摘要
本文以4,5-二芳基噁唑类非甾体抗炎药(NSAIDs)奥沙普秦(Oxaprozin)为先导化合物,利用生物电子等排原理及4,5-二芳基噁唑类NSAIDs 的构效关系及NSAIDs 的作用机制,采用与环氧化酶分子对接的方法,辅助设计了3 类新化合物,从中筛选出新化合物3-〔4-(4-氟苯基)-5-(4-氨基磺酰基-3-氟苯基)噁唑-2-基〕丙酸(NC-2142)进行合成,并合成得到七个新的重要中间体,同时也对NC-2142 的合成工艺进行了考察。经药理实验证明NC-2142 对二甲苯、蛋清、角叉菜胶等所致急性炎症均有明显的抑制作用,对小鼠扭体法及热板法致痛也具有明显的抑制作用。由此表明,NC-2142 是一个具有较强的抗炎和镇痛作用且极具开发价值的新化合物。这为进一步研究高效、低毒的新型NSAIDs 提供了一个新的研究方法。
Nonsteroidal anti-inflammation drugs(NSAIDs) are among themost widely used therapeutics, primarily for the treatment of pain,inflammation and pyretics. However they may cause seriousgastrointestinal side effect after a along term use, even ulcers, bleedsand perforation, not only for their blocking the PGs production ininflammation cells but also for interfering with the homeostaticproduction of PGs in the gastrointestinal track, which has greatly limitedthe development of this agents. Therefore agents that selectively inhibitthe pathological PGs production while sparing physiological PGsrepresent a major target of drug research.
With the discovery of COX-2 in recent years, a lot of selectiveCOX-2 inhibitors have been developed for their good effect, reduced GItoxicity, and improved safety profiles. Unfortunately, the COX-2 inhibitorsstill remain some of the side effects seen with traditional dual COX
inhibitors (nonsteroidal anti-inflammatory drugs),especially increae riskof myocardial infarction and strokes after a long term use.It is necessaryto develop a novel class of potent NSAIDs without of serious side effect . A major mechanism of action of NSAIDs is lowering prostaglandinproduction through inhibition of cyclooxygenase ,a key enzyme inprostaglandin biosynthesis.It has been pointed out that inhibiting onlythe cox pathway could shunt the metabolism of arachidonic acid(AA)towards the 5-lipoxygenase(5-LO) pathway which generatesleukotrienes(LTs).Leukotrienes are particularly important mediator ininflammation process and leucocyte activator,which can increasemicrovascular permeability. LTB4 is directly associated with acute gastricand intestinal damage induced by classic NSAIDs. The dual inhibition of COX-2 and 5-LO not only can block theproduction of PGs and LTs,but also reduce the GI-damaging.Obviously,dual acting anti-inflammatory drugs will be an important part ofNSAIDs study. Oxaprozin which was developed by Wyeth USA is a NSAID withlong-term effect NSAIDs. Its mechanism of action is blocking thebiosynthesis of PGs by dual inhibition of COX/5-Lo and haveanalgesic,antipyretic and anti-inflammatory activity. Oxaprozin showed alonger term effect and little GI toxicity than other NSAIDs, but the poorselectivity, high dose and long half life have limited the wide use ofOxaprozin, and the structure modification and optimization of Oxaprozinwould be very promising and valuable.
1.Design of target compound Oxaprozin is belong to 4,5-diaryloxazole derivatives. In conclusion,the variants of functionalities at the 2-position of oxazole ring are directlyassociated with the bioactivity. The more side chains the substituentshave, the poorer activity and selectivity are; While the analogues bearinga fluoro moiety in para-position of 4-aryl show strong COX-2 activity invitro and in vivo. Introduction of a para methyl sulfone or sulfonamidesubstituent to 5-aryl can enhance the oral activity and pharmacokineticcharacter. In general, the sulfonamide derivatives were superior tomethyl sulfone derivatives; A halo could be introduced to meta-positionof 5-aryl, among which the fluoro is the best. We have to design our target compound using as the lead,incorporating the SAR and the mechanism of action of 4,5-diaryloxazole.In the process of structure modification of Oxaprozin, we have found thatintroduction of a fluoro and groups with larger polarity such asaminosulfonamide and methylsulfonamide can decurtate the t1/2 andimprove the in vivo absorptiothiand pharmacokinetic character and hasdecreased the dose and reduced side effects in gastric andcardiovascular system by improving selectivity. Therefore it would be anovel class of NSAIDs with better effect and lower toxicity. So wedesigned three types new compounds using InsightⅡand selected anewcompound-3-[4-(4-fluorophenyl)-5-(3-fluorophenyl)-oxazole-2-yl]propanoic acid, which had stronger inhibition activity against COX-2. To study the new compound that we had designed in advance, weinvestigated synthesis and bioactivity evaluation of NC-2142 so that we
could find new type NSAIDs with lower toxicity.2.Sythesis of NC-2142 We designed and improved the synthesis of NC-2142 and selectedan optimized one from several routines. The target compound wassynthesized from intermediate, α-(3-fluophenyl)-4-fluoroaceto-phenone by chlorination and ammonolysis, which was obtained from3-[4-(4-fluorophenyl)-5-(3-fluorophenyl)oxazole-2-yl]propanoic acid bybromination, hydrolysis, esterification and cyclization. In bromination, we have compared several brominating agents,solvents and temperature and found that the best result was NBS,chloroform and 50-60℃. However, the reaction time is long and thenbenzoyl peroxide was used as a catalyst to decrease reaction time. Wealso compared several alkaline reagents, solvents and temperature inhydrolysis and found that the best result was bicarbonate, acetone and50℃. The product of hydrolysis, α-(3-fluophenyl)-α-hydroxy -4-fluoroacetophenone, esterfied with succinic anhydride in pyridine undernitrogen circumstance with temperature at 90-95℃. Then it was cyclizedwith acetic acid ammonium salt and acetic acid at above temperature.Then 3-[4-(4-fluorophenyl)-5-(3-fluorophenyl) oxazole-2-yl] propanoicacid was obtained with 80% yield. In chlorination, we found that theoptimized routine adopted chlorosulfonic acid with 96h at 25℃. Afterpurification of 3-[4-(4-fluorophenyl)-5-(4-amino sul-fonic-3-fluoro-phynyl)-oxazole-2-yl]propanoic acid, the yield of reaction was 20%more than that without purification. We compared many syntheses of α-(3-fluophenyl)-4-fluo roac-
Nonsteroidal anti-inflammation drugs(NSAIDs) are among themost widely used therapeutics, primarily for the treatment of pain,inflammation and pyretics. However they may cause seriousgastrointestinal side effect after a along term use, even ulcers, bleedsand perforation, not only for their blocking the PGs production ininflammation cells but also for interfering with the homeostaticproduction of PGs in the gastrointestinal track, which has greatly limitedthe development of this agents. Therefore agents that selectively inhibitthe pathological PGs production while sparing physiological PGsrepresent a major target of drug research.
With the discovery of COX-2 in recent years, a lot of selectiveCOX-2 inhibitors have been developed for their good effect, reduced GItoxicity, and improved safety profiles. Unfortunately, the COX-2 inhibitorsstill remain some of the side effects seen with traditional dual COX
inhibitors (nonsteroidal anti-inflammatory drugs),especially increae riskof myocardial infarction and strokes after a long term use.It is necessaryto develop a novel class of potent NSAIDs without of serious side effect . A major mechanism of action of NSAIDs is lowering prostaglandinproduction through inhibition of cyclooxygenase ,a key enzyme inprostaglandin biosynthesis.It has been pointed out that inhibiting onlythe cox pathway could shunt the metabolism of arachidonic acid(AA)towards the 5-lipoxygenase(5-LO) pathway which generatesleukotrienes(LTs).Leukotrienes are particularly important mediator ininflammation process and leucocyte activator,which can increasemicrovascular permeability. LTB4 is directly associated with acute gastricand intestinal damage induced by classic NSAIDs. The dual inhibition of COX-2 and 5-LO not only can block theproduction of PGs and LTs,but also reduce the GI-damaging.Obviously,dual acting anti-inflammatory drugs will be an important part ofNSAIDs study. Oxaprozin which was developed by Wyeth USA is a NSAID withlong-term effect NSAIDs. Its mechanism of action is blocking thebiosynthesis of PGs by dual inhibition of COX/5-Lo and haveanalgesic,antipyretic and anti-inflammatory activity. Oxaprozin showed alonger term effect and little GI toxicity than other NSAIDs, but the poorselectivity, high dose and long half life have limited the wide use ofOxaprozin, and the structure modification and optimization of Oxaprozinwould be very promising and valuable.
1.Design of target compound Oxaprozin is belong to 4,5-diaryloxazole derivatives. In conclusion,the variants of functionalities at the 2-position of oxazole ring are directlyassociated with the bioactivity. The more side chains the substituentshave, the poorer activity and selectivity are; While the analogues bearinga fluoro moiety in para-position of 4-aryl show strong COX-2 activity invitro and in vivo. Introduction of a para methyl sulfone or sulfonamidesubstituent to 5-aryl can enhance the oral activity and pharmacokineticcharacter. In general, the sulfonamide derivatives were superior tomethyl sulfone derivatives; A halo could be introduced to meta-positionof 5-aryl, among which the fluoro is the best. We have to design our target compound using as the lead,incorporating the SAR and the mechanism of action of 4,5-diaryloxazole.In the process of structure modification of Oxaprozin, we have found thatintroduction of a fluoro and groups with larger polarity such asaminosulfonamide and methylsulfonamide can decurtate the t1/2 andimprove the in vivo absorptiothiand pharmacokinetic character and hasdecreased the dose and reduced side effects in gastric andcardiovascular system by improving selectivity. Therefore it would be anovel class of NSAIDs with better effect and lower toxicity. So wedesigned three types new compounds using InsightⅡand selected anewcompound-3-[4-(4-fluorophenyl)-5-(3-fluorophenyl)-oxazole-2-yl]propanoic acid, which had stronger inhibition activity against COX-2. To study the new compound that we had designed in advance, weinvestigated synthesis and bioactivity evaluation of NC-2142 so that we
could find new type NSAIDs with lower toxicity.2.Sythesis of NC-2142 We designed and improved the synthesis of NC-2142 and selectedan optimized one from several routines. The target compound wassynthesized from intermediate, α-(3-fluophenyl)-4-fluoroaceto-phenone by chlorination and ammonolysis, which was obtained from3-[4-(4-fluorophenyl)-5-(3-fluorophenyl)oxazole-2-yl]propanoic acid bybromination, hydrolysis, esterification and cyclization. In bromination, we have compared several brominating agents,solvents and temperature and found that the best result was NBS,chloroform and 50-60℃. However, the reaction time is long and thenbenzoyl peroxide was used as a catalyst to decrease reaction time. Wealso compared several alkaline reagents, solvents and temperature inhydrolysis and found that the best result was bicarbonate, acetone and50℃. The product of hydrolysis, α-(3-fluophenyl)-α-hydroxy -4-fluoroacetophenone, esterfied with succinic anhydride in pyridine undernitrogen circumstance with temperature at 90-95℃. Then it was cyclizedwith acetic acid ammonium salt and acetic acid at above temperature.Then 3-[4-(4-fluorophenyl)-5-(3-fluorophenyl) oxazole-2-yl] propanoicacid was obtained with 80% yield. In chlorination, we found that theoptimized routine adopted chlorosulfonic acid with 96h at 25℃. Afterpurification of 3-[4-(4-fluorophenyl)-5-(4-amino sul-fonic-3-fluoro-phynyl)-oxazole-2-yl]propanoic acid, the yield of reaction was 20%more than that without purification. We compared many syntheses of α-(3-fluophenyl)-4-fluo roac-
引文
[1] 仉文生,李安良.药物化学[M].北京:高等教育出版社,1999:348-355
[2] Vane JR,Botting RM.Aspiri and other salicylates[M].London: Chapman& Hall Medical,1992,3-16
[3] Vane JR.Inhibition of prostaglandin synthesis as a mechanism of acition for aspirin-like drugs[J].Nature New Biol,1971,231(25):232-235
[4] Samuelsson B. An elucidation of the arachidonic acid cascade discovery of prosrglandins,thromboxane and leukotrienes[J].Drugs,1987, 33(Supp1 1):2-9
[5] 苏伟,王飞武.环氧酶和脂氧酶双重抑制剂研究进展[J].现代应用药学,1992,9(2):94-99
[6] Vane JR.The evolution of nonsteroidal anti-inflammatory dyugs and their mechanis ms of action[J].Drugs,1987,33(Supp1 1):18-27
[7] Smith JB,Willis AL.Asipirin selectively inhibits prostaglandin production in human platelets[J].Nature New Biol,1971,231(19):235-237
[8] Hemler M,Lands WEM,Smith WL.Purification of the cyclooxygenase-that forms prostaglandins[J].J Bilo Chem,1976,251(16-18):5575-5579
[9] Bakhle YS.Structure of COX-1 and COX-2 enzymes and their interac-tion with inhibitors[J].Drugs Today,1999,35(4-5):237-250
[10] Picot D,Loll PJ,Garavito RM,et al.The x-ray crystal structure of the membrane protein prostaglandin H2 synthase-1[J].Nature,1994,367 (6460):243-249
[11] Masferrer JL, Seibert K, Zweifel BS,et al.The induction and suppres-sion of prostaglandin H2 synthase(cyclooxygenase) in human mono cyt-es [J].J Biol Chem,1990,265(28):16737-16740.
[12] Xie WL, Chipman JG, Robertson DL,et al.Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing[J].Proc Natl Acad Sci USA,1991,88(6): 2692-2696.
[13] Jouzeau JY,Terlain B,Abid A,et al.Cyclooxygenase isoenzymes:how recent findings affect thinking about nonsteroidal antiinfl-amatory druga.DRUGS,1997,53(4):563-582
[14] O′Neill GP,Ford-Hutchinson AW.Expression of mRNA for cycloox-ygenase-1 and cyclooxygenase-2 in human tissues[J].FEBS Lett,1997, 330:150-163
[15] Peil KG,Hardy P,Li DY,Varma DR,et al.Prostaglandin G/H synthase-2 is a major contriutor of brain prostaglandins in the newbom[J].J Biol Chem,1995,270(41):24615-24620
[16] Seibert K,Zhang Y,Lcaky K,et al.Pharmacological and biochemical demonstration of the role of cyclooxygenase-2 in inflammation and pain[J].Proc Natl Acad Sci USA,1994,91:12013
[17] Rofecoxib[J].Drugs Fut,1998,23(12):1287-1296
[18] 李玲.环氧化酶-2 及其研究进展[J].国外医学·分子生物学分册,1999, 21(3):174-178
[19] Appleby SB,Ristimaki A,Neilson K,et al.Structure of the human cyclooxygenase-2 gene[J].Biochem J,1994,302:723-727
[20] Asano K,Lilly Craig M, Drazen JM, et al.Prostaglandin G/H synthase-2 is the constitutive and dominant isoform in cultured human lung epithelial cells[J]. Am J Physiol,1996,271(1):126-131
[21] Barrios-Rodiles M,Keller K,Belley A,et al.Nonsteroidal anti-inflam matory drugs inhibit tcyclooxygenase-2 enzyme activity but not mRNA expression in human macrophages[J].Biochem Biophys Res Comm un,1996,225:896-900
[22] 王兆钺等.国外医学生理病理科学与临床,1996,16(1):97
[23] Bertolini A,Ottani A,Sandrini M.Dual acting anti-inflammatory drugs:a reappraisal[J].Pharmacological Research.Vol.,2001:437-450
[24] Morita I,et al.Different intracellular locations for prostaglandin endopreroxide H stnthase-1and-2[J].J Biol Chem,1995,270(18): 10902 -10908
[25] Cannon GW.Cyclooxygenase 2 selective inhibitors[J].Drugs Today, 1999,35:487-496.
[26] 陈蓓,唐福林.非甾体抗炎药的作用机理及研究进展[J].北京医学,1998,20(3):167-168
[27] Kurubail RG,Stevens AM,Gerse JK,et al.Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents [J].Nature,1996,384(6610):644-648
[28] Eyn JV,Pairet M.Clinical experience with cyclooxygenase-2 inhibitor [J].Inflamm Res,1999,48(5):247-254.
[29] 桑诺尔,叶铁虎.新型特异性COX-2 抑制剂[J].Parecoxib,2002,22(4): 254-255.
[30] Vane JR,Botting RM.Snti-inflammatory drugs and their mechanism of action[J].Inflamm Res,1998,47(Supp1 2):78-87
[31] Hawkey CJ.COX-2 inhibitors[J].Lancet,1999,353(9149):307-314
[32] 高鹏,周君,白海燕.环氧化酶-2 及其选择性抑制剂的研究现状与展望[J].天津药学,2002,14(2):25-27
[33] 敖桂珍,张玉彬,张奕华.新型非甾体抗炎药作用靶环氧酶-2 研究进展 [J].中国新药杂志,2001,10(7):492-496
[34] Dannhardt G, Kiefer W.Cyclooxygenase inhibitorscurrent status and future prospects[J].Eur J Med Chem,2001,36(2):109-126
[35] Herschman HR, Talley JJ, Dubois R,et al.Cyclooxygenase-2 (COX -2) as a target for therapy and noninvasive imaging[J].Mol Imaging Biol, 2003,5(5):286-303.
[36] Marnett LJ, Kalgutkar AS.Design of selective inhibitors of cyclooxyg enase-2 as nonulcerogenic anti-inflammatory agents[J].Curr opin Chem Biol,1998,2(4):482-490.
[37] Frolich JC.A classification of NSAIDs according to the relative inhi-bition of cyclooxygenase isoenzymes[J].Tips,1997,18(1):30-34.
[38] Warner T,Giuliano F,Vojnovic I,et al.Nonstroid drug selectivities for cyclooxygenase-1 rather than cyclooxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis[J].Proc Natl Acad Sci USA,1999,96(13-14):7563
[39] Rabasseda X.Nimesulide: A selective cyclooxyfenase 2 inhibitor antiinflammatory drug[J].Drugs Today,1996,32(5):365-384
[40] Shah A,Murray F,Fizgerald D.The in vivo assessment of nimesulide cyclooxygenase-2 selectivity.Rheumatol Oxford,1999, 38(Suppl 1):19
[41] Futaki N,Arai I,Hamasaka Y,et al.Seletive inhibitor of NS-398 on progtanold production in inflamed tissue in rat carrageenan-airpouch inflammation[J].J Pharm Pharmmacol.1993,45(1-9):753-755
[42] 朱七庆,屈凌波,雷新胜等.环氧合酶-2 抑制剂的对接(Dock)研究[J].中国药物化学杂志,1999,9:114
[43] Hirschelmann R,Hentschel M,Rickingger V,et al.CGP28238,a new potent nonsteroidal anti-inflammatory agent:its relation to arachidonic acid metabolism[J].Agent Actions,1991,32(1-2):54-55
[44] Chan CC,Boyce S,Brideau C,et al.Pharmacology of a selective cyclooxygenase-2 inhibitor,L-745337:A novel nonsteroidal antiinf-alammatory agent with an ulcerogenic sparing effect in rat and nonhu-man primate stomach[J].J Pharmacol Exp Ther,1995,274(3):1531-1537
[45] Otterness IG,Moore PF.Carrageenan foot eclema test[J].Methods Enzymol,1988,162:320-327
[46] Talley JJ.Prog Med Chem.1999,36:201-234
[47] Li JJ,Anderson GD,Bureon EG,et al.1,2-Diarylcychlpentenes as selective cyclooxygenase-2 inhibitors and ofally active anti-inflammatory agents[J].J Med Chem,1995,38(21-26):4570-4578
[48] Gans KR,Galbraith W,Roman RJ,et al.Antiinflammatory and safety profile of Dup-697,a novel orally effective prostaglandin synthesis inhibitor[J].J Pharmacol Exp Ther,1999,245:180
[49]Kiyoushi T,Katsuya N,Nobukiyo K, et al.Studies on anti-inflammatory agents. Ⅳ.Synthesis and pharmacological properties of 1,5-di-arylpyrazole and related derivatives[J].Chem Pharm Bull,1997,45(6):987-995
[50] Reitz DB,Li JJ,Norton MB,et al.Selective cyclooxygenase inhibitors novel 1,2-diarylcyclopentencs acspot entand or ally active COX-2 inhibitotors[J].J Med Chem,1994,37(23):3878-3881
[51]Penning TD,Talley JJ,Bertenshaw SR,et al.Synthesis and biological evaluation of the 1,5-diarylpyra-zole class of cyclooxygenase-2 inhibito-rs : Identification of 4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol -1-yl]benzene sulfonamide(SC-58635,Celecoxib)[J].J Med Chem, 1997, 40(9):1347-1365.
[52] Clemett D,Goa KL,Celecoxib,A review of its use in osteoarthritis, rheumatoid arthritis and acute pain[J].Drugs,2000,59(4):957-980
[53] Day R.O.,Francis H,Vial J,et al.Naproxen concentrations in plasma and synovial fluid and effects on prostanoid concentrations[J].J Rheumatol,1995,22:2295
[54] Celecoxib.Drugs Fut,1999,24:795
[55] Zang Y,Shaffer A,Portanova J,et al.Inhibition of cyclooxygenase-2 rapidly reverses inflammatory hyperalgesia and prostaglandin E2 proeluction[J].J Pharmacal Exp Ther,1997,283:1069
[56] Plount Price ML,Jorgensen WL.Analysis of binding affinities for Celecoxib analogues with COX-1 and COX-2 from combined docking and monte carlo simulations and insight into the COX-2/COX-1 selectivity[J].J Am Chem Soc,2000,122(39):9455-9466.
[57] Habeeb AG, Praveen Rao PN, Knaus EE,et al.Design and synthesis of Celecoxib and Rofecoxib analogues as selective cyclooxygenase (COX-2) inhibitors:Replacement of sulfonamide and methylsulfonyl pharmacophores by an azido bioisostere[J].J Med Chem,2001,44(18): 3039-3042.
[58] Uddin MJ, Praveen Rao PN, Knaus EE,et al. Design and synthesis of Celecoxib analogues as selective cyclooxygenase (COX-2) inhibito-rs:Replacement of the sulfonamide pharmacophore by a sulfonylazide bioisostere[J].Bioorg Med Chem,2003,11(23):5273-5280.
[59] Kurumbail RG, Kiefer JR,Marnett LJ,et al.Cyclooxygenase enzym- es:catalysis and inhibition[J].Curr Opin Struct Biol,2001,11(6):752-760
[60] Black WC, Brideau C, Chan CC,et al.3,4-Diaryl-5-hydroxy-furanon-es:Highly selective inhibitors of cyclooxygenase-2 with aqueous solubi-lity[J].Bioorg Med Chem Lett,2003,13(6):1195-1198
[61] 廖斌, 丛欣, 廖清江, 等.2002 年世界上市的新药[J]. 药学进展,2003,27(3):190-193
[62] Talley JJ, Bertenshaw SR,Brown DL,et al.N-[[(5-Methyl-3-phenyl-isoxazol-4-yl)phenyl]sulfon-yl]pr-opanamide,Sodium salt, parecoxib so-dium:a potent and selective inhibitor of COX-2 for parenteraladministr-ation[J].J Med Chem,2000,49(9):1661-1663
[63] Pal M, Madan M, Padakanti S,et al.Synthesis and cyclooxygenase -2 inhibiting property of 1,5-diaryl pyrazoles with substituted benzene-sulfonamide moiety as pharmacophore:Preparation of sodium salt for injectable formulation[J].J Med Chem,2003, 46(19): 3975-3984
[64] Singh SK, Reddy PG, Rao KS,et al.Polar substitutions in the ben-zenesulfonamide ring of celecoxib afford a potent 1,5-diaryl-pyrazole class of COX-2 inhibitors[J].Bioorg Med Chem Lett,2004,14(2): 499-504
[65] Song Y, Connor DT, Doubleday R,et al. Synthesis, structureactivity relationships, and in vivo evaluations of substituted ditert-butylphenols as a novel class of potent, selective, and orally active cyclooxygenase-2 inhibitors. 1. Thiazolone and oxazolone series [J].J Med Chem, 1999, 42 (7): 1151 -1160.
[66] Song Y, Connor DT, Sercel AD,et al. Synthesis, structureactivity rel-ationships, and in vivo evaluations of substituted ditert-butylphenols as a novel class of potent, selective, and orally active cyclooxygenase-2 inhibitors. 2. 1,3,4-and 1,2,4-thiadi-azole series [J].J Med Chem, 1999,42(7): 1161 -1169
[67] Janusz JM, Young PA, Scherz MW,et al.New cyclooxygenase-2/5-lipoxygenase inhibitors. 2.7-tert-butyl-2,3-dihydro-3,3-dimethyl benzofu-ran derivatives as gastrointestinal safe anti-inflammatory and analgesic agents:Variations of the dihydrobenzofuranring[J].J Med Chem,1998, 41 (7):1124-1137
[68] Barbey S,Goossens L, Taverne T,et al.Synthesis and activity of a new methoxytetrahydropyran derivative as dual cyclooxygenase -2/5-lipoxygenase inhibitor[J].Bioorg Med Chem Lett,2002,12(5): 779-782
[69] Ranatunge RR, Augustyniak M,Bandarage UK,et al.Synthesis and selective cyclooxygenase-2 inhibitoryactivity of a series of novel,nitric oxide donor-containing pyrazoles[J].J Med Chem, 2004, 47(9):2180-2193
[70] Balsamo A, Coletta I, Guglielmotti A,et al.Synthesis of heteroaroma-tic analogues of (2-aryl-1-cyclo-pentenyl-1-alkyli dene)-(arylmethyloxy)-amine COX-2 inhibitors:effects on the inhibitory activity of the repla cem-ent of the cyclopentene central core with pyrazole,thiophene or isoxazo-le ring[J].Eur J Med Chem, 2003,38(2):157-168
[71] Rapposelli S, Lapucci A, Minutolo F,et al.Synthesis and COX-2 inhibitory properties of N-phenyl and N-benzyl-substituted amides of 2-(4-methylsulfonylphenyl)cyclopent-1-ene-1-carboxylic acid and of their pyrazole,thiophene and isoxazole analogs[J].II Farmco, 2004, 59 (1): 25-31
[72] Singh SK,Vobbalareddy S, Shivaramakrishna S,et al. Methane sulfonamide group at position-4 of the C-5-phenyl ring of 1,5-diarylpyrazole affords a potent class of cyclooxygenase-2 (COX-2) inhibitors[J].Bioorg Med Chem Lett,2004,14(7):1683-1688
[73] Dannhardt G,Laufer S.Structural approaches to explain the selectivity of cyclooxygenase-2 inhibitors: is there a common pharmaco-phore[J].Curr Med Chem,2000,7(11):1101-1112.
[74] Van RJ, Trummlitz G, Pairet M, et al.Cyclooxygenase-2 seleci vity and inflammatory processes[J].Curr Med Chem ,2000,7(11): 1145-1161
[75] Sui Z,Guan J, Ferro MP,et al.1,3-Diarylcycloalkano-pyrazoles and diphenyl hydrazides as selective inhibitors ofcyclooxygenase-2 [J]. Bioorg Med Chem Lett,2000,10(6):601-604
[76] Banoglu E,Akoglu C,Unlu S,et al.Amide derivatives of [6-(5-Methyl -3-phenylpyrazole-1-yl)-3(2H) –pyridazinone-2-yl]acetic acid as poten-tial analgesic and antiinflammatory compounds[J].Arch Pharm Pharm Med Chem,2004,337(1):7-14
[77] Bertenshaw SR,Talley JJ, Rogier DJ,et al.Conformationally restric-ted 1,5-diarylpyrazoles are selective COX-2 inhibitors[J]. Bioorg Med Chem Lett,1996,6(23):2827-2830.
[78] Almansa C, Arriba AF, Cavalcanti FL,et al.Synthesis and SAR of a new series of COX-2-selective inhibitors:Pyrazolo[1,5-a] pyrimidines[J].J Med Chem,2001,44(3):350-361.
[79] Ranatunge RR, Garvey DS, Janero DR,et al.Synthesisi and selecti-ve cyclooxygenase-2 (COX-2) inhibitory activity of a series of novel bicy-clic pyrazoles[J].Bioorg Med Chem,2004,12(6):1357-1366.
[80] Baruah B,Dasu K,Vaitilingam B,et al.1,2-Diaryl-1-ethanone and pyr- azolo[4,3-c]quinoline-4-one as novel selective cyclooxygenase -2 inhibi-tors[J].Bioorg Med Chem Lett,2004,14(2):445-448.
[81] Prasit P,Wang Z, Brideau C,et al. Synthesis and preliminary biological evaluation of new alpha-amino amide anticonvulsants incorporating a dextromethorphan moiety[J]. Bioorg Med Chem Lett, 1999,9(13):1773-1788
[82] Chan CC,Boyce S,Brideau C,et al.Rofecoxib:a potent and orally active cyclooxygenase-2 inhibitor.Pharmacological and biochemical profiles[J].J Pharmacol Exp Ther,1999,290(2):551-980
[83] Chun-Sing Li,Riendeau D,Therien M,et al.A new structural variation on the methanesulfonylphenyl class of selective cyclooxy-genase-2 inhibitors[J].Bioorg Med Chem Lett,1999,9(22):3181-3186.
[84] Leblanc Y,Roy P,Boyce S,et al.SAR in the alkoxy lactone series: the discovery of DFP, a potent and orally active COX-2 inhibitor [J].Bioorg Med Chem Lett,1999,9(15):2207-2212.
[85] Lau CK,Brideau C,Chan CC,et al.Synthesis and biological evalua-tion of 3-heteroaryloxy-4-phenyl-2(5H)-furanones as selective COX-2 inhibitors[J].Bioorg Med Chem Lett, 1999,9(22):3187-3192.
[86] Rahim MA,Rao PNP,Knaus EE,et al. Isomeric acetoxy analogues of rofecoxib: A novel class of highly potent and selective cyclooxygenase-2 inhibitors [J].Bioorg Med Chem Lett,2002,12(19): 2753-2756.
[87] Phillip G, Hochgesang J,Jennifer F,et al.Functional analysis of the molecular determinants of cyclooxygensae-2 acetylatin by 2-acetoxy phenylhept-2-ynyl sulfide[J].Arch biochem biophys,2003, 409:127
[88] Marnett LJ, Kalgutkar AS,Trends Pharmacol[J].Sci,1999,20,465
[89] Khanna IK,Weier RM,Yu Y,et al. 1,2-Diarylimidazoles as potent, cyclooxygenase-2 selective,and orally active antiinflammatory agents [J].J Med Chem,1997,40(11):1634-1647.
[90] Uddin MJ.J Heterocyclic Chem,2003,40:861
[91] Joo Hyun Moh.Bioorg Med Chem Lett,2004,14:1757
[92] Leblanc Y,Roy P, Wang Z,et al. Discovery of a potent and selective COX-2 inhibitor in the alkoxy lactone series with optimized metabolic profile[J].Bioorg Med Chem Lett,2002,12(22): 3317-3320
[93] Chan CC, Boyce S,Brideau C,et al.Inflammation Res.1997,46, S 242.
[94] Talley JJ,Bertenshaw SR,Brown DL,et al. N-(((5-methyl-3-phenylisoxazol-4-yl)-phenyl)sulfonyl)propanamide, sodium salt, pareco-xib sodium: A potent and selective inhibitor of COX-2 for parenteral administration[J].J Med Chem,2000,43(9):1661-1663.
[95] Shin SS,Noh MS,Byun YJ,et al.2,2-Dimethyl-4,5-diaryl-3(2H) furanone derivatives as selective cyclo-oxygenase-2 inhibitors [J].Bioorg Med Chem Lett, 2001,11(2):165-168.
[96] Rao PNP,Amini M,Li H,et al.6-Alkyl, alkoxy, or alkylthio-substituted3-(4-methanesulfonylphenyl)-4-phenylpyran-2-ones:A novel class of diarylheterocyclic selective cyclooxygenase-2 inhibitors[J]. Bioorg Med Chem Lett,2003,13(13):2205-2209.
[97] Pal M,Veeramaneni VR,Nagaballi M,et al.Conformationally restricted 3,4-diarylfuranones (2,3a,4,5-tetrahydro-naphthafu ranones) as selective cyclooxygenase-2 inhibitors[J]. Bioorg Med Chem Lett, 2003,13(10):1639-1643.
[98] Dewitt DL.COX-2 Selective inhibitors:the new super aspi-rins.mol[J]. Pharmacol,1999,55:625-631
[99] Jobn JJ,Stepben RB,David LB,et al. 4,5-Diaryloxazole inhibitors of cyclooxygenase-2(COX-2)[J].Medicinal Research Reviews,1999,19(3): 199-208
[100] Gierse JK,Hauser SD,Creeley DP,et al.Expression and selective inhibition of the constitutive and inducible forms of human cyclooxy-genase[J].Biochem J,1995,305:479-484
[101] Masferrer JL,Zweifel BS,Manning PT,et al.Selective inhibition of inducible cyclooxygenase 2 in vivo is anti-inflam-matory and nonulcerogenic[J].Proc Natl Acad Sci USA, 1994,91:3228-3232
[102] Winter CA,Risley EA,Nuss GW,et al.Carrageenan-induced edema in hind paw of the rat as an assay for anti-inflammatory drugs [J].Proc Soc Exp Biol Med,1962,305:479-484
[103] Jaffee BD,Kerr JS,Jones EA,et al.The effect of immunomodulating drugs on adjuvant-induced arthritis in lewis rats[J].Agents actions,1989, 27:344-346
[104]Haruta,Junichi;Hashimoto,Hiromasa;Matsushita,Mutsuyoshi.Prepar ation of heteroaromatic oxazole compounds as selective inhibitors of cyclooxygenase 2[P],JP,WO19463.1996.
[105] Silvestre J,Leeson P a,Castaner J,et al.JTE-522[J].Drugx Fut,1998, 23:598
[106] Talley JJ,Brown DL,Carter JS,et al.4-[5-Methyl-3-phe-nyl-isoxazol -4-yl]-benzenesulfonamide,Valdecoxib:A Potent and Seletive Inhibitor of COX-2[J].J Med Chem,2000,43(5):775-777
[107] Leese PT,Recker D,Kuss ME.A double-blind,plasebo-controlled study to evaluate the effects of valdecoxib,a novel cox-2 specific inhibitor,on platelet function in the elderly [J]. Anesthesiology, 2000, 93:227
[108] Leese PT,Recker D,Kuss ME.The novel cox-2 specific inhibitor valdecoxib,does not affect platelet function in healthy adults [J]. Anesthesiology,2000,93:228
[109] Camu F,Beecher T,Recker DP,et al.valdecoxib,a cox-2 specific inhibitor,is an efficacious,opioid-sparing analgesic in patients undergoing hip arthroplasy[J].Am J Ther,2002,9:43-51
[110] Fricke J,Varkalis J,Zwillich S,et al.Valdecoxib is more efficacious than rofecoxib in relieving pain associated with oral surgery[J].Am J Ther,2002,9:89-97
[111] Desjiardins PJ,Shu VS,Recker DP,et al.A single preoperative oral dose of Valdecoxib,a new cyclooxygenase-2 specific inhibitor, relieves postoral surgery or bunionectomy pain[J].Anesthesiology, 2002,97 (1-3): 565-573
[112] Daniels SE,Desjardins PJ,Talwalker S,et al.The analgesic efficacy of valdecoxib vs oxycodonel/acetaminophen after oral surgery[J].J Am Dent Assoc,2002,133:611-621
[113] Kivitz A,Eisen G,Zhao WW,et al.Randomized placebocontrolled trial comparing efficacy and safety of valdecoxib with naproxen in patients with osteoarthritis[J].J Fam Pract,2002,51:530-537
[114] Makarowski W,Zhao WW,Bevirt T,et al.Efficacy and safety of the cox-2 specific inhibitor valdecoxib in the management of osteoarthritis of the hip: a randomized,double-blind placebo-controlled compaison with naproxen.Osteoarthritis Cartilage,2002, 10:290-296
[115] Habeeb AG,Rao PNP,Knaus EE,et al.Design and Synthesis of 4,5-Diphenyl-4-isoxazolines:Novel Inhibitors of Cyclooxygenase-2 with Analgesic and Antiinflammatory Activity[J].J Med Chem, 2001,44(18):2921-2927
[116] Carles Puig,Maria I.Crespo,Nuria Godessart,et al.Synthesis and biological evaluation of 3,4-Diaryloxazolones:A new class of orally active cyclooxygenase-2 inhibitors[J].J Med Chem,2000,43(2): 214-223
[117] Kalgutkar A.S.,Crews B.C.,Rowlinson S.w.,et al.Aspirin-like molecules that covalently inactivate cyclooxygenase-2[J].Science, 1998,280(5367):1268-1270
[118] Black WC,Bayly C,Belley M,et al. From indomethacin to a selective COX-2 inhibitor: Development of indolalkanoic acids as potent and selective cyclooxygenase-2 inhibitors [J].Bioorg Med Chem Lett,1996, 6(6):725-730
[119] Leblance Y,Black WC,Chan CC,et al. Synthesis and biological evaluation of both enantiomers of L-761,000 as inhibitors of cyclooxygenase 1 and 2 [J].Bioorg Med Chem Lett,1996,6(6):731-736
[120] Kalgutkar AS,Kalgukar SW,Crews BC,et al. Amide derivatives of meclofenamic acid as selective cyclooxygenase-2 inhibitors [J].Bioorg Med Chem Lett,2002,12(4):521-524
[121] Surh YJ,Lee JY,Choi KJ,et al.Effects of selected ginsenosides on phorbol ester-induced expression of cyclooxygenase-2 and activation of NF-Kb and ERK1/2 in mouse skin[J].Ann N Y Acad Sci.2002, 973: 396-401
[122] Yagi A,Kabash A,Okanmra N,et al.Antioxidant free radical scaneging and anti-inflammatory effects of aloesin derivatives in Aloe[J].Planta Med,2002,68(11):957-960
[123] Jayaprakasam B,Seeram NP,Nair MG.Anticancer and anti-inflammatory activities of cucurbitacins from Cucurbita andreana[J]. Cancer Lett,2003,189(1):11-16
[124] Yang LL,Liang YC,Chang CW,et al.Effects of sphondin,isolated feom Heracleum laciniatum,on IL-1 βinduced cyclooxygenase-2 expression in human pulmonary epithelial cells[J].Life Sci,2002,72(2): 199-213
[125] Gilroy DW,Tomilison A,Willoughby DA.Differential effects of inhibitors of cyclooxygenase(cyclooxygenase 1 and cyclooxygenase 2)in acute inflammation[J].Eur J Pharmacol.1998,355:211-217
[126] Willoughby DA,Moore AR,Colville-Nash PR.COX-1,COX-2,and COX-3 and the future treatment of chronic inflammatory disease [J]. Lancet,2000,355:646-648
[127] 周剑涛,万英.环氧合酶-3[J].生命化学,2003,23(4):272～274
[128]Chandrasekharan NV,Dai H,Roos KL,et al.COX-3,a Cyclooxy-genase-1 variant inhibited by acetaminophen and oth er anal gesic/antipyretic drugs: Cloning,structure,and expression [J].J Proc Natl Acad Sci,2002,99(21):13926-13931
[129] Warner TD,Mitchell JA.Cyclooxygenase-3(COX-3):filling in the qaps toward a COX continuum?[J].J Proc Natl Acad Sci,2002,99(21): 13371-13373
[130] Kulkarni SK,Jingh A.Nitric oxide-releasing NSAIDs:a new dimension in nonsteriodal antiin-flammatory drugs[J].Drugs Fut, 2001, 26(5):485-489
[131] Cena C,Lolli ML,Lazzarato L,et al.Antiinflammatory, gastr osparing,andanti-inflammatory,gastrosparing,andantiplatelt properties of new NO-donor esters of Aspirin[J].J Med Chem,2003,46 (5):747-754
[132] Wallace JL,Soldato PD.The therapeutic potential of NO-NSAIDs [J].Fundam Clin Pharmacol,2003,17(1):11-20
[133] Wallace JL,Chin BC. New generation NSAIDS: The benefits without the risks?[J].Drugs Today,1997,33(6):371-378
[134] 傅德才,王淑月,荣杰,等.非甾体抗炎药(NSAIDs)的新进展[J].河北工业科技,2004,21(3):55-57
[135] Mitchell JA,Cirion G,Akarasereenont P,et al.Flurbiprofen ni troxybutylester:a norel anti-inflammatory drug devoid of ulcerogenic activity,Inhibits cyclooxygenase-1 and cyclooxy-genase-2[J].Can J Phyi ol Pharmacol,1994,72:720
[136] Takaeachi K,Ukawa H,Konoka A,et al.Effect of nitric oxide releasing aspirin derivative on gastric functional and vicerogenic responses in rats:comparision with aspirin[J].J Pharmacol Exp Ther, 1998,286:115-121
[137] Cuzzolin L,Confort A,Adami A,et al. Anti-inflammatory potency and gastrointestinal toxicity of a new compound, nitronaproxen [J]. Pharmac ol Res,1995,31(1):61-65
[138] Wallace JL, Bak A,McKnight W,et al.Cyclooxygenase 1 contributes to inflammatory responses in rats and mice: implications for gastrointe-stinal toxicity [J].Gastroenterology, 1998,115(1):101-109
[139] Davies NM,Rostch AG,Appleycerd CB,et al.NO-naproxen vs naproxen: ulcerogenic,Analgesic and Antiinflammatory Effects[J]. Aliment Pharmacol Ther,1997,11(1):69-79
[140] Bargaud JL,Benedini F,Robinson EM,et al.HCT-1026 Flurbiprofen nitroxybutyl ester[J].Drugs of the Future,1999,24(8): 858-861
[141] Girino G,Galignano A,Sannicolo F,et al.Antiinflammatory, analgesic, anti-thromboticdrugs:NCX-4016[J].Drugs Fut,1997,22(11): 1231-1233
[142] Wallace JL,Moscara MN,Mckight W,et al.In:vivo Antithrombotic Effects of nitric oxidereleasing aspirin derivatives,NCX-4016[J]. Thromb Res,1999,93(1):43-50
[143]Elliott SN,Mcknight W,Cirino G,et al.A nitric oxiderealedsing nonsteriod antiflammatory drug auelerates gastric ulcer healing in nats[J].Gastroeuterology,1995,109(2):524-530
[144] 李瑞文,张奕华,季晖,等.苯磺酰基呋咱氮氧化物与双氯酚酸偶联化合物的合成与抗炎活性[J].药学学报,2001,36(11):821-826
[145] 冯晓春,季晖,张奕华,等.ZLR-8 对大鼠溃疡愈合的影响及体外一氧化氮释放作用[J].中国药科大学学报,2004,35(4):357-360
[146] 王未东,张奕华,季晖,等.一氧化氮供体型氟罗布酚衍生物的合成与抗炎活性[J].中国药物化学杂志,2004,14(1):1-8
[147] Bobert M,Clanc Y,Steven B.Nitric oxide:A Novel mediator of in flammation,Pros Soc Exp Biol Med,1995,210(2):93-101
[148] Carini M,Aldini G,Stefani R,et al.Nitrosylhemoglobn,an unequi vocalindex of nitric oxide release from nitroaspirin:in vitro and in vivo studies in the rat by ESR spectroscopy[J].J Pharm Biomed Anal,2001, 26(5):509-518
[149] Kashfi K,Rgann Y,Qiao LL,et al.Nitric oxidedonating nonsteroidal anti-inflammatory drugs inhibitit the growth of various culotured human cancer cells:evidence of a tissue typeindependent effect[J].J Pharmucol Exp Ther,2002,303(3):1273-1282
[150] Kuchar M,Matarova E,Brunova B,et al.Quantitative relations between structure and anti-inflammatory activity of aryloxoalkanoic acids[J].Collect Czech Commum,1988,53(7-9):1862-1872
[151] Lewis RA,Austen KF,Sobeman RJ,et al.Leukotrienes and other products of the 5-lipoxygenase pathway[J].New Engl J Med,1990,323 (10):645-655
[152] Fuynn DL,Capiris T,Cetenko WJ,et al.Nonsteroildol anti-inflammatory drug hydroxamic acids,dual 5-lipoxygenase and cyclooxy-genase inhibitors[J].J Med Chem,1990,33(5-8):2070-2072
[153] Janusz JM,Young PA,Ridgeway JM,et al.New cyclooxygenase -2/5-lipoxygenase inhibitors 1,7-tertbutyl-2,3-dihydro-3,3-dimethyl-ben-zofuran derivatives as gastrointestinal safe anti-inflammatory and analgesic agents:discovery and variation of the 5-ketosubs-tituent[J].J Med Chem,1998,41(7): 1112-1123
[154] Lee SJ,Frieson MR,Wong S,et al.BF-389 Antiinflammatory [J].Drugs Fut,1992,17(1):12-14
[155] Tkuta H,Sbirota H,Kobayashi Y,et al.Synthesis and anti-inflammatory activities os 3-(3,5-ditertbutyl-4-hydroxy-benzyllidine) pynolidin-2-ones[J].J Med Chem,1987,30(1):1995-2004
[156] Marfin L,Rabasseda X,Castaner J,et al.Darbufelone mesilate: Prop INNM, antiarthritic, lipoxygenase inhibitor, cyclooxygenase-2 inhibitor: CI-1004 PD-136095-0073[J].Drugs of the Future,1999, 24(8):853-857.
[157] Unangst PC,Connor DT,Cetenko WA,et al.Synthesis and boliogical evaluation of 5-[[3,5-bis-(1,1-dimethylethyl) -4-hydroxylphenyl]methyl-lene]oxazoles,-khiazoles,-imidazoles:novel dual 5-lipoxygenase and cyclooxygenase inhibitors with anti-inflamroatory activity[J].J Med Chem,1994,37(2):322-328
[158] Kneen G,Jackson WP,Islip PJ,et al.Preperation of arylhydroxamic acid derivative compositions containing them,and their use in medicane and otherapplications.EP 196184,1986-10-1
[159] Nagaki M,Tsuri T,Jyoyama H,et al.Novel antiarthritic agents with 1,2-isothiazolidine-1,1-dioxide( γ-sultam)skeleton:cytokine suppreasive dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase [J].J Med Chem,2000,43:2040-3048
[150] Laufer SA,Auguatin J,Dannhardt G,et al.(6,7-Diaryldihydro-pynolizin-5-yl)acetic axids,a novel class of potent dualinhibi-torsof 5-lipoxygenase and cyclooxygenase[J].J Med Chem,1994,37(2): 1894-1897
[161]敖桂珍,吉念宁,张奕华,等.环氧酶/5-脂氧酶双重抑制剂的定量构效关系研究[J].计算机与应用化学,2003,20(1):6-8
[162] Reddy BS,Rao CV,Rivenson A,et al.Ihbitory effects of aspirin on azoxymathane induced colon carcinogenesis in F344 rats[J]. Carcinogenesis,1993,328:1313-1316
[163] Sorensen HT,friis S,Norgard B,et al.Risk of cancer in a large cohort of nonaspirin NSAID users:a population-based study[J].Br J Cancer, 2003,88(11):1687-1692
[164] Gardiner PS,Gilmer JF.The medlcinal chemistry implications of the anticancer effects of aspirin and other NSAIDs[J].Mini Rev Med Chem,2003,3(5):461-470
[165] Xu XC.COX-2 inhibitors in cancer treatment and prevention,a recent development[J].Anticancer Drugs,2002,13:127-137
[166] Sawaoka H,Kawano S,Tsuji S,et al.Effects of NSAIDs on proliferation of gastric cancer cells in vitro:possible implication of cyclooxygenase-2 in cancer developmet[J].J Clin Gastroenterol, 1998,27(Suppl):S47-S52
[167] Hongmiao S,Jinyi S,Kirkland SC,et al.Inhibition of human colon cancer cell growth by selective inhibition of cyclooxy-genase-2[J].J Clin Invest,1997,99:2245-2259
[168] Halliday G,Robinson SR,Shepherd C,et al.Alzheimer′s disease and inflammation:a review of cellular and therapeutic mechanisms[J]. Clin Exp Pharmacol Physio,2000,27:1-8
[169] Van JR,Booting RM.Meched anism of acfion of nonseeriodal an liinpiammatoty drags[J].Am J Med,1998,104(3):2
[170] Graharm DY.Prevention of gastroduodenal injury induced by chronic nonsteroidal antiinfla matory drug therapy[J].Gast roeent-erology,1989,96(1-4):675
[171] Armstrong CP,blower AL.Nonsteroidal antiinfla matory drugs and life threatening complications of pepctic upceration[J].Cut, 1987,28:527
[172] Maricic N,Ehrlich K,Gretzer B,et al.Selective cyclooxy-genase-2 inhibitors aggravate ischaemia reperfusion injury in the rat stomach[J].Br J Pharmacol,1999,128(8):1659-1666
[173] Reuben SS,Steinberg R.Gastric perforation associat with the use of celecoxib[J].Anesthesiology,1999,91(5):1548-1549
[174] Ahmad SR,Kortepeter C,Brinker A,et al.Renal failure associa-ted with the use of celecoxib and rofecoxib[J].Drug Saf,2002,25(7): 527
[175] Cheng HF,Wang JL,Zhang MZ,et al.Angiotensin Ⅱattenant esrenal cortical cyclooxygenase-2 expressior[J].J J Clin Invest, 1999,103(7):953-961
[176] 陈芬儿. 有机药物合成法[M], 北京: 中国医药科技出版社,1999:199-200
[177] Lewis AJ,Current Therapeutic Research.1983,34:777-794
[178] Todd PA,Drug,1986,32(2(:291
[179] 叶德泳. 计算机辅助药物设计导论[M]. 北京: 化学工业出版社,2003:90-123
[180] 仇缀百.药物设计学[M].北京:高等教育出版社,1999:6-7
[181] 沈同,王镜岩.生物化学[M].北京:高等教育出版,1990:164-l67
[182] 蒋华良,胡增建,陈建忠,等.配体-受体相互作用的计算机模拟及其在药物设计中的应用[J].化学进展,1998,10(4),427-441
[183] Gulda WC.Software for structure-based drug design[J].Curr Opin Struct Biol,1994,4:777-781
[184] Blaney JM,Dixon JS. A good ligand is hard to find:automated docking methods[J],Perspect Drug Discov Des,1993,l: 301-319
[185] Wodak SJ,Janin J.Computer analysis of protein interaction[J].J Mol Biol,1978,124: 323-342
[186] 阎隆飞,孙之荣.蛋白质分子结构[M].北京:清华大学出版社,1995:244-248
[187] Holland J.Adaptation in nature and artificial systems [M].University of Michigan Press,1975:120-142
[188] Bhatt MV,Reddy GS.A new synthesis of oxazoles[J].Tetrahedron Letters,1980,21:2359-2360
[189] 春田纯一,桥本宏正,松下睦佳.噁唑类杂环芳香族化合物及其用途
[2] Vane JR,Botting RM.Aspiri and other salicylates[M].London: Chapman& Hall Medical,1992,3-16
[3] Vane JR.Inhibition of prostaglandin synthesis as a mechanism of acition for aspirin-like drugs[J].Nature New Biol,1971,231(25):232-235
[4] Samuelsson B. An elucidation of the arachidonic acid cascade discovery of prosrglandins,thromboxane and leukotrienes[J].Drugs,1987, 33(Supp1 1):2-9
[5] 苏伟,王飞武.环氧酶和脂氧酶双重抑制剂研究进展[J].现代应用药学,1992,9(2):94-99
[6] Vane JR.The evolution of nonsteroidal anti-inflammatory dyugs and their mechanis ms of action[J].Drugs,1987,33(Supp1 1):18-27
[7] Smith JB,Willis AL.Asipirin selectively inhibits prostaglandin production in human platelets[J].Nature New Biol,1971,231(19):235-237
[8] Hemler M,Lands WEM,Smith WL.Purification of the cyclooxygenase-that forms prostaglandins[J].J Bilo Chem,1976,251(16-18):5575-5579
[9] Bakhle YS.Structure of COX-1 and COX-2 enzymes and their interac-tion with inhibitors[J].Drugs Today,1999,35(4-5):237-250
[10] Picot D,Loll PJ,Garavito RM,et al.The x-ray crystal structure of the membrane protein prostaglandin H2 synthase-1[J].Nature,1994,367 (6460):243-249
[11] Masferrer JL, Seibert K, Zweifel BS,et al.The induction and suppres-sion of prostaglandin H2 synthase(cyclooxygenase) in human mono cyt-es [J].J Biol Chem,1990,265(28):16737-16740.
[12] Xie WL, Chipman JG, Robertson DL,et al.Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing[J].Proc Natl Acad Sci USA,1991,88(6): 2692-2696.
[13] Jouzeau JY,Terlain B,Abid A,et al.Cyclooxygenase isoenzymes:how recent findings affect thinking about nonsteroidal antiinfl-amatory druga.DRUGS,1997,53(4):563-582
[14] O′Neill GP,Ford-Hutchinson AW.Expression of mRNA for cycloox-ygenase-1 and cyclooxygenase-2 in human tissues[J].FEBS Lett,1997, 330:150-163
[15] Peil KG,Hardy P,Li DY,Varma DR,et al.Prostaglandin G/H synthase-2 is a major contriutor of brain prostaglandins in the newbom[J].J Biol Chem,1995,270(41):24615-24620
[16] Seibert K,Zhang Y,Lcaky K,et al.Pharmacological and biochemical demonstration of the role of cyclooxygenase-2 in inflammation and pain[J].Proc Natl Acad Sci USA,1994,91:12013
[17] Rofecoxib[J].Drugs Fut,1998,23(12):1287-1296
[18] 李玲.环氧化酶-2 及其研究进展[J].国外医学·分子生物学分册,1999, 21(3):174-178
[19] Appleby SB,Ristimaki A,Neilson K,et al.Structure of the human cyclooxygenase-2 gene[J].Biochem J,1994,302:723-727
[20] Asano K,Lilly Craig M, Drazen JM, et al.Prostaglandin G/H synthase-2 is the constitutive and dominant isoform in cultured human lung epithelial cells[J]. Am J Physiol,1996,271(1):126-131
[21] Barrios-Rodiles M,Keller K,Belley A,et al.Nonsteroidal anti-inflam matory drugs inhibit tcyclooxygenase-2 enzyme activity but not mRNA expression in human macrophages[J].Biochem Biophys Res Comm un,1996,225:896-900
[22] 王兆钺等.国外医学生理病理科学与临床,1996,16(1):97
[23] Bertolini A,Ottani A,Sandrini M.Dual acting anti-inflammatory drugs:a reappraisal[J].Pharmacological Research.Vol.,2001:437-450
[24] Morita I,et al.Different intracellular locations for prostaglandin endopreroxide H stnthase-1and-2[J].J Biol Chem,1995,270(18): 10902 -10908
[25] Cannon GW.Cyclooxygenase 2 selective inhibitors[J].Drugs Today, 1999,35:487-496.
[26] 陈蓓,唐福林.非甾体抗炎药的作用机理及研究进展[J].北京医学,1998,20(3):167-168
[27] Kurubail RG,Stevens AM,Gerse JK,et al.Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents [J].Nature,1996,384(6610):644-648
[28] Eyn JV,Pairet M.Clinical experience with cyclooxygenase-2 inhibitor [J].Inflamm Res,1999,48(5):247-254.
[29] 桑诺尔,叶铁虎.新型特异性COX-2 抑制剂[J].Parecoxib,2002,22(4): 254-255.
[30] Vane JR,Botting RM.Snti-inflammatory drugs and their mechanism of action[J].Inflamm Res,1998,47(Supp1 2):78-87
[31] Hawkey CJ.COX-2 inhibitors[J].Lancet,1999,353(9149):307-314
[32] 高鹏,周君,白海燕.环氧化酶-2 及其选择性抑制剂的研究现状与展望[J].天津药学,2002,14(2):25-27
[33] 敖桂珍,张玉彬,张奕华.新型非甾体抗炎药作用靶环氧酶-2 研究进展 [J].中国新药杂志,2001,10(7):492-496
[34] Dannhardt G, Kiefer W.Cyclooxygenase inhibitorscurrent status and future prospects[J].Eur J Med Chem,2001,36(2):109-126
[35] Herschman HR, Talley JJ, Dubois R,et al.Cyclooxygenase-2 (COX -2) as a target for therapy and noninvasive imaging[J].Mol Imaging Biol, 2003,5(5):286-303.
[36] Marnett LJ, Kalgutkar AS.Design of selective inhibitors of cyclooxyg enase-2 as nonulcerogenic anti-inflammatory agents[J].Curr opin Chem Biol,1998,2(4):482-490.
[37] Frolich JC.A classification of NSAIDs according to the relative inhi-bition of cyclooxygenase isoenzymes[J].Tips,1997,18(1):30-34.
[38] Warner T,Giuliano F,Vojnovic I,et al.Nonstroid drug selectivities for cyclooxygenase-1 rather than cyclooxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis[J].Proc Natl Acad Sci USA,1999,96(13-14):7563
[39] Rabasseda X.Nimesulide: A selective cyclooxyfenase 2 inhibitor antiinflammatory drug[J].Drugs Today,1996,32(5):365-384
[40] Shah A,Murray F,Fizgerald D.The in vivo assessment of nimesulide cyclooxygenase-2 selectivity.Rheumatol Oxford,1999, 38(Suppl 1):19
[41] Futaki N,Arai I,Hamasaka Y,et al.Seletive inhibitor of NS-398 on progtanold production in inflamed tissue in rat carrageenan-airpouch inflammation[J].J Pharm Pharmmacol.1993,45(1-9):753-755
[42] 朱七庆,屈凌波,雷新胜等.环氧合酶-2 抑制剂的对接(Dock)研究[J].中国药物化学杂志,1999,9:114
[43] Hirschelmann R,Hentschel M,Rickingger V,et al.CGP28238,a new potent nonsteroidal anti-inflammatory agent:its relation to arachidonic acid metabolism[J].Agent Actions,1991,32(1-2):54-55
[44] Chan CC,Boyce S,Brideau C,et al.Pharmacology of a selective cyclooxygenase-2 inhibitor,L-745337:A novel nonsteroidal antiinf-alammatory agent with an ulcerogenic sparing effect in rat and nonhu-man primate stomach[J].J Pharmacol Exp Ther,1995,274(3):1531-1537
[45] Otterness IG,Moore PF.Carrageenan foot eclema test[J].Methods Enzymol,1988,162:320-327
[46] Talley JJ.Prog Med Chem.1999,36:201-234
[47] Li JJ,Anderson GD,Bureon EG,et al.1,2-Diarylcychlpentenes as selective cyclooxygenase-2 inhibitors and ofally active anti-inflammatory agents[J].J Med Chem,1995,38(21-26):4570-4578
[48] Gans KR,Galbraith W,Roman RJ,et al.Antiinflammatory and safety profile of Dup-697,a novel orally effective prostaglandin synthesis inhibitor[J].J Pharmacol Exp Ther,1999,245:180
[49]Kiyoushi T,Katsuya N,Nobukiyo K, et al.Studies on anti-inflammatory agents. Ⅳ.Synthesis and pharmacological properties of 1,5-di-arylpyrazole and related derivatives[J].Chem Pharm Bull,1997,45(6):987-995
[50] Reitz DB,Li JJ,Norton MB,et al.Selective cyclooxygenase inhibitors novel 1,2-diarylcyclopentencs acspot entand or ally active COX-2 inhibitotors[J].J Med Chem,1994,37(23):3878-3881
[51]Penning TD,Talley JJ,Bertenshaw SR,et al.Synthesis and biological evaluation of the 1,5-diarylpyra-zole class of cyclooxygenase-2 inhibito-rs : Identification of 4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol -1-yl]benzene sulfonamide(SC-58635,Celecoxib)[J].J Med Chem, 1997, 40(9):1347-1365.
[52] Clemett D,Goa KL,Celecoxib,A review of its use in osteoarthritis, rheumatoid arthritis and acute pain[J].Drugs,2000,59(4):957-980
[53] Day R.O.,Francis H,Vial J,et al.Naproxen concentrations in plasma and synovial fluid and effects on prostanoid concentrations[J].J Rheumatol,1995,22:2295
[54] Celecoxib.Drugs Fut,1999,24:795
[55] Zang Y,Shaffer A,Portanova J,et al.Inhibition of cyclooxygenase-2 rapidly reverses inflammatory hyperalgesia and prostaglandin E2 proeluction[J].J Pharmacal Exp Ther,1997,283:1069
[56] Plount Price ML,Jorgensen WL.Analysis of binding affinities for Celecoxib analogues with COX-1 and COX-2 from combined docking and monte carlo simulations and insight into the COX-2/COX-1 selectivity[J].J Am Chem Soc,2000,122(39):9455-9466.
[57] Habeeb AG, Praveen Rao PN, Knaus EE,et al.Design and synthesis of Celecoxib and Rofecoxib analogues as selective cyclooxygenase (COX-2) inhibitors:Replacement of sulfonamide and methylsulfonyl pharmacophores by an azido bioisostere[J].J Med Chem,2001,44(18): 3039-3042.
[58] Uddin MJ, Praveen Rao PN, Knaus EE,et al. Design and synthesis of Celecoxib analogues as selective cyclooxygenase (COX-2) inhibito-rs:Replacement of the sulfonamide pharmacophore by a sulfonylazide bioisostere[J].Bioorg Med Chem,2003,11(23):5273-5280.
[59] Kurumbail RG, Kiefer JR,Marnett LJ,et al.Cyclooxygenase enzym- es:catalysis and inhibition[J].Curr Opin Struct Biol,2001,11(6):752-760
[60] Black WC, Brideau C, Chan CC,et al.3,4-Diaryl-5-hydroxy-furanon-es:Highly selective inhibitors of cyclooxygenase-2 with aqueous solubi-lity[J].Bioorg Med Chem Lett,2003,13(6):1195-1198
[61] 廖斌, 丛欣, 廖清江, 等.2002 年世界上市的新药[J]. 药学进展,2003,27(3):190-193
[62] Talley JJ, Bertenshaw SR,Brown DL,et al.N-[[(5-Methyl-3-phenyl-isoxazol-4-yl)phenyl]sulfon-yl]pr-opanamide,Sodium salt, parecoxib so-dium:a potent and selective inhibitor of COX-2 for parenteraladministr-ation[J].J Med Chem,2000,49(9):1661-1663
[63] Pal M, Madan M, Padakanti S,et al.Synthesis and cyclooxygenase -2 inhibiting property of 1,5-diaryl pyrazoles with substituted benzene-sulfonamide moiety as pharmacophore:Preparation of sodium salt for injectable formulation[J].J Med Chem,2003, 46(19): 3975-3984
[64] Singh SK, Reddy PG, Rao KS,et al.Polar substitutions in the ben-zenesulfonamide ring of celecoxib afford a potent 1,5-diaryl-pyrazole class of COX-2 inhibitors[J].Bioorg Med Chem Lett,2004,14(2): 499-504
[65] Song Y, Connor DT, Doubleday R,et al. Synthesis, structureactivity relationships, and in vivo evaluations of substituted ditert-butylphenols as a novel class of potent, selective, and orally active cyclooxygenase-2 inhibitors. 1. Thiazolone and oxazolone series [J].J Med Chem, 1999, 42 (7): 1151 -1160.
[66] Song Y, Connor DT, Sercel AD,et al. Synthesis, structureactivity rel-ationships, and in vivo evaluations of substituted ditert-butylphenols as a novel class of potent, selective, and orally active cyclooxygenase-2 inhibitors. 2. 1,3,4-and 1,2,4-thiadi-azole series [J].J Med Chem, 1999,42(7): 1161 -1169
[67] Janusz JM, Young PA, Scherz MW,et al.New cyclooxygenase-2/5-lipoxygenase inhibitors. 2.7-tert-butyl-2,3-dihydro-3,3-dimethyl benzofu-ran derivatives as gastrointestinal safe anti-inflammatory and analgesic agents:Variations of the dihydrobenzofuranring[J].J Med Chem,1998, 41 (7):1124-1137
[68] Barbey S,Goossens L, Taverne T,et al.Synthesis and activity of a new methoxytetrahydropyran derivative as dual cyclooxygenase -2/5-lipoxygenase inhibitor[J].Bioorg Med Chem Lett,2002,12(5): 779-782
[69] Ranatunge RR, Augustyniak M,Bandarage UK,et al.Synthesis and selective cyclooxygenase-2 inhibitoryactivity of a series of novel,nitric oxide donor-containing pyrazoles[J].J Med Chem, 2004, 47(9):2180-2193
[70] Balsamo A, Coletta I, Guglielmotti A,et al.Synthesis of heteroaroma-tic analogues of (2-aryl-1-cyclo-pentenyl-1-alkyli dene)-(arylmethyloxy)-amine COX-2 inhibitors:effects on the inhibitory activity of the repla cem-ent of the cyclopentene central core with pyrazole,thiophene or isoxazo-le ring[J].Eur J Med Chem, 2003,38(2):157-168
[71] Rapposelli S, Lapucci A, Minutolo F,et al.Synthesis and COX-2 inhibitory properties of N-phenyl and N-benzyl-substituted amides of 2-(4-methylsulfonylphenyl)cyclopent-1-ene-1-carboxylic acid and of their pyrazole,thiophene and isoxazole analogs[J].II Farmco, 2004, 59 (1): 25-31
[72] Singh SK,Vobbalareddy S, Shivaramakrishna S,et al. Methane sulfonamide group at position-4 of the C-5-phenyl ring of 1,5-diarylpyrazole affords a potent class of cyclooxygenase-2 (COX-2) inhibitors[J].Bioorg Med Chem Lett,2004,14(7):1683-1688
[73] Dannhardt G,Laufer S.Structural approaches to explain the selectivity of cyclooxygenase-2 inhibitors: is there a common pharmaco-phore[J].Curr Med Chem,2000,7(11):1101-1112.
[74] Van RJ, Trummlitz G, Pairet M, et al.Cyclooxygenase-2 seleci vity and inflammatory processes[J].Curr Med Chem ,2000,7(11): 1145-1161
[75] Sui Z,Guan J, Ferro MP,et al.1,3-Diarylcycloalkano-pyrazoles and diphenyl hydrazides as selective inhibitors ofcyclooxygenase-2 [J]. Bioorg Med Chem Lett,2000,10(6):601-604
[76] Banoglu E,Akoglu C,Unlu S,et al.Amide derivatives of [6-(5-Methyl -3-phenylpyrazole-1-yl)-3(2H) –pyridazinone-2-yl]acetic acid as poten-tial analgesic and antiinflammatory compounds[J].Arch Pharm Pharm Med Chem,2004,337(1):7-14
[77] Bertenshaw SR,Talley JJ, Rogier DJ,et al.Conformationally restric-ted 1,5-diarylpyrazoles are selective COX-2 inhibitors[J]. Bioorg Med Chem Lett,1996,6(23):2827-2830.
[78] Almansa C, Arriba AF, Cavalcanti FL,et al.Synthesis and SAR of a new series of COX-2-selective inhibitors:Pyrazolo[1,5-a] pyrimidines[J].J Med Chem,2001,44(3):350-361.
[79] Ranatunge RR, Garvey DS, Janero DR,et al.Synthesisi and selecti-ve cyclooxygenase-2 (COX-2) inhibitory activity of a series of novel bicy-clic pyrazoles[J].Bioorg Med Chem,2004,12(6):1357-1366.
[80] Baruah B,Dasu K,Vaitilingam B,et al.1,2-Diaryl-1-ethanone and pyr- azolo[4,3-c]quinoline-4-one as novel selective cyclooxygenase -2 inhibi-tors[J].Bioorg Med Chem Lett,2004,14(2):445-448.
[81] Prasit P,Wang Z, Brideau C,et al. Synthesis and preliminary biological evaluation of new alpha-amino amide anticonvulsants incorporating a dextromethorphan moiety[J]. Bioorg Med Chem Lett, 1999,9(13):1773-1788
[82] Chan CC,Boyce S,Brideau C,et al.Rofecoxib:a potent and orally active cyclooxygenase-2 inhibitor.Pharmacological and biochemical profiles[J].J Pharmacol Exp Ther,1999,290(2):551-980
[83] Chun-Sing Li,Riendeau D,Therien M,et al.A new structural variation on the methanesulfonylphenyl class of selective cyclooxy-genase-2 inhibitors[J].Bioorg Med Chem Lett,1999,9(22):3181-3186.
[84] Leblanc Y,Roy P,Boyce S,et al.SAR in the alkoxy lactone series: the discovery of DFP, a potent and orally active COX-2 inhibitor [J].Bioorg Med Chem Lett,1999,9(15):2207-2212.
[85] Lau CK,Brideau C,Chan CC,et al.Synthesis and biological evalua-tion of 3-heteroaryloxy-4-phenyl-2(5H)-furanones as selective COX-2 inhibitors[J].Bioorg Med Chem Lett, 1999,9(22):3187-3192.
[86] Rahim MA,Rao PNP,Knaus EE,et al. Isomeric acetoxy analogues of rofecoxib: A novel class of highly potent and selective cyclooxygenase-2 inhibitors [J].Bioorg Med Chem Lett,2002,12(19): 2753-2756.
[87] Phillip G, Hochgesang J,Jennifer F,et al.Functional analysis of the molecular determinants of cyclooxygensae-2 acetylatin by 2-acetoxy phenylhept-2-ynyl sulfide[J].Arch biochem biophys,2003, 409:127
[88] Marnett LJ, Kalgutkar AS,Trends Pharmacol[J].Sci,1999,20,465
[89] Khanna IK,Weier RM,Yu Y,et al. 1,2-Diarylimidazoles as potent, cyclooxygenase-2 selective,and orally active antiinflammatory agents [J].J Med Chem,1997,40(11):1634-1647.
[90] Uddin MJ.J Heterocyclic Chem,2003,40:861
[91] Joo Hyun Moh.Bioorg Med Chem Lett,2004,14:1757
[92] Leblanc Y,Roy P, Wang Z,et al. Discovery of a potent and selective COX-2 inhibitor in the alkoxy lactone series with optimized metabolic profile[J].Bioorg Med Chem Lett,2002,12(22): 3317-3320
[93] Chan CC, Boyce S,Brideau C,et al.Inflammation Res.1997,46, S 242.
[94] Talley JJ,Bertenshaw SR,Brown DL,et al. N-(((5-methyl-3-phenylisoxazol-4-yl)-phenyl)sulfonyl)propanamide, sodium salt, pareco-xib sodium: A potent and selective inhibitor of COX-2 for parenteral administration[J].J Med Chem,2000,43(9):1661-1663.
[95] Shin SS,Noh MS,Byun YJ,et al.2,2-Dimethyl-4,5-diaryl-3(2H) furanone derivatives as selective cyclo-oxygenase-2 inhibitors [J].Bioorg Med Chem Lett, 2001,11(2):165-168.
[96] Rao PNP,Amini M,Li H,et al.6-Alkyl, alkoxy, or alkylthio-substituted3-(4-methanesulfonylphenyl)-4-phenylpyran-2-ones:A novel class of diarylheterocyclic selective cyclooxygenase-2 inhibitors[J]. Bioorg Med Chem Lett,2003,13(13):2205-2209.
[97] Pal M,Veeramaneni VR,Nagaballi M,et al.Conformationally restricted 3,4-diarylfuranones (2,3a,4,5-tetrahydro-naphthafu ranones) as selective cyclooxygenase-2 inhibitors[J]. Bioorg Med Chem Lett, 2003,13(10):1639-1643.
[98] Dewitt DL.COX-2 Selective inhibitors:the new super aspi-rins.mol[J]. Pharmacol,1999,55:625-631
[99] Jobn JJ,Stepben RB,David LB,et al. 4,5-Diaryloxazole inhibitors of cyclooxygenase-2(COX-2)[J].Medicinal Research Reviews,1999,19(3): 199-208
[100] Gierse JK,Hauser SD,Creeley DP,et al.Expression and selective inhibition of the constitutive and inducible forms of human cyclooxy-genase[J].Biochem J,1995,305:479-484
[101] Masferrer JL,Zweifel BS,Manning PT,et al.Selective inhibition of inducible cyclooxygenase 2 in vivo is anti-inflam-matory and nonulcerogenic[J].Proc Natl Acad Sci USA, 1994,91:3228-3232
[102] Winter CA,Risley EA,Nuss GW,et al.Carrageenan-induced edema in hind paw of the rat as an assay for anti-inflammatory drugs [J].Proc Soc Exp Biol Med,1962,305:479-484
[103] Jaffee BD,Kerr JS,Jones EA,et al.The effect of immunomodulating drugs on adjuvant-induced arthritis in lewis rats[J].Agents actions,1989, 27:344-346
[104]Haruta,Junichi;Hashimoto,Hiromasa;Matsushita,Mutsuyoshi.Prepar ation of heteroaromatic oxazole compounds as selective inhibitors of cyclooxygenase 2[P],JP,WO19463.1996.
[105] Silvestre J,Leeson P a,Castaner J,et al.JTE-522[J].Drugx Fut,1998, 23:598
[106] Talley JJ,Brown DL,Carter JS,et al.4-[5-Methyl-3-phe-nyl-isoxazol -4-yl]-benzenesulfonamide,Valdecoxib:A Potent and Seletive Inhibitor of COX-2[J].J Med Chem,2000,43(5):775-777
[107] Leese PT,Recker D,Kuss ME.A double-blind,plasebo-controlled study to evaluate the effects of valdecoxib,a novel cox-2 specific inhibitor,on platelet function in the elderly [J]. Anesthesiology, 2000, 93:227
[108] Leese PT,Recker D,Kuss ME.The novel cox-2 specific inhibitor valdecoxib,does not affect platelet function in healthy adults [J]. Anesthesiology,2000,93:228
[109] Camu F,Beecher T,Recker DP,et al.valdecoxib,a cox-2 specific inhibitor,is an efficacious,opioid-sparing analgesic in patients undergoing hip arthroplasy[J].Am J Ther,2002,9:43-51
[110] Fricke J,Varkalis J,Zwillich S,et al.Valdecoxib is more efficacious than rofecoxib in relieving pain associated with oral surgery[J].Am J Ther,2002,9:89-97
[111] Desjiardins PJ,Shu VS,Recker DP,et al.A single preoperative oral dose of Valdecoxib,a new cyclooxygenase-2 specific inhibitor, relieves postoral surgery or bunionectomy pain[J].Anesthesiology, 2002,97 (1-3): 565-573
[112] Daniels SE,Desjardins PJ,Talwalker S,et al.The analgesic efficacy of valdecoxib vs oxycodonel/acetaminophen after oral surgery[J].J Am Dent Assoc,2002,133:611-621
[113] Kivitz A,Eisen G,Zhao WW,et al.Randomized placebocontrolled trial comparing efficacy and safety of valdecoxib with naproxen in patients with osteoarthritis[J].J Fam Pract,2002,51:530-537
[114] Makarowski W,Zhao WW,Bevirt T,et al.Efficacy and safety of the cox-2 specific inhibitor valdecoxib in the management of osteoarthritis of the hip: a randomized,double-blind placebo-controlled compaison with naproxen.Osteoarthritis Cartilage,2002, 10:290-296
[115] Habeeb AG,Rao PNP,Knaus EE,et al.Design and Synthesis of 4,5-Diphenyl-4-isoxazolines:Novel Inhibitors of Cyclooxygenase-2 with Analgesic and Antiinflammatory Activity[J].J Med Chem, 2001,44(18):2921-2927
[116] Carles Puig,Maria I.Crespo,Nuria Godessart,et al.Synthesis and biological evaluation of 3,4-Diaryloxazolones:A new class of orally active cyclooxygenase-2 inhibitors[J].J Med Chem,2000,43(2): 214-223
[117] Kalgutkar A.S.,Crews B.C.,Rowlinson S.w.,et al.Aspirin-like molecules that covalently inactivate cyclooxygenase-2[J].Science, 1998,280(5367):1268-1270
[118] Black WC,Bayly C,Belley M,et al. From indomethacin to a selective COX-2 inhibitor: Development of indolalkanoic acids as potent and selective cyclooxygenase-2 inhibitors [J].Bioorg Med Chem Lett,1996, 6(6):725-730
[119] Leblance Y,Black WC,Chan CC,et al. Synthesis and biological evaluation of both enantiomers of L-761,000 as inhibitors of cyclooxygenase 1 and 2 [J].Bioorg Med Chem Lett,1996,6(6):731-736
[120] Kalgutkar AS,Kalgukar SW,Crews BC,et al. Amide derivatives of meclofenamic acid as selective cyclooxygenase-2 inhibitors [J].Bioorg Med Chem Lett,2002,12(4):521-524
[121] Surh YJ,Lee JY,Choi KJ,et al.Effects of selected ginsenosides on phorbol ester-induced expression of cyclooxygenase-2 and activation of NF-Kb and ERK1/2 in mouse skin[J].Ann N Y Acad Sci.2002, 973: 396-401
[122] Yagi A,Kabash A,Okanmra N,et al.Antioxidant free radical scaneging and anti-inflammatory effects of aloesin derivatives in Aloe[J].Planta Med,2002,68(11):957-960
[123] Jayaprakasam B,Seeram NP,Nair MG.Anticancer and anti-inflammatory activities of cucurbitacins from Cucurbita andreana[J]. Cancer Lett,2003,189(1):11-16
[124] Yang LL,Liang YC,Chang CW,et al.Effects of sphondin,isolated feom Heracleum laciniatum,on IL-1 βinduced cyclooxygenase-2 expression in human pulmonary epithelial cells[J].Life Sci,2002,72(2): 199-213
[125] Gilroy DW,Tomilison A,Willoughby DA.Differential effects of inhibitors of cyclooxygenase(cyclooxygenase 1 and cyclooxygenase 2)in acute inflammation[J].Eur J Pharmacol.1998,355:211-217
[126] Willoughby DA,Moore AR,Colville-Nash PR.COX-1,COX-2,and COX-3 and the future treatment of chronic inflammatory disease [J]. Lancet,2000,355:646-648
[127] 周剑涛,万英.环氧合酶-3[J].生命化学,2003,23(4):272～274
[128]Chandrasekharan NV,Dai H,Roos KL,et al.COX-3,a Cyclooxy-genase-1 variant inhibited by acetaminophen and oth er anal gesic/antipyretic drugs: Cloning,structure,and expression [J].J Proc Natl Acad Sci,2002,99(21):13926-13931
[129] Warner TD,Mitchell JA.Cyclooxygenase-3(COX-3):filling in the qaps toward a COX continuum?[J].J Proc Natl Acad Sci,2002,99(21): 13371-13373
[130] Kulkarni SK,Jingh A.Nitric oxide-releasing NSAIDs:a new dimension in nonsteriodal antiin-flammatory drugs[J].Drugs Fut, 2001, 26(5):485-489
[131] Cena C,Lolli ML,Lazzarato L,et al.Antiinflammatory, gastr osparing,andanti-inflammatory,gastrosparing,andantiplatelt properties of new NO-donor esters of Aspirin[J].J Med Chem,2003,46 (5):747-754
[132] Wallace JL,Soldato PD.The therapeutic potential of NO-NSAIDs [J].Fundam Clin Pharmacol,2003,17(1):11-20
[133] Wallace JL,Chin BC. New generation NSAIDS: The benefits without the risks?[J].Drugs Today,1997,33(6):371-378
[134] 傅德才,王淑月,荣杰,等.非甾体抗炎药(NSAIDs)的新进展[J].河北工业科技,2004,21(3):55-57
[135] Mitchell JA,Cirion G,Akarasereenont P,et al.Flurbiprofen ni troxybutylester:a norel anti-inflammatory drug devoid of ulcerogenic activity,Inhibits cyclooxygenase-1 and cyclooxy-genase-2[J].Can J Phyi ol Pharmacol,1994,72:720
[136] Takaeachi K,Ukawa H,Konoka A,et al.Effect of nitric oxide releasing aspirin derivative on gastric functional and vicerogenic responses in rats:comparision with aspirin[J].J Pharmacol Exp Ther, 1998,286:115-121
[137] Cuzzolin L,Confort A,Adami A,et al. Anti-inflammatory potency and gastrointestinal toxicity of a new compound, nitronaproxen [J]. Pharmac ol Res,1995,31(1):61-65
[138] Wallace JL, Bak A,McKnight W,et al.Cyclooxygenase 1 contributes to inflammatory responses in rats and mice: implications for gastrointe-stinal toxicity [J].Gastroenterology, 1998,115(1):101-109
[139] Davies NM,Rostch AG,Appleycerd CB,et al.NO-naproxen vs naproxen: ulcerogenic,Analgesic and Antiinflammatory Effects[J]. Aliment Pharmacol Ther,1997,11(1):69-79
[140] Bargaud JL,Benedini F,Robinson EM,et al.HCT-1026 Flurbiprofen nitroxybutyl ester[J].Drugs of the Future,1999,24(8): 858-861
[141] Girino G,Galignano A,Sannicolo F,et al.Antiinflammatory, analgesic, anti-thromboticdrugs:NCX-4016[J].Drugs Fut,1997,22(11): 1231-1233
[142] Wallace JL,Moscara MN,Mckight W,et al.In:vivo Antithrombotic Effects of nitric oxidereleasing aspirin derivatives,NCX-4016[J]. Thromb Res,1999,93(1):43-50
[143]Elliott SN,Mcknight W,Cirino G,et al.A nitric oxiderealedsing nonsteriod antiflammatory drug auelerates gastric ulcer healing in nats[J].Gastroeuterology,1995,109(2):524-530
[144] 李瑞文,张奕华,季晖,等.苯磺酰基呋咱氮氧化物与双氯酚酸偶联化合物的合成与抗炎活性[J].药学学报,2001,36(11):821-826
[145] 冯晓春,季晖,张奕华,等.ZLR-8 对大鼠溃疡愈合的影响及体外一氧化氮释放作用[J].中国药科大学学报,2004,35(4):357-360
[146] 王未东,张奕华,季晖,等.一氧化氮供体型氟罗布酚衍生物的合成与抗炎活性[J].中国药物化学杂志,2004,14(1):1-8
[147] Bobert M,Clanc Y,Steven B.Nitric oxide:A Novel mediator of in flammation,Pros Soc Exp Biol Med,1995,210(2):93-101
[148] Carini M,Aldini G,Stefani R,et al.Nitrosylhemoglobn,an unequi vocalindex of nitric oxide release from nitroaspirin:in vitro and in vivo studies in the rat by ESR spectroscopy[J].J Pharm Biomed Anal,2001, 26(5):509-518
[149] Kashfi K,Rgann Y,Qiao LL,et al.Nitric oxidedonating nonsteroidal anti-inflammatory drugs inhibitit the growth of various culotured human cancer cells:evidence of a tissue typeindependent effect[J].J Pharmucol Exp Ther,2002,303(3):1273-1282
[150] Kuchar M,Matarova E,Brunova B,et al.Quantitative relations between structure and anti-inflammatory activity of aryloxoalkanoic acids[J].Collect Czech Commum,1988,53(7-9):1862-1872
[151] Lewis RA,Austen KF,Sobeman RJ,et al.Leukotrienes and other products of the 5-lipoxygenase pathway[J].New Engl J Med,1990,323 (10):645-655
[152] Fuynn DL,Capiris T,Cetenko WJ,et al.Nonsteroildol anti-inflammatory drug hydroxamic acids,dual 5-lipoxygenase and cyclooxy-genase inhibitors[J].J Med Chem,1990,33(5-8):2070-2072
[153] Janusz JM,Young PA,Ridgeway JM,et al.New cyclooxygenase -2/5-lipoxygenase inhibitors 1,7-tertbutyl-2,3-dihydro-3,3-dimethyl-ben-zofuran derivatives as gastrointestinal safe anti-inflammatory and analgesic agents:discovery and variation of the 5-ketosubs-tituent[J].J Med Chem,1998,41(7): 1112-1123
[154] Lee SJ,Frieson MR,Wong S,et al.BF-389 Antiinflammatory [J].Drugs Fut,1992,17(1):12-14
[155] Tkuta H,Sbirota H,Kobayashi Y,et al.Synthesis and anti-inflammatory activities os 3-(3,5-ditertbutyl-4-hydroxy-benzyllidine) pynolidin-2-ones[J].J Med Chem,1987,30(1):1995-2004
[156] Marfin L,Rabasseda X,Castaner J,et al.Darbufelone mesilate: Prop INNM, antiarthritic, lipoxygenase inhibitor, cyclooxygenase-2 inhibitor: CI-1004 PD-136095-0073[J].Drugs of the Future,1999, 24(8):853-857.
[157] Unangst PC,Connor DT,Cetenko WA,et al.Synthesis and boliogical evaluation of 5-[[3,5-bis-(1,1-dimethylethyl) -4-hydroxylphenyl]methyl-lene]oxazoles,-khiazoles,-imidazoles:novel dual 5-lipoxygenase and cyclooxygenase inhibitors with anti-inflamroatory activity[J].J Med Chem,1994,37(2):322-328
[158] Kneen G,Jackson WP,Islip PJ,et al.Preperation of arylhydroxamic acid derivative compositions containing them,and their use in medicane and otherapplications.EP 196184,1986-10-1
[159] Nagaki M,Tsuri T,Jyoyama H,et al.Novel antiarthritic agents with 1,2-isothiazolidine-1,1-dioxide( γ-sultam)skeleton:cytokine suppreasive dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase [J].J Med Chem,2000,43:2040-3048
[150] Laufer SA,Auguatin J,Dannhardt G,et al.(6,7-Diaryldihydro-pynolizin-5-yl)acetic axids,a novel class of potent dualinhibi-torsof 5-lipoxygenase and cyclooxygenase[J].J Med Chem,1994,37(2): 1894-1897
[161]敖桂珍,吉念宁,张奕华,等.环氧酶/5-脂氧酶双重抑制剂的定量构效关系研究[J].计算机与应用化学,2003,20(1):6-8
[162] Reddy BS,Rao CV,Rivenson A,et al.Ihbitory effects of aspirin on azoxymathane induced colon carcinogenesis in F344 rats[J]. Carcinogenesis,1993,328:1313-1316
[163] Sorensen HT,friis S,Norgard B,et al.Risk of cancer in a large cohort of nonaspirin NSAID users:a population-based study[J].Br J Cancer, 2003,88(11):1687-1692
[164] Gardiner PS,Gilmer JF.The medlcinal chemistry implications of the anticancer effects of aspirin and other NSAIDs[J].Mini Rev Med Chem,2003,3(5):461-470
[165] Xu XC.COX-2 inhibitors in cancer treatment and prevention,a recent development[J].Anticancer Drugs,2002,13:127-137
[166] Sawaoka H,Kawano S,Tsuji S,et al.Effects of NSAIDs on proliferation of gastric cancer cells in vitro:possible implication of cyclooxygenase-2 in cancer developmet[J].J Clin Gastroenterol, 1998,27(Suppl):S47-S52
[167] Hongmiao S,Jinyi S,Kirkland SC,et al.Inhibition of human colon cancer cell growth by selective inhibition of cyclooxy-genase-2[J].J Clin Invest,1997,99:2245-2259
[168] Halliday G,Robinson SR,Shepherd C,et al.Alzheimer′s disease and inflammation:a review of cellular and therapeutic mechanisms[J]. Clin Exp Pharmacol Physio,2000,27:1-8
[169] Van JR,Booting RM.Meched anism of acfion of nonseeriodal an liinpiammatoty drags[J].Am J Med,1998,104(3):2
[170] Graharm DY.Prevention of gastroduodenal injury induced by chronic nonsteroidal antiinfla matory drug therapy[J].Gast roeent-erology,1989,96(1-4):675
[171] Armstrong CP,blower AL.Nonsteroidal antiinfla matory drugs and life threatening complications of pepctic upceration[J].Cut, 1987,28:527
[172] Maricic N,Ehrlich K,Gretzer B,et al.Selective cyclooxy-genase-2 inhibitors aggravate ischaemia reperfusion injury in the rat stomach[J].Br J Pharmacol,1999,128(8):1659-1666
[173] Reuben SS,Steinberg R.Gastric perforation associat with the use of celecoxib[J].Anesthesiology,1999,91(5):1548-1549
[174] Ahmad SR,Kortepeter C,Brinker A,et al.Renal failure associa-ted with the use of celecoxib and rofecoxib[J].Drug Saf,2002,25(7): 527
[175] Cheng HF,Wang JL,Zhang MZ,et al.Angiotensin Ⅱattenant esrenal cortical cyclooxygenase-2 expressior[J].J J Clin Invest, 1999,103(7):953-961
[176] 陈芬儿. 有机药物合成法[M], 北京: 中国医药科技出版社,1999:199-200
[177] Lewis AJ,Current Therapeutic Research.1983,34:777-794
[178] Todd PA,Drug,1986,32(2(:291
[179] 叶德泳. 计算机辅助药物设计导论[M]. 北京: 化学工业出版社,2003:90-123
[180] 仇缀百.药物设计学[M].北京:高等教育出版社,1999:6-7
[181] 沈同,王镜岩.生物化学[M].北京:高等教育出版,1990:164-l67
[182] 蒋华良,胡增建,陈建忠,等.配体-受体相互作用的计算机模拟及其在药物设计中的应用[J].化学进展,1998,10(4),427-441
[183] Gulda WC.Software for structure-based drug design[J].Curr Opin Struct Biol,1994,4:777-781
[184] Blaney JM,Dixon JS. A good ligand is hard to find:automated docking methods[J],Perspect Drug Discov Des,1993,l: 301-319
[185] Wodak SJ,Janin J.Computer analysis of protein interaction[J].J Mol Biol,1978,124: 323-342
[186] 阎隆飞,孙之荣.蛋白质分子结构[M].北京:清华大学出版社,1995:244-248
[187] Holland J.Adaptation in nature and artificial systems [M].University of Michigan Press,1975:120-142
[188] Bhatt MV,Reddy GS.A new synthesis of oxazoles[J].Tetrahedron Letters,1980,21:2359-2360
[189] 春田纯一,桥本宏正,松下睦佳.噁唑类杂环芳香族化合物及其用途