高选择性环氧化酶—2抑制剂的进展与评价

目的 :介绍高选择性环氧化酶 - 2抑制剂———昔布类药物进展 ,并评价其临床疗效 ,以供临床参考。方法 :查阅国内、外近期相关文献进行分析、评价。结果与结论 :昔布类高选择性环氧化酶 - 2抑制剂进展十分迅速 ,对环氧化酶 - 2的选择性高 ,在治疗骨关节炎和类风湿性关节炎、关节痛、术后疼痛和肿瘤上展现了良好的治疗前景     

选择性环氧化酶-2抑制剂的研究与安全性

近年研究发现,环氧化酶有两种同工酶,即COX-1和COX-2。COX-1对机体功能具有生理性保护作用,而COX-2主要参与炎症等病理反应的调节。非甾体类药物的抗炎镇痛等作用源于对COX-2的抑制,而胃肠道等不良反应的发生则与COX-1被抑制密切相关。本文介绍了COX-1与COX-2的主要特点;目前已上市的几种选择性COX-2抑制剂及其在治疗肿瘤、老年性痴呆、动脉粥样硬化等方面的前景;以及增加心血管不良事件等方面研究进展。     

选择性环氧化酶—2—抑制剂

非甾体抗炎药(NSAID)是一类目前临床广泛应用的解热、镇痛、抗炎药物.讫今已有一百多个品种.按化学结构下同,大致可分为3大类:吡唑酮类.昔康类和羧酸类.其作用机制主要是通过抑制环氧化酶(COX).从而阻断花生四烯酸合成前列腺素(PG).而PG在体内又具有广泛的生理功能,对神经系统可导致炎症与疼痛.对心血管系统可扩张肾血管,增加肾血流.尿及钠排出增加.对消化系统可抑制胃酸分泌.保护日粘膜作用.因此,常用的NSAlD在发挥治疗作用的同时也会引起对胃肠道的刺激.从而致消化性溃疡以及产生肾毒性.90年代后国外学者发现COX存在两种形式.即COX_1和COX_2..两者除具有相同的相对分子质量和60%相同的氨基酸序列外.其他许多方面却不同.COX_1存在于大多数人体组织中(尤其是胃、肾和血小板),通过合成生理需要的PG来调节细胞正常生理活性.如抑制胃     

新的研究进一步证实环氧化酶—2抑制剂的胃肠道安全性

最近 ,ＢＭＪ组织公布的 2项研究结果进一步证实了环氧化酶 - 2 (ＣＯＸ - 2 )抑制剂与传统的非甾体抗炎药 (ＮＳＡＩＤ)相比 ,对胃肠道的不良反应显著降低 ,编者指出 ,将进一步确认可能发生的其他非胃肠道的不良反应。ＣＯＸ - 2抑制剂的风险 /效益比率还不清楚。英国的研究者报道 ,Ｃｅｌｅｃｏｘｉｂ与其他非甾体抗炎药对骨关节炎和类风湿性关节炎症状的解除疗效相当 ,但明显改善了对胃肠道的安全性和耐受性。他们进行了系统性随机试验比较了Ｃｅｌｅｃｏｘｉｂ与其他ＮＳＡＩＤ或安慰剂用于治疗骨关节炎和风湿性关节炎的≥ 12周的有效性…     

环氧化酶-2选择性抑制剂研究进展

本世纪９０年代初发现环氧化酶（ＣＯＸ）存在两种不同亚型：环氧化酶－１（ＣＯＸ－１）和环氧化酶－２（ＣＯＸ－２）。对ＣＯＸ－１和ＣＯＸ－２的抑制,分别构成传统非甾体抗炎药（ＮＳＡＩＤｓ）不良胃肠反应和有效治疗作用的基础。开发ＣＯＸ－２选择性抑制剂成为ＮＳＡＩＤｓ发展的热点和前沿。笔者就近年来国外ＣＯＸ－２抑制剂的研究进展作一报道。     

特异性环氧化酶-2抑制剂的评价

<正>1 昔布类药物现状合成前列腺素(PGs)的关键酶——环氧化酶 (cyclooxygenase,COX)是1971年发现的,1991年又发现COX有两种异构体——COX-1和COX-2,     

昔布类高选择性环氧化酶-2抑制剂

综述国内外文献介绍高选择性环氧化酶-2抑制剂--昔布类药物的新进展.昔布类高选择性环氧化酶-2抑制剂研究进展十分迅速,它对环氧化酶-2的选择性高,在治疗骨关节炎和类风湿性关节炎、关节痛、术后疼痛和肿瘤方面展现了良好的治疗前景.     

环氧化酶-2选择性抑制剂的研究与开发

综述环氧化酶-2选择性抑制剂的分子基础及其构效关系。甾体抗炎药的有效治疗作用源于对环氧化酶-2的抑制作用，其副作用则是由于对环氧化酶-1的抑制作用所致，因此寻找高效环氧化酶-2选择性抑制剂成为甾体抗炎药的研究热点。     

环氧化酶和环氧化酶—2抑制剂

非甾体抗炎药通过抑制环氧化酶,减少前列腺素的生成合理而呈现抗炎作用。现在发现,环氧化酶至少有两种异构体,即环氧化酶－１和环氧化酶－２。环氧化酶－１－可催人人体正常生理功能所需的前列腺素的合成;环氧化酶－２则由炎性刺激所产生。     

Significance and creation of novel cyclooxygenase-1 (COX-1) selective inhibitors

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to relieve physical and mental pain, and to improve patients' quality of life. However, stomach irritation is a major side effect. Most NSAIDs inhibit cyclooxygenases (COXs), and inhibition of COX-1 on the stomach mucous membrane is thought to be responsible for the gastric disturb- ance. Consequently, development efforts have focused on COX-2-selective inhibitors, while COX-1-selective inhibitors have been rather neglected. Subsequently, however, it was shown that inhibition of either COX-1 or COX-2 alone does not induce gastric damage. Therefore, we have developed the COX-1-selective inhibitor N-(4-aminophenyl)-4-trifluoromethylbenzamide (TFAP), which shows analgesic activity without causing gastric damage. However, metabolism of TFAP generates a colored metabolite, resulting in red-purple coloration of urine after administration. In addition, the analgesic activity of TFAP is weaker than that of indomethacin. Thus, we designed a series of new COX-1-selective inhibitors, the 5-amino-2-ethoxy-N-(substituted)benzamide (ABEX) series, in order to avoid formation of the colored metabolite by modifying the diaminopyridine skeleton. As a result of structural modification and in vitro and in vivo testing of compounds in the ABEX series, we found a novel COX-1-selective inhibitor, 5-amino-2-ethoxy-N-(3-trifluoromethylphenyl)benzamide (ABEX-3TF), which shows better analgesic activity than indomethacin, and does not cause coloration of urine.     

Glycosylation of human cyclooxygenase-2 (COX-2) decreases the efficacy of certain COX-2 inhibitors

Prostanoids play an important role in a variety of physiological and pathophysiological processes including inflammation and cancer. The rate-limiting step in the prostanoid biosynthesis pathway is catalyzed by cyclooxygenase-2 (COX-2). COX-2 exists as two glycoforms, 72 and 74 kDa, the latter resulting from an additional glycosylation at Asn(580). In this study, Asn(580) was mutated, and the mutant and wild-type COX-2 genes were expressed in COS-1 cells to determine how glycosylation affects the inhibition of COX-2 activity by aspirin, flurbiprofen, ibuprofen, celecoxib, and etoricoxib. Results indicate that certain inhibitors were 2-5 times more effective at inhibiting COX-2 activity when the glycosylation site was eliminated, indicating that glycosylation of COX-2 at Asn(580) decreases the efficacy of some inhibitors.     

Cyclooxygenase (COX)-2 selective inhibitors: aspirin, a dual COX-1/COX-2 inhibitor, to COX-2 selective inhibitors

Aspirin was developed as a non-steroidal anti-inflammatory drug (NSAID) in 1899. During the century after that, aspirin has been found to show its anti-inflammatory, analgesic and anti-pyretic activities by reducing prostaglandins biosynthesis through inhibition of cyclooxygenase (COX); and then COX was found to be constituted of two isoforms, constitutive COX-1 and inducible COX-2. Currently, novel NSAIDs, acting through selective inhibition of COX-2, that have efficacy as excellent as aspirin with significantly lower incidence of gastrointestinal adverse effects are available in America and some other countries, but not in Japan. Physiological and pathophysiological roles of COX-1 and COX-2 have been explained from studies in experimental animals, but there are many differences in species and diseases between animals and humans. Thus, physiological and pathophysiological roles of COX-2 were considered from the standpoint of clinical effects of the two latest COX-2 selective inhibitors, celecoxib and rofecoxib, on inflammation, pain, fever and colorectal cancer together with their adverse effects on gastrointestinal, renal and platelet functions; and the usefulness and limits of COX-2-selective inhibitors were discussed with the trends of new NSAIDs development.     

Synthesis and structure-activity relationship of novel, highly potent metharyl and methcycloalkyl cyclooxygenase-2 (COX-2) selective inhibitors

A novel series of benzo-1,3-dioxolane metharyl derivatives was synthesized and evaluated for cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) inhibition in human whole blood (HWB). In the present study, structure-activity relationships (SAR) in the metharyl analogues were investigated. The spacer group and substitutions in the spacer group were found to be quite important for potent COX-2 inhibition. Compounds in which a methylene group (8a-c), carbonyl group (12a-c), or methylidene group (7a-c) connected cycloalkyl groups to the central benzo-1,3-dioxolane template were found to be potent and selective COX-2 inhibitors. Aryl-substituted compounds linked to the central ring by either a methylene or a carbonyl spacer resulted in potent, highly selective COX-2 inhibitors. In this series of substituted-(2H-benzo[3,4-d]1,3-dioxolan-5-yl))-1-(methylsulfonyl)benzene compounds, SAR studies demonstrated that substitution at the 3-position of the aryl group optimized COX-2 selectivity and potency, whereas substitution at the 4-position attenuated COX-2 inhibition. Mono- or difluoro substitution at meta position(s), as in 22c and 22h, was advantageous for both in vitro COX-2 potency and selectivity (e.g., COX-2 IC(50) for 22c = 1 microM and COX-1 IC(50) for 22c = 20 microM in HWB assay). Several novel compounds in the (2H-benzo[3,4-d]1,3-dioxolan-5-yl))-1-(methylsulfonyl)benzene series, as shown in structures 7c, 8a, 12a, 21c, 22c, 22e, and 22h, selectively inhibited COX-2 activity by 40-50% at a test concentration of 1 microM in an in vitro HWB assay.     

Selective cyclooxygenase-2 (COX-2) inhibitors and potential risk of cardiovascular events

Selective cyclooxygenase-2 (COX-2) inhibitors were developed as a response to the gastrointestinal toxicity of conventional nonsteroidal anti-inflammatory agents (NSAIDs). However, COX-2 inhibitors decrease vascular prostacyclin (PGI(2)) production and may disrupt the homeostatic mechanisms that limit the effects of platelet activation. Basic and clinical data raise concerns about a potential prothrombotic effect of this class of drugs. The widespread popularity of these agents mandates their prospective evaluation in patients with cardiovascular diseases or who are at risk for cardiovascular events.     

奥曲肽治疗慢性肾功能衰竭并发的上消化道出血

慢性肾功能衰竭合并胃镜证实消化道大出血７例（男性３例，女性４例；年龄５４±ｓ９ａ）。腹膜透析病人用奥曲肽０．１ｍｇ加２５％葡萄糖液２０ｍＬ，ｉｖ０．４－０．５ｍｇ加１０％葡萄糖液１０００ｍＬ，ｉｖｇｔｔ，２４ｈ，用至粪隐血阴性；血液透析病人用０．１ｍｇ加２５％葡萄糖液２０ｍＬ，ｉｖ，０．１ｍｇ，ｓｃ，ｑ８ｈ或ｑ１２ｈ，用至粪隐血阴性。全部止血成功，未见明显副作用。     

Defects in mouse nephrogenesis induced by selective and non-selective cyclooxygenase-2 inhibitors

BACKGROUND AND PURPOSE

Deletion of the cyclooxygenase-2 (COX-2) gene causes impairment of kidney development, but the effect of selective inhibitors of COX-2 (coxibs) or the non-selective inhibitors of COX (the classical non-steroidal anti-inflammatory drugs; NSAIDs) on kidney development was less well described.

EXPERIMENTAL APPROACH

We assessed the effects of equipotent analgesic doses of celecoxib, rofecoxib, valdecoxib, etoricoxib and lumiracoxib and of the NSAIDs, diclofenac and naproxen, on postpartum kidney development in mice, from postnatal day 1 (P1) to P21.

KEY RESULTS

All the COX inhibitors, at the doses used, blocked COX-2 activity by more than 80% as assayed by PGE₂ synthesis in lipopolysaccharide-stimulated mouse blood samples. Rofecoxib, etoricoxib and lumiracoxib exerted the most marked impairment of postpartum kidney development, demonstrated by attenuation of kidney growth, reduction in size of glomeruli, increase in immature superficial glomeruli, thinning of subcapsular cortical mass and reduction in size of juxtamedullary glomeruli. These defects were less severe than those in kidneys from COX-2^−/− mice. Administration of diclofenac and naproxen revealed renal defects similar to those after coxib treatment, but both NSAIDs induced greater arrest of immature superficial glomeruli in the outer cortex and increased the number of undifferentiated proliferating cell nuclear antigen-positive cells. Treatment with celecoxib or valdecoxib caused only minimal changes in renal morphology.

CONCLUSIONS AND IMPLICATIONS

Classical NSAIDs cause similar or even stronger nephrodysgenesis than the coxibs. Also, the ranking of coxibs regarding adverse effects on renal development, using equi-analgesic doses, is rofecoxib = etoricoxib = lumiracoxib > valdecoxib > celecoxib.     

Arylpyridazinones as selective cyclooxygenase-2 inhibitors

Selective cyclooxygenase-2 (COX-2) inhibitors now represent a new generation of anti-inflammatory drugs with reduced gastrointestinal side effects compared to current non-steroidal anti-inflammatory drugs (NSAIDs). The present patent claims selective COX-2 inhibitors based on the pyridazinone template in the tricyclic class, which was derived from DuP-697.     

选择性环氧合酶-2抑制剂的研究现状及进展

非甾体抗炎药（NSAIDs）是临床上应用非常广泛的一类药物，但严重的不良反应使其应用受到很大限制。研究已经发现，NSAIDs对炎症的有效治疗源干其对环氧合酶-2（COX-2）的抑制作用。综述了选择性COX-2抑制剂作用的分子基础、构效关系及其目前研究开发的现状和最新进展。     

COX-2 selective inhibitors and bone

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed medications for relief of pain and inflammation. Recent animal studies using models of fracture healing and bone ingrowth suggest that NSAIDs (both non-selective NSAIDs and selective COX-2 inhibitors) adversely affect these bone-related processes. The dose and time-relationships of these medications and their resulting effects on bone have not yet been fully elucidated. Furthermore, whether COX-2 inhibitors and non-selective NSAIDs lead to clinically relevant adverse effects on bone healing in humans is unknown.