【作者】 敖桂珍；

【导师】 张奕华；

【作者基本信息】 中国药科大学 ， 药物化学， 2002， 博士

【摘要】 炎症是一类极其复杂的病理生理过程,由多种炎性介质介导产生。非甾体抗炎药(NSAIDs)抑制前列腺素(PGs)、白三烯(LTs)等炎性介质,具有优良的抗炎、镇痛和解热作用,其临床应用极为广泛,是仅次于抗感染药的第二大类药。但NSAIDs 的不良反应也相当常见。流行病学调查结果显示,使用NSAIDs 的人群,25%出现胃肠道(GI)副作用,15%~20%长期服用者可出现严重GI 并发症(包括溃疡、出血和穿孔)。美国每年因NSAIDs 诱发GI 损伤而死亡的人数高达16500。NSAIDs 的GI 副作用不仅危害健康,增加死亡率,而且也大大增加了医疗费用。在美国,每年用于治疗NSAIDs 的GI 副作用的费用就高达40 亿美元。我国虽无这方面的统计数字报道,但情况大体上类似。NSAIDs 引起GI 损伤的主要原因是其在抑制炎症部位PGs 合成的同时,也抑制了GI 具有粘膜保护性质的PGs 的生成。因此选择性地抑制炎症部位PGs 的产生,降低NSAIDs 的GI 不良反应是近年来研究和开发新型NSAIDs 的基本出发点之一。20 世纪90 年代以来,这方面的工作已取得了一系列突破性的进展。本论文根据NSAIDs 研究的最新成果,应用药物设计的基本理论,结合计算机辅助药物设计手段,设计合成了一系列α-取代的对甲磺酰基苯丙烯酸及其衍生物(I-V),并得到一类副产物(VI),对这六类化合物进行了抗炎活性筛选和GI 不良反应观察。在此基础上进行了定性定量构效关系分析,为进一步研究此类化合物提供依据,目的是要获得抗炎活性强、GI 副作用小的新型NSAIDs。论文分为以下五部分: 第一部分非甾体抗炎药(NSAIDs)的研究现状与发展趋势综述了各类炎性介质及近年来NSAIDs 研究的最新进展,包括环氧酶更多还原

【Abstract】 Inflammation is a very complicated pathophysiological process, in which many inflammatory mediators are involved. Nonsteroidal anti-inflammatory drugs (NSAIDs) block the synthesis of inflammatory mediators, such as prostaglandins (PGs), leukotrienes (LTs), etc, to exert anti-inflammatory, analgesic and antipyretic activities. NSAIDs are among the most widely used prescribed drugs. However, side effects associated with NSAIDs limit their usage. Epidemiology survey suggested that 25% NSAIDs users suffer from gastrointestinal (GI) tract side effects, and 15%~20% long-term users have severe GI complications, which included ulcer, bleeding and perforation. In the United States, people who die annually from NSAIDs-induced GI lesions amount to 16500. The cost of treating GI side effects exceeds $4 billion every year. As a consequence, GI lesions not only harm people’s health and increase mortality, but also greatly enlarge medical expenses. In China, the situation is basically similar to that in the US. The main reason why NSAIDs result in GI damage is that the synthsis of beneficial PGs in GI tract is inhibited while NSAIDs block the form of PGs at the site of inflammation. So reducing NSAIDs-induced GI lesions is recently one of the major challenging task of developing novel NSAIDs. Base on the progress on NSAIDs study, a series of α-substituted p-methylsulfonylphenylpropenoic acid compounds (I-V) have been designed and synthesized by applying the basic theories of drug design and the means of computer aided drug design. Their anti-inflammatory activity against xylene-induced mice ear swelling and carrageenin-induced rat paw edema was biologically evaluated, and their GI side effects in the rats were examined. On the basis of biology results, the structure-activity relationships (SARs) were studied in order to obtain some useful information for further developing novel NSAIDs with stronger anti-inflammatory activity but less GI side effects. This dissertation consists of five parts as follows: Part One The status quo and prospect of NSAIDs This part reviews several inflammatory mediators and progress on current NSAIDs research, including cyclooxygenase-2 (COX-2) selective inhibitors, COX/5-Lipoxygenase (5-LO) dual inhibitors, nitric oxide-releasing NSAIDs (NO-NSAIDs), cytokine inhibitors, etc. The prospect of future NSAIDs is also presented. Part Two Design So far most COX-2 selective inhibitors structurally belong to tricyles. They are characterized by a moiety of cis-stilbene with a functional group p-methylsulfonyl or p-aminosulfonyl in one of the aryls. It was also reported that some trans-phenylpro-penoic acid derivatives were COX/5-LO dual inhibitors. On the basis of computer aided drug design, a series of α-substituted p-methylsulfonylphenylpropenoic acid (I) were designed by combining the feature structure of trans-phenylpropenoic acid and Rofecoxib, a tricycle type of COX-2 selective inhibitor which entered market in 1999. NO-NSAIDs (II) were synthesized by coupling I and NO donors; III were obtained by conversion of I to amides in order to increase COX-2 selective activity; IV were formed by conversion of I to hydroxamic acids in order to gain COX/5-LO dual inhibitory properties. V were designed by replacement of 3,5-di-tert-butyl-4-hydroxy-phenyl in the structure of some COX/5-LO dual inhibitors by p-methylsulfonylphenyl which is a key pharmacophore of COX-2 selective inhibitors. We expect these targetcompounds exhibit stronger anti-inflammatory activity and less GI side effects. Part Three Chemistry Sixty-seven target compounds (I-V), 5 byproducts (VI) and two positive controls (Rofecoxib and CI-1004) were synthesized. Seventy of them were novel compounds, whose structures were determined by IR, 1HNMR, MS and elemental analysis. Many efforts were made to synthsize and optimize the synthetic procedures of target compounds and to study the mechanism by which some byproducts formed. For example, in preparation of II, I1, 3, 13, 15, 16 reacted respectively with alcohol 57 in the presence of dicyclohexyl更多还原