Unit5TextB注释及译文Word下载.doc

1、不受大家欢迎的;讨厌的找到先导化合物是开展任何一项药物化学课题研究的前提。一种先导化合物应该具有与治疗作用有关的某些特性。药物作用的靶点决定寻找先导化合物所进行的试验，试验决定所能发现的先导化合物的特性。先导化合物的生物活性可能不是很强，这无关紧要。因为先导化合物不能被直接用作临床药物，它只是开发临床上有用的化合物的起点。先导化合物是否具有毒性或不良反应同样也不重要。因为药物设计的目的就是要提高先导化合物的期望效应，去除不良反应。Lead compounds can be obtained from a variety of different sources such as the flor

2、a and fauna of the natural world, or synthetic compounds made in the laboratory. There is also the potential of designing lead compounds using computer modeling or NMR spectroscopic studies.1. variety vraiti n. 品种, 种类；种种, 各种；变化, 多样化2. flora fl:r n. （某地区或某时期的）植物群;植物区系; 植物志 3. fauna f:n n. （某一地区或某一时期的

3、）动物群4. synthetic sinetik adj. 合成的, 人造的；口假的, 非天然的; 虚伪的n.合成物, 5. NMR = nuclear magnetic resonance reznns 核磁共振6. spectroscopic ,spektrskpik adj. 分光镜的，光谱的spectroscope spektrskup n. 分光镜 spectroscopy spektrskpi n. 光谱学先导化合物可以有多种来源，例如来源于自然界的菌群和动物群或者来自实验室合成的化合物。通过计算机模拟或者核磁共振光谱研究也可能设计出先导化合物。In order to search

4、 for lead compounds, a suitable test is required. This could be a test that reveals a physiological effect in a tissue preparation, organ or test animal. Alternatively, it could be a cellular effect resulting from the interaction of a lead compound with a particular target, such as a receptor or an

5、enzyme; or a molecular effect, such as the binding of a compound with a receptor. In the last two situations, the molecular target is considered important to a particular disease state, and in such cases, the lead compound may not have desired physiological activity at all! For example, there have b

6、een several examples where the natural agonist for a receptor was used as the lead compound in order to design a receptor antagonist. Here, the crucial property for the lead compound was that it should be recognized and bound to the binding site of the target receptor. The lead compound was then mod

7、ified to bind as an antagonist rather than as an agonist. For example, the chemical messenger histamine was used as the lead compound in developing the anti-ulcer agent cimetidine. Histamine is an agonist that activates histamine receptors in the stomach wall to increase gastric acid release. Cimeti

8、dine acts as an antagonist at these receptors, thus reducing the levels of gastric acid released and allowing the body to heal the ulcer.1. alternatively :lt:ntivli adv.做为选择,二者择一地2. receptor rsept n. 感受器;受体 3. molecular mlekjl adj. 分子的 molecule mlikju:l n. 分子4. state steit n. 状态, 状况；国家, 政府；州; 邦vt.陈述

9、; 敘述；规定, 指定, 排定5. agonist nist n. 激动剂 antagonist ntgnst n. 拮抗剂 6. modify mdifai vt. & vi. 修改, 更改 vt. 修饰7. histamine histmi:n n. 组胺 8. ulcer ls n. 溃疡；腐烂物；道德败坏;腐败;弊病9. cimetidine saimetidi:n n. 甲氰咪胍,甲腈咪胍,甲腈咪胺10. stomach stmk n. 胃；腹部；食欲, 胃口; 欲望11. gastric gstrk adj. 胃的,胃部的为了寻找先导化合物，需要开展适当的试验。这些试验可能揭示先导

10、化合物对以组织、器官或试验动物的生理功能的影响；或者先导化合物与特定的靶点，例如受体和酶，相互作用而引起的细胞效应；或者先导化合物与受体结合等引起的分子效应。在后面两种情况下，对于先导化合物而言，重要的是具有与某种疾病状态有关的分子靶向作用，此时，先导化合物可能根本不具有与治疗作用有关的生理活性。以受体的天然激动剂为先导化合物来研制某种受体的拮抗剂就是如此。目前，已有一些这方面的实例。此时，先导化合物最重要的性质是能被该受体识别并与之结合。接下来的工作是对先导化合物进行修饰，使其与受体结合后具有拮抗作用而不是激动作用。例如，组胺是一种化学信使，在抗溃疡药西咪替丁的研发过程中被用作先导化合物。组

11、胺是一种激动剂，可以激活胃壁上的组胺受体，促进胃酸释放。西咪替丁则是这些受体的拮抗剂，抑制胃酸分泌，使溃疡得以愈合。The natural world is particularly rich in potential lead compounds. For example, plants, trees, snakes, lizards, frogs, fungi, corals and fish have all yielded potent lead compounds which have either resulted in clinically useful drugs or hav

12、e the potential to do so. There is a good reason why nature should be so rich in potential lead compounds. Years of evolution have resulted in the selection of biologically potent natural compounds that have proved useful to the natural host for a variety of reasons. For example, a fungus that produ

13、ces a toxin can kill off its microbiological competitors and take advantage of available nutrients.1. fugus fs n. 真菌 fungi fga fungal fl adj. 真菌的, 由真菌引起的2. potent putnt adj. （药等）效力大的; 威力大的；强有力的; 有说服力的3. toxin tksn n. 毒素4. competitor kmpett n. 竞争者,对手,敌手5. nutrient nju:trint adj. 营养的,滋养的 n.营养物,滋养物自然界中

14、蕴藏着极其丰富的、具有成为先导化合物潜力的物质。例如，许多活性很强的先导化合物来源于草本植物，树木、蛇类、蜥蜴、蛙类、真菌类、珊瑚和鱼类。这些先导化合物最终被开发成临床用药或者具有这样潜力的物质。自然界中蕴藏着如此丰富的、具有成为先导化合物潜力的物质，有其必然的道理。多年的进化和自然选择使得那些由于各种各样的原因对于宿主有用的、具有很强生物活性的天然物质被保存下来。例如，某种真菌能够产生一种毒素，这种毒素可以杀光与该真菌竞争的微生物，从而使该真菌能够充分的利用有限的养料。真菌得以存活，毒素也得以保存。Large numbers of novel structures are synthesiz

15、ed in research laboratories across the world for a diverse range of synthetic projects. These are a potential source of lead compounds, and pharmaceutical companies will often enter into arguments with research teams in order to test their compounds. Many of these structures may have been synthesize

16、d in research topics unrelated to medicinal chemistry, but are still potential lead compounds. The history of medicinal chemistry has many examples of lead compounds that were discovered from synthetic projects that had no medicinal objective in mind. For example, prontosil was manufactured as a dye

17、, but was the lead compound for the development of the sulfonamides.1. synthesize sn,saz vt. 综合, 使合成；人工合成2. diverse daivs adj. 不同的, 多种多样的diversity daivsiti n. 多样化;（人在种族、民族、宗教等方面的）多样性；3. prontosil prntsil n.百浪多息（偶氮磺胺的商标名）4. sulfonamide slfnmaid n. 磺胺 adj. 磺胺的在世界各地的科研实验室中，科研人员为种种合成项目合成了大量的新型结构的化合物。这些化

18、合物是先导化合物的潜在资源，因而制药公司也会经常与科研团队讨论其合成的化合物有否可能具有生理活性。许多新型结构的化合物是在与医药无关的合成项目中发现的，但是仍然具有成为先导化合物的潜力。在药物化学的历史上有许多这样的例子，许多先导化合物是从本身没有医药目的的项目中发现的。例如，合成偶氮磺胺本来是作为一种染料，但是在研发磺胺类药物的时候将其用作先导化合物。Strategies in the Search for New Lead CompoundsA retrospective analysis of the ways leading to discovery of new drugs sugg

19、ests that there are four types of successful strategies leading to new lead compounds.1. retrospective ,retrspektv adj. 回顾的；（指法律、支付关系等）有追溯效力的2. strategy strtdi n. 战略；对策；技巧对发现新药的方法进行回顾性研究，结果提示我们在发现先导化合物方面有四种方法比较成功。The first strategy consists of systematic screening of sets of compounds arbitrarily ch

20、osen for their diversity, by selected biological assays. This approach was useful in the past for the discovery of new antibiotics such as streptomycin and for the identification of compactin as an HMG-CoA reductase inhibitor. Presently, as high-throughput screening （HTS）, it is applied in a very ge

21、neral manner to synthetic as well as to natural compounds. Experience gathered has confirmed that high-throughput screening allows for the rapid identification of numerous hits, and the literature is full of success stories obtained with that approach. Among them, one could mention the discovery of

22、insulin mimetics, of ORL1 receptor agonists, of protein tyrosine phosphatase-I B inhibitors, of selective neuropeptide Y5 receptor antagonists, of selective COX-2 inhibitors, of corticotropin releasing factor （CRF） receptor modulators, and of CXCR2 receptor antagonists. Yet the HTS strategy for drug

23、 discovery has several limitations. It suffers from inadequate diversity, has low hit rates, and often leads to compounds with poor bioavailability or toxicity profiles.1. systematic ,sistmtik adj. 有系统的; 有规则的; 彻底的2. screening skri:ni n. 放映；筛查3. arbitrary :bitrri adj. 随意的, 主观的；专横的, 独断专行的4. assay s,e,

24、 sen. 化验；试金;分析试验；化验报告,分析报告；试样,试料；试验;分析评价；vt. 化验；试验,检验；考验；分析；评价；尝试;试图vi. 经检验证明内含成分5. antibiotic ,ntbatk n.抗生素, 抗菌素 adj. 抗生的；抗菌的6. streptomycin ,streptmasn n. 链霉素7. identification ai,dentifikein n. 鉴定, 验明, 认出；身份证明；认同identity aidentiti n. 身份；个性, 特性；同一性, 一致性identical aidentikl adj. 同一的8. insulin nsln n.

25、 胰岛素9. mimic mmk n.模仿名人言行的娱乐演员, 滑稽剧演员；善于模仿的人或物vt.（尤指为了逗乐而）模仿；酷似adj.模拟的；假的, 伪装的10. mimetic mimetik adj.模仿的11. tyrosine phosphatase tar,si:n fsfteis 酪氨酸磷酸（酯）酶12. neuropeptide ,njurpeptaid n. 神经肽13. corticotrophin ,k:tikutrufin n. 促肾上腺皮质激素14. profile prufail n. 侧面, 侧面像；轮廓, 外形；简介, 概况, 传略第一种方法是以某些选定的生物活性

26、为指标，随机选择多种结构差异很大的化合物进行系统的筛选。以前，通过这种方法发现了新抗生素，例如，链霉素，通过这种方法确定康帕丁（美伐他汀）是一种HMG-CoA还原酶抑制剂。目前，作为高通量筛选法，这种方法已广泛应用于对合成化合物及天然产物的筛选。现有的经验表明，通过高通量筛选法可以迅速的鉴定出大量活性化合物，而且通过这种方法成功发现先导化合物的文献报道不胜枚举。其中值得一提是胰岛素模拟物、ORL1受体拮抗剂、蛋白质酪氨酸磷酸酶-I B抑制剂、神经肽Y5受体的选择性拮抗剂、COX-2的选择性抑制剂、促（肾上腺）皮质（激素）释放因子（CRF）受体调节剂和CXCR2受体拮抗剂的发现。但是通过高通量筛

27、法研发新药还存在问题：已发现的化合物结构缺乏多样性，成功率低，并且经常出现筛选出的化合物生物利用度低或毒性大的情况。The second strategy is based on the modification and improvement of existing active molecules. The objective is to start with known active principles and, by various chemical transformations, prepare new molecules （sometimes referred to as “m

28、e-too compounds） for which an increase in potency, a better specific activity profile, improved safety, and a formulation that is easier to handle by physicians and nurses or more acceptable to the patient are claimed. A typical illustration of this approach is found in the series of lovastatin analogues （lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, etc.） In the pharmaceutical industry, motivations for th