新藥研究與策略（下）

前言

本卷針對藥物化學(xué)家關(guān)心的問題，從戰(zhàn)略角度討論制藥（和生物技術(shù)）研究和開發(fā)，用多種互補(bǔ)性視角闡明如何思考該領(lǐng)域許許多多重要而有趣的問題。本卷是《藥物化學(xué)百科》系列新增的一部分，在第1版沒有獨立成卷。本卷將吸引在生物技術(shù)和制藥領(lǐng)域眾多從業(yè)人員，無論是技術(shù)專家還是管理人士。就戰(zhàn)略預(yù)測技術(shù)而言，本卷專題討論的內(nèi)容，在全書其他分卷也可能出現(xiàn)，特別是第1卷（總論）和第8卷（實例分析）；關(guān)于更多的科學(xué)觀點細(xì)節(jié)，可能出現(xiàn)在第3卷（技術(shù)）、第4卷（計算機(jī)輔助藥物設(shè)計）、第5卷（藥動學(xué)和相關(guān)技術(shù)）、第6卷（治療領(lǐng)域）以及第8卷（實例分析）。本卷將對上述領(lǐng)域提供一個共同背景，一種進(jìn)入其他章節(jié)的臺階，指引讀者閱讀相關(guān)文獻(xiàn)，查找經(jīng)典論文、綜述、原始文獻(xiàn)、最新報刊、網(wǎng)絡(luò)引文、典型事例、珍聞軼事、奇術(shù)怪招、簡短而代表性的研究范例。什么是藥物研究戰(zhàn)略？戰(zhàn)略即為達(dá)到特定目標(biāo)而設(shè)計的行動計劃，用最小的隊伍和最簡單的手段到達(dá)終點。藥物研究的最終目標(biāo)是將一種候選藥逐步向前推進(jìn)，通過R&D后期各階段，直至上市。即使新藥上市，病人使用后獲得成功治療，研究也不能停止；還要收集安全性資料，研究新適應(yīng)癥，研究改變劑型和藥物制劑，改進(jìn)疾病新的治療方法等。這個過程似乎總在循環(huán)往復(fù)，永無休止。在常人看來，這個過程雖然是高技術(shù)、大規(guī)模、成本昂貴，但常見的是試驗和差錯。當(dāng)然，正如您將看到的，實際過程要復(fù)雜和豐富得多。戰(zhàn)略問題對制藥和生物技術(shù)企業(yè)特別重要。這是因為開發(fā)一種新藥需要10年甚至20年，花費(fèi)10億美元以上，不得不給予更多注意。在學(xué)術(shù)界與工業(yè)界的交叉領(lǐng)域、強(qiáng)與弱、老與新、戰(zhàn)略與戰(zhàn)術(shù)交織混雜之處，市場力量如何運(yùn)作？對以上問題，本書都將涉及。對領(lǐng)導(dǎo)和管理的科學(xué)基礎(chǔ)，項目管理中從研究到開發(fā)的轉(zhuǎn)換，哪些依托單位內(nèi)部完成和哪些依靠外部資源進(jìn)行，哪些知識產(chǎn)權(quán)在本單位創(chuàng)造，哪些由許可證交易獲得，都從實用角度一一討論決策。挑戰(zhàn)與機(jī)會、管理科學(xué)家、領(lǐng)導(dǎo)、企業(yè)家與雇員，以及促進(jìn)創(chuàng)新，都全方位給予思考。本書對比了制藥企業(yè)和生物技術(shù)公司怎樣審查、如何及為何采用新技術(shù)新方法，怎樣對待肽類或肽模擬物，生物電子等排體或手性藥物，或者下一種令人傾倒的先進(jìn)技術(shù)。最后還討論了公司對治療領(lǐng)域藥物靶標(biāo)如何選擇決策（包括相關(guān)背景信息），以及討論比較了多元模式和聚焦模式。對于全人類和生命中每一階段，健康都是最重要的。有機(jī)會工作在制藥業(yè)和生物技術(shù)R8LD舞臺，應(yīng)當(dāng)深感榮幸和愉快。如果本卷盡了綿薄之力，有助于指導(dǎo)當(dāng)今技術(shù)發(fā)展，以便救治更多生命，提高生活質(zhì)量，就達(dá)到了我們的目的。謹(jǐn)作序于斯，希望您閱讀愉快。

內(nèi)容概要

本冊是《藥物化學(xué)百科Ⅱ》該書以幾類重要靶標(biāo)為背景，系統(tǒng)介紹了靶標(biāo)策略和藥物研究。 本冊分為兩個部分，共9章。第一部分：選擇單一靶標(biāo)與選擇治療領(lǐng)域的策略比較(第19章)：介紹了現(xiàn)代制藥業(yè)中生物技術(shù)的驅(qū)動性作用以及新藥研發(fā)中主要的靶標(biāo)選擇的策略；明確了新藥研究中靶標(biāo)相關(guān)的幾個概念，包括靶標(biāo)、分子靶標(biāo)、治療靶標(biāo)、可用作藥物的靶標(biāo)、藥物靶標(biāo)；客觀評述了“基因組學(xué)泡沫”對藥物靶標(biāo)發(fā)現(xiàn)的影響；同時在可實踐的水平介紹了基于不同的靶標(biāo)選擇策略建立研發(fā)公司的類型及新靶標(biāo)中的知識產(chǎn)權(quán)的情況。第二部分：8類最重要的藥物靶標(biāo)的背景與藥物研究(第20～27章)，從通用命名法、分子生物學(xué)分類、蛋白質(zhì)結(jié)構(gòu)、生理學(xué)功能、信號途徑、原型藥物藥理學(xué)、原型藥物治療學(xué)、與疾病的遺傳相關(guān)性和今后研究方向等方面依次介紹了8類藥物靶標(biāo)及其藥物。

作者簡介

作者：（美國）穆斯 編者：張禮和

書籍目錄

靶標(biāo)  2.19 選擇靶標(biāo)和治療領(lǐng)域的多元模式和聚焦模式　2.20 G-蛋白偶聯(lián)受體　2.21 電壓門控離子通道　2.22 配體門控離子通道　2.23 磷酸二酯酶　2.24 信號轉(zhuǎn)導(dǎo)通路相關(guān)蛋白激酶和蛋白磷酸化酶　2.25 核激素受體　2.26 核酸(脫氧核糖核酸和核糖核酸)　2.27 氧化還原酶縮寫詞表符號表主題索引

章節(jié)摘錄

插圖：There have been a number of reviews written in the past several years indicating that there has been a decline in thenumber of new chemical entities being approved by the FDA for marketing.8z-84 There have been almost as manysuggestions on how the drug discovery process can be fixed.82's3'85-89 Drugs for oncology have one of the lowest success ratesfrom first-in-human to registration of any of the therapeutic areas.Many companies launched efforts into thedevelopment of oncology drugs, attempting to respond to the great unmet medical need. Additionally, the severity of thedisease would require shorter clinical trials, and the tolerance for side effects in this disease is greater than for othertherapeutic areas. However, many of these efforts have foundered on lack of sufficient efficacy and unacceptable side effects. A number of concepts are beginning to mature, facilitated by improving technologies that are predicted to increasethe success rate of compounds moving into clinical testing. The concept of biomarkers has become almost universal,and returns to center stage the study of pharmacodynamics. During the drug discovery phase, increased effort andemphasis has been placed on developing assays that will allow the determination of target inhibition in a functionalassay. A simple example is to monitor the phosphorylation of a kinase substrate within the cell environment afterexposure to the respective kinase inhibitor. Elaboration of this assay to in vivo and then the clinical setting would allowmonitoring of target inhibition following dosing. These types of assays will allow the assessment of the magnitude,duration, and consequence of inhibition, leading to a more rapid conclusion of whether inhibition of the target will havetherapeutic benefit. However, often with such assays, translation from discovery to development can be difficult, andalternatives need to be considered. The increasing use of gene chip arrays has prompted some to consider global geneexpression of some readily sampled tissue in response to treatment as an alternative. Moving to this type of assayshould more generally be considered a surrogate of response, rather than a marker of inhibition. Additionally, as diseasesare becoming more molecularly defined, both in etiology and progression, the opportunity for more specific therapies ispresented. A recent example of this would be imatinib, a compound approved for CML.s3 Ninety-five percent of CMLpatients have a particular chromosomal translocation that creates a mutant tyrosine kinase called bcr-abl. Imatinib wasdeveloped to target this particular mutation. Looking to the future, the potential of defining a disease by the molecularpathology and employing specific antagonists to create a 'tailor-made' therapy can be imagined.   The major difficulty with any new technologies introduced into drug discovery is the long time frames before theresults are realized by new drugs on the market.91 There are two facets of drug discovery where improvements in theindividual processes would speed the approval process and decrease the amount of money required to bring drugs tomarket. The first area where improvements need to be made is in the overall attrition rates of compounds from first-in-human to approval. Recent estimates put the overall success rate for new chemical entities at 11%.1"83'90 By reducingattrition rates, the expense for the whole process would decrease due to failures in clinical trials, which are the mostexpensive part of the discovery process.

編輯推薦

《新藥研究與策略(下)(導(dǎo)讀版)》引言，前言和目錄均已譯成中文，正文部分保留英文原版，別附王莉莉研究員所作中文導(dǎo)讀一篇。

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