复旦大学：《药物设计学》课程教学资源（课件讲稿）第一章 基于筛选途径的药物发现 Screening Based Drug Discovery

〔筛选途径的药物发现 Screening Based Drug Discovery 药物设计学 李炜 wei-li@fudan.edu.cn 复旦大学药学院 药物化学教研室 September 17, 2018

September 17, 2018 药物设计学 复旦大学药学院 药物化学教研室 李 炜 wei-li@fudan.edu.cn 筛选途径的药物发现 Screening Based Drug Discovery

New medicines discovered by Janssen’ s team OH N H2c N haloperidol fentanyl N、CH 3 N(CH3 N HO F CI risperidone loperamide More than 80 new medicines(absolute world record), at the wide range of his inventions in psychopharmacology, neuropharmacology, gastroenterology, cardiology parasitology, virology, immunology, anaesthesiology, and analgesia

New medicines discovered by Janssen’s team haloperidol risperidone fentanyl loperamide More than 80 new medicines (absolute world record), at the wide range of his inventions in psychopharmacology, neuropharmacology, gastroenterology, cardiology, parasitology, virology, immunology, anaesthesiology, and analgesia 4

Classic of Phenotypic screening Iterative evolution process Conception A lead compd Test feedback A picture of ppropriate Synthesis bioassay Bioassay structure activity Unmet medical evaluation relationship need Active in least 3 /5 authentic exo-vivo or in vivo pharmacological models purpose? or When fit for its Judgment E xperience Workup Creativity Imagination Aesthetic intuition A concept-driven project

Classic of Phenotypic screening Conception A lead compd Appropriate bioassay Unmet medical need Iterative evolution process Synthesis Bioassay evaluation Test feedback A picture of structure￾activity relationship Active in least 3/5 authentic exo-vivo or in vivo pharmacological models When Fit for its purpose? Judgment Experience Imagination Aesthetic intuition —— A concept-driven project Workup Creativity When Fit for its purpose? Judgment Experience Imagination Aesthetic intuition 5

筛选途径需要解决的基本问题 结构多样性( Diversity) I.转化医学( ranslational medicine, from bench to bedside)

筛选途径需要解决的基本问题 I. 结构多样性（Diversity） II. 转化医学（Translational Medicine, from bench to bedside）

药物设计基本原理 多样性 Diversity 药物分子的多样性 天然产物提取分离、 合成以及半合成 合成化合物的筛选 组合化学 View of PubChem chemical space Reymond, J L, ACS Chem. Neurosci. 3(9): 649657

药物设计基本原理—— 多样性 Diversity • 药物分子的多样性 • 天然产物提取分离、 合成以及半合成 • 合成化合物的筛选 • 组合化学 View of PubChem chemical space Reymond, J.L, ACS Chem. Neurosci. 3 (9): 649–657 11

天然产物的分离、合成及半合成 1971年提取、分离、鉴定 HO BZ CH Nho H3 CH OH CH OH HO AcO BZ0 Pacific yew 太平洋紫杉 “卵巢癌和转移性乳腺癌治愈率达 33%,总有效率达75%以上 1991年FDA批准 “ taxol Bristol-Myers Squibb Company Monroe e. wall and Mansukh C. Wani 2000年销售20亿美元 Research triangle institute

天然产物的分离、合成及半合成 Monroe E. Wall and Mansukh C.Wani Pacific Yew 太平洋紫杉 1971年提取、分离、鉴定 1991年 FDA 批准 2000年 销售20亿美元 “卵巢癌和转移性乳腺癌治愈率达 33%，总有效率达75%以上” “taxol” Research Triangle Institute. 12

生源问题 紫杉醇含量为树皮干重0005%-0.07%,1公斤紫杉醇需要15 30吨树皮,剥1500-200棵大树(50-250年成材) ·紫杉醇产量500公斤/年;市场需求达48吨年;原料药价格 (18万美元/kg) HO 四步反应 CH HO H2c OH BZ-NH CH OH CH HO ACH A CH OH HO AcO HO : AcO BZO BZO 10-去乙酰浆果赤霉素 影杉醇 (10去乙酰巴卡亭I) 13

生源问题 • 紫杉醇含量为树皮干重0.005%-0.07%，1公斤紫杉醇需要15- 30吨树皮，剥1500-2000棵大树（50-250年成材） • 紫杉醇产量500公斤/年；市场需求达4.8吨/年；原料药价格 （18万美元/kg） HO OCH3 OH O H AcO BzO H3C O HO CH3 CH3 O OH NH Bz HO OCH3 OH O H AcO BzO H3 C HO HO CH3 CH3 四步反应 10-去乙酰浆果赤霉素 （10-去乙酰巴卡亭III） 紫杉醇 13

紫杉醇与多西他赛 H2C CH BOC H3C HO CH NH OH3C NH O H3C HO OCH3 OH o VCH HO AcO OH AcO BzO 紫杉醇 多西他赛 Taxol Docetaxel 水溶性比紫杉醇好,抗 肿瘤谱更广;同等情况 下活性优于紫杉醇

紫杉醇与多西他赛 紫杉醇 Taxol 多西他赛 Docetaxel BOC 水溶性比紫杉醇好，抗 肿瘤谱更广；同等情况 下活性优于紫杉醇 14

鸦片生物碱与半合成鸦片 Opiate alkaloids And semi-synthetic Opiates (from 3400 B C. to 1930s) CH CH- 吗啡 海洛因 morphine BAYER heroin (10-14%)H2coco OCOCH (1897) OH CH3 BAYER Send for samples PHARMACEUTICALASPIRIN and Literature to 天然鸦片生物碱 可待因 PRODUC心s codeine (13.5%) HcO OH HEROIN LYCETD CH FRIEOR BAYER&C9 BERFEL 帮巴因 Heroin thebaine FARBENFABRIKEN OF 40 STONE STREET (0.2%) ELBERFELD CO NEW YORK HCO

鸦片生物碱与半合成鸦片 Opiate Alkaloids And Semi-synthetic Opiates (from 3400 B.C. to 1930s) 15 吗 啡 morphine (10-14%) 天 然 鸦 片 生 物 碱 可待因 codeine (1-3.5%) 蒂巴因 thebaine (0.2%) 海洛因 heroin (1897)

蒂巴因的半合成物 Semi-sythetic Products of Thebaine CH3 蒂巴因 thebaine HcO OCH3 opium poppies CH CH CH3 CH N N OH OH H3CO O Haco HO O HO 羟吗时酮羟考酮 PURDUE 氢可酮 氢吗啡酮 oxymorphone oxycodone hydrocodone (1914) (1916) 奥施康定 ydromorphone Oxycontin (1920) (192 Earned more than 31 billion by 2016 16

蒂巴因的半合成物 Semi-sythetic Products of Thebaine 16 蒂巴因 thebaine 氢吗啡酮 hydromorphone (1924) 羟吗啡酮 oxymorphone (1914) 羟考酮 oxycodone (1916) 奥施康定® Oxycontin® Earned more than $31 billion by 2016 氢可酮 hydrocodone (1920) opium poppies