Agenda 1.药物发现整体框架:药物作用的靶标、知识价值、首创药物、模拟创新、双靶标药 物、老药新用 2.药物筛选与设计(先导化合物的发现与优化、单克隆抗体,计算机辅助设计) 3.药代动力学PKPD(药代过程、动力学参数、吸收、分布、转化、消除;前药、 软药) 4.药物的构效关系(药效团、毒性基团、构象、结构解析、定量构效、活性测定) 5.心血管类药物(钙通道阻滞剂、钠钾通道阻滞剂、血管紧张素、N○供体、强心药 调血脂药) 6.中枢神经系统 7.抗癌药物(抗代谢药、DNA药物、抗微观蛋白剂、分子靶向药、个体化治疗)
Agenda 1. 药物发现整体框架: 药物作用的靶标、知识价值、首创药物、模拟创新、双靶标药 物、老药新用 2. 药物筛选与设计（先导化合物的发现与优化、单克隆抗体，计算机辅助设计） 3. 药代动力学PKPD（药代过程、动力学参数、吸收、分布、转化、消除；前药、 软药） 4. 药物的构效关系（药效团、毒性基团、构象、结构解析、定量构效、活性测定） 5. 心血管类药物（钙通道阻滞剂、钠钾通道阻滞剂、血管紧张素、NO供体、强心药、 调血脂药） 6. 中枢神经系统 7. 抗癌药物（抗代谢药、DNA药物、抗微观蛋白剂、分子靶向药、个体化治疗）
Pharmaceutical Industry Goiwuenallofwcn NOVARTIS Revenue(2009): $62B Phzer Revenue(2009): $45B Employees: 115.5K Employees: 99.8K Revenue(2009): $50B gsk Employees: 116.5K AstraZeneca X Glaxosmithkline Revenue(2009): $32 8B Revenue(2009): $45B sanofi aventis Employees: 63K Employees: 99.9K Revenue(2009):$44B Employees: 105K Abbott A Posse for Life Revenue(2009):$21.8B Revenue(2009): $30.7B C MERCKEmployees:404K Employees: 73K Bristol-Myers Squibb Revenue(2008): $23 8B Revenue(2009): $188B $0. 5M / employee Employees: 55. 2K Employees: 28K
Pharmaceutical Industry Revenue (2008): $23.8B Employees: 55.2K Revenue (2009): $32.8B Employees: 63K Revenue (2009): $45B Employees: 99.8K Revenue (2009): $50B Employees: 116.5K Revenue (2009): $18.8B ~ $0.5M / employee Employees: 28K Revenue (2009): $21.8B Employees: 40.4K Revenue (2009): $44B Employees: 105K Revenue (2009): $45B Employees: 99.9K Revenue (2009): $62B Employees: 115.5K Revenue (2009): $30.7B Employees: 73K
1.1药物发现模式 1980以前主要模式: 研究阶段( Research) 民间医学 生物测定发现苗头化 ead Hit to lead Drug 偶然发现 合物 optimization Candidate 1980~ 发现新靶确认新靶 标 标 开发阶段( Development) 原料药、制剂 Phase Phase Phase 药效、药代药 上市 Preclinical Development
民间医学 偶然发现 生物测定 发现苗头化 合物 Hit to Lead 1980以前主要模式： Phase III Phase II Phase I Preclinical Development Drug Candidate Lead optimization 发现新靶 标 确认新靶 标 1980~ 上市 研究阶段（Research） 开发阶段（Development） 原料药、制剂 药效、药代药 动、安全性 1.1 药物发现模式
以表型为基础的研究模式 Biology Research Developmen Candidate market Chemistry 以生物靶标为核心的研究模式 High-capecity Cellular Safety Pharmacy Clinical eening Biology assessment development Manufacturing Hit identification Lead Preclinical Clinical Clinical Clinical identification/optimization development phase∥ phase ll∥ phase Candidate Market Genetics andComputational Medicinal Clinical DMPK genomics chemistry Regulatory Figure 4 Evolution of the drug discovery process during the second half of the twentieth century. (a) The process as used in the 1950s and 1960s, where research was mainly driven by biological screening and serendipity.()The process has evoled, embracing novel technologies, but also in many cases greater organizational complexity. DMPK, drug metabolism and macokinetics
以表型为基础的研究模式 以生物靶标为核心的研究模式
1.2 Drug Discovery Process SSSS- SSSSSSSSSSSSSS arg Lead Lead Preclinical Phase Phase Phase Identification Generation Optimisation Development Candidate Drug First in human High Risk, High investment, High reward Drug >$1 billion, 12 years! safety and dosage Development is far more expensive than discovery dont fail late Efficacy Discovery bottlenecks Validated targets quality Hits subsequent Leads Optimisation of the Leads Launch Only quality compounds should leave Discovery(前面10%的贡献度决定后面90%的命运) Paul et al, Nature Reviews Drug Discovery, 2010, 9, 203
Candidate Drug First in human Drug safety and dosage Efficacy Launch Phase III Phase II Phase I Target Identification Lead Generation Lead Optimisation Preclinical Development $ $ $$ $$$ $$$$ - $$$$$$$$$$$$$$ Paul et al, Nature Reviews Drug Discovery, 2010, 9, 203 • High Risk, High investment, High reward – >$1 billion, 12 years! • Development is far more expensive than discovery – don’t fail late • Discovery bottlenecks – Validated targets – Quality Hits & subsequent Leads – Optimisation of the Leads • Only quality compounds should leave Discovery (前面10%的贡献度决定后面90%的命运） 1.2 Drug Discovery Process