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
Hit-to-le ad optimization Preclinical Phase I Phase Phase Ill Submission P(TS) WIP needed for 1 launch Cost per WIP per Phase 525 50 Cycle time years Cost per launch(out of pocket)$24 549 5146 s185 s23 S44 5873 Total cost per NME Cost of capital Cost per launch(capitalized)[$94$166$414[ S150 5273 s314 s48 □D Figure 2 RGD model yielding costs to successfully discover and develop a single new molecular entity. The model defines the distinct phases of drug discovery and development from the initial stage of target-to-hit to the final stage, launch The model is based on a set of industry-appropriate R6D assumptions(industry benchmarks and data from Eli Lilly and Company) defining the performance of the RGD process at each stage of development(see Supplementary information SZ (box) for details). RGD parameters include: the probability of successful transition from one stage to the next(p(TS), the phase cost for each project, the cycle time required to progress through each stage of development and the cost of capital, reflecting the returns required by shareholders to use their money during the lengthy R6D process. With these inputs(darker shaded boxes), the model calculates the number of assets(work in process, WIP)needed in each stage of development to achieve one new molecular entity(NME)launch. Based on the assumptions for success rate, cycle time and cost, the model further calculates the 'out of pocket cost per phase as well as the total cost to achieve one NME launch per year(US$873 million). Lighter shaded boxes show calculated values based on assumed inputs. Capitalizing the cost, to account for the cost of capital during this period of over 13 years, yields a capitalized cost of $1, 778 million per NME launch. It is important to note that this model does not include investments for exploratory discovery research, post-launch expenses or overheads (that is, salaries for employees not engaged in RoD activities but necessary to support the organization) NATURE REVIEWS DRUG DISCOVERY VOLUME 9 MARCH 2010 203
1.2.1交通灯系统评估药物靶标 靶标确认没有或仅有较弱的证遗传或化学证据表明靶遗传和化学证据都表明靶标对 据表明靶标对细胞的标对细胞的生长,存活,细胞的生长,存活,侵入或扩 生长,存活,侵入或侵入或扩散有重要意义|散有重要意义 扩散有重要意义 检测技术尚无非活体检测手段已有非活体检测手段,已有板模式的分析检测手段 ssay 或所需试剂有明显局有开发为板模式的可行并可在合理时间范围内提供足 feasibility)限性 性 量的蛋白 可药性 新型的靶标体系,尚靶标体系或抑制物已有对靶标体系的机制有较为清晰 无已知的抑制剂或底一定研究报道 的理解,小分子抑制剂的结构 物类似物 具有类似药物的物化特性或有 基因家族中的临床前导物。 毒性 已有宿主类似物,但已有宿主类似物,有一具有针对癌细胞的特异性,或 缺乏结构,化学或其定的结构,化学或其它已知的宿主类似物对人体健康 它证据表明选择性抑证据表明选择性抑制的‖并非必要 制的可能性 可能性 结构信息尚无靶标蛋白的结构不含配基的靶标蛋白结高解析度的蛋白配基复合体结 或相关的同族体 构已知,或结构解析度‖构已知 较低(大于2.3埃),或 相关同族体和配基的结 构已知 Frearson et al. Trends in Parasitology 2007
靶标确认 没有或仅有较弱的证 据表明靶标对细胞的 生长,存活,侵入或 扩散有重要意义 遗传或化学证据表明靶 标对细胞的生长,存活, 侵入或扩散有重要意义 遗传和化学证据都表明靶标对 细胞的生长,存活,侵入或扩 散有重要意义 检测技术 (assay feasibility) 尚无非活体检测手段, 或所需试剂有明显局 限性 已有非活体检测手段, 有开发为板模式的可行 性 已有板模式的分析检测手段, 并可在合理时间范围内提供足 量的蛋白 可药性 新型的靶标体系,尚 无已知的抑制剂或底 物类似物 靶标体系或抑制物已有 一定研究报道 对靶标体系的机制有较为清晰 的理解,小分子抑制剂的结构 具有类似药物的物化特性或有 基因家族中的临床前导物。 毒性 已有宿主类似物,但 缺乏结构,化学或其 它证据表明选择性抑 制的可能性 已有宿主类似物,有一 定的结构,化学或其它 证据表明选择性抑制的 可能性 具有针对癌细胞的特异性,或 已知的宿主类似物对人体健康 并非必要 结构信息 尚无靶标蛋白的结构 或相关的同族体 不含配基的靶标蛋白结 构已知,或结构解析度 较低(大于2.3埃),或 相关同族体和配基的结 构已知 高解析度的蛋白-配基复合体结 构已知 Frearson et al. Trends in Parasitology 2007 ● ● ● 1.2.1 交通灯系统评估药物靶标
首创药物和模拟创新药物 Pioneering drug Follow-on drug(me-too /me better) 目标 First in class Best in class 靶标 全新 已知 药物结构未知 已知 化学空间大 局限 市场 暂无竞争,投入大,风险大竞争激烈,投入较小,风险较小 驱动力生物 化学 模拟创新必要性: 首创药物有巨大的优化空间 2.路径清晰,成功率高 3.克服耐药性 Sidenafil (viagra Vardenafil 4.|P 靶标:PDE5 (phosphodiesterase type 5 Udenafil
首创药物和模拟创新药物 Pioneering drug Follow-on drug (me-too / me better) 目标 First in class Best in class 靶标 全新 已知 药物结构 未知 已知 化学空间 大 局限 市场 暂无竞争,投入大,风险大 竞争激烈,投入较小,风险较小 驱动力 生物 化学 模拟创新必要性: 1. 首创药物有巨大的优化空间 2. 路径清晰,成功率高 3. 克服耐药性 4. IP N HN N N CH3 CH3 O O CH3 S O O N N H3C Sidenafil (Viagra) N N H3C S O O O CH3 N HN N N O CH3 H3C Vardenafil N NH S N N H N N CH3 CH3 O CH3 CH3 O O O Udenafil 靶标:PDE5 (phosphodiesterase type 5)
双靶标药物 多种药物组合 作用于多靶标的单一化合物(表123) 两个受体的调节剂:如GPCR 两个酶的抑制剂:如 Kinase活性位点结构相似 作用于受体和酶的双功能分子 作用于受体与转运蛋白/离子通道的双功能分子 Lapatinib (breast cancer) Terbogre(抗血栓):抑制血栓烷 EGFR/HER2 kinase抑制剂 A2合成酶和血栓烷A2受体
双靶标药物 多种药物组合 作用于多靶标的单一化合物 (表12-3) • 两个受体的调节剂:如GPCR • 两个酶的抑制剂:如Kinase活性位点结构相似 • 作用于受体和酶的双功能分子 • 作用于受体与转运蛋白/离子通道的双功能分子 Lapatinib (breast cancer): EGFR/HER2 kinase 抑制剂 Terbogrel(抗血栓):抑制血栓烷 A2合成酶和血栓烷A2受体
老药新用( New Drug Indication) 杂泛性( Promiscuity) Selective Optimization of side activity (SOSA) 药物有适宜的物理化学性质 良好的药代动力学性质 安全性 5-HT 优化的结构/活性新颖性 CH 从抗菌药到提高认知能力药物 磺胺化合物发现5-HTA受体拮抗 剂 K⑤HT6)=46.8nM H2N Ki(5HT 6)=12nM O-CH3 CH3 NH- pK(5HT6)=8.3 H3c pK(5HT6)=92 pK(5HT6)=89
老药新用(New Drug Indication) 杂泛性(Promiscuity) Selective Optimization of side activity (SOSA) 药物有适宜的物理化学性质 • 良好的药代动力学性质 • 安全性 • 优化的结构/活性新颖性 N H NH2 HO 5-HT S NH N N NH2 NH CH3 HN CH3 O O S NH N H2N HN CH3 NH CH3 O O Ki(5HT 6 )=46.8nM Ki(5HT6 )=12nM S NH Br O CH3 O O N N CH3 pKi(5HT 6 )=8.3 S NH O CH3 O O N N CH3 S H3C pKi(5HT 6 )=9.2 pKi(5HT 6 )=8.9 S H3C S NH O CH3 O O N N H 从抗菌药到提高认知能力药物 磺胺化合物发现5-HT6A受体拮抗 剂