Core C Pharmacology

摘要 20世纪90年代末进行的研究得出结论，不良的药代动力学(PK)和毒性是主要原因 药物开发的代价高昂的后期失败。抗生素临床前开发候选人必须具有 效力、暴露(PK)和治疗指数(有效与毒性的可接受比率)之间的正确平衡 浓度)。对于感染部位复杂、隔离的传染病，组织分布 构成了毒品线索的另一个关键特征。体外和啮齿动物吸收模型的整合， 分布、代谢和消除(ADME)和体外毒性测试大大减少了药物的磨损 发现和发展。药理学核心的目标是评估这些特性中的每一种 药物化学家为支持五个联合体而进行的命中到领先和领先优化阶段 项目。我们建议利用一个完全集成的分析平台和最先进的动物设施 在PHRI(新泽西州纽瓦克)的区域生物遏制实验室帮助组装的团队开发 高威胁细菌制剂的治疗对策。核心领导维罗尼克·达托瓦博士有更多报道。 在抗感染药物的药理评价方面有12年以上的经验。 为了支持Hit-to-Lead计划，我们提出了一系列体外ADME分析和啮齿类动物的药物动力学 以建立结构活性关系为目标的研究。在迭代中对结果进行积分 几轮药物化学直到化合物显示出理想的药代动力学、效力和毒性 属性，也称为引线。对于主要障碍是化合物渗透的选定项目 通过病原菌的细胞壁和细胞内停留时间，我们建立了细菌内PK检测方法 摄取、排出和代谢。对于铅优化计划，我们建议代谢物鉴定分析， 剂量递增PK和在啮齿动物中的耐受性，组织分布的常规质谱学和激光- 获取显微解剖和体外安全筛选，以指导临床前开发的提名 候选人。我们将进行药代动力学-药效学(PK-PD)研究，以优化剂量和剂量 临床前开发化合物的治疗方案。中空纤维系统将用于识别PK-PD驱动器 药效，并确定感染部位所需的浓度范围，以达到最大 功效。总而言之，我们将与所有项目和所有核心互动，为每种药物提供必要的服务 发现阶段。基于ADME和毒理学分析的适当优先顺序和通过/不通过决策将 在药物发现过程的后期将与PK和毒性相关的磨损风险降至最低。 好了！

Abstract Studies conducted in the late 1990s concluded that poor pharmacokinetics (PK) and toxicity were major causes of costly late-stage failures in drug development. Antibiotic preclinical development candidates must have the right balance of potency, exposure (PK) and therapeutic index (acceptable ratio between efficacious and toxic concentrations). For infectious diseases with complex and sequestered sites of infection, tissue distribution constitutes another critical feature of drug leads. The integration of in vitro and rodent models of absorption, distribution, metabolism and elimination (ADME), and in vitro toxicity assays, has largely reduced attrition in drug discovery and development. The objective of the Pharmacology Core is to assess each of these properties at the hit-to-lead and lead optimization stages carried out by the medicinal chemists to support the five consortium Projects. We propose to leverage a fully integrated analytical platform and state-of-the-art animal facility available at the Regional Biocontainment Lab of the PHRI (Newark, NJ) to assist the assembled team in developing therapeutic countermeasures to high-threat bacterial agents. Core C Leader, Dr Véronique Dartois, has more than 12 years of experience in the pharmacological evaluation of anti-infectives. To support hit-to-lead programs, we propose a battery of in vitro ADME assays and rodent pharmacokinetic studies with the objective of establishing structure activity relationships. The results are integrated in iterative rounds of medicinal chemistry until compounds exhibit desirable pharmacokinetics, potency and toxicity properties, also called leads. For selected projects where the major barrier is penetration of the compounds through the pathogen’s cell wall and intracellular residence time, we have developed intrabacterial PK assays of uptake, efflux and metabolism. For lead optimization programs, we propose metabolite identification assays, dose escalation PK and tolerability in rodents, tissue distribution by conventional mass spectrometry and laser- capture microdissection, and in vitro safety screens, to guide the nomination of preclinical development candidates. We will conduct pharmacokinetic-pharmacodynamic (PK-PD) studies to optimize doses and dosing regimen of preclinical development compounds. Hollow fiber systems will be used to identify PK-PD drivers of efficacy, and determine the concentration range required at the site of infection in order to achieve maximum efficacy. In summary, we will interact with all projects and all cores to deliver services essential to each drug discovery stage. Adequate prioritization and go-no/go decisions based on ADME and toxicology profiling will minimize the risk of PK- and toxicity-related attrition later in the drug discovery process. !