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 药物开发后期代价高昂的失败。抗生素临床前开发候选药物必须具有 正确平衡效力、暴露（PK）和治疗指数（有效和毒性之间的可接受比例） 浓度）。对于具有复杂和隔离感染部位的传染病，组织分布 构成了毒品线索的另一个重要特征体外和啮齿动物吸收模型的整合， 分布、代谢和消除（ADME）以及体外毒性试验，大大减少了药物的消耗。 发现和发展。药理学核心的目标是评估这些特性中的每一个， 药物化学家为支持五个联合体而开展的先导药物和先导药物优化阶段 项目我们建议利用完全集成的分析平台和最先进的动物设施 在PHRI（纽瓦克，新泽西州）的区域生物防护实验室，协助组装团队开发 针对高威胁细菌制剂的治疗对策。核心C领导人Véronique Dartois博士有更多 在抗感染药物的药理学评价方面拥有超过12年的经验。 为了支持命中铅计划，我们提出了一个电池的体外ADME测定和啮齿动物药代动力学 以建立结构活性关系为目标的研究。结果被集成在迭代 直到化合物表现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 通过病原体的细胞壁和细胞内停留时间，我们已经开发了细菌内PK测定， 吸收、流出和代谢。对于铅优化程序，我们提出代谢物鉴定分析， 啮齿类动物中剂量递增的PK和耐受性，通过常规质谱法和激光法测定的组织分布， 捕获显微切割和体外安全性筛选，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，以优化剂量和给药 临床前开发化合物的方案。中空纤维系统将用于识别PK-PD驱动程序， 有效性，并确定在感染部位所需的浓度范围，以达到最大的 功效总之，我们将与所有项目和所有核心互动，以提供对每种药物至关重要的服务 发现阶段根据ADME和毒理学特征分析， 最大限度地降低药物发现过程后期PK和毒性相关损耗的风险。 !

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. !