Core C Pharmacology

核心C药理学

• 批准号: 10394987
• 负责人: Veronique Dartois
• 金额: $ 86.47万
• 依托单位: HACKENSACK UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394987
• 关键词: Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics; Biological Assay; Cell Wall; Communicable Diseases; Complex; Data; Development; Dose; Drug Kinetics; Drug or chemical Tissue Distribution; Equilibrium; Evaluation; Exhibits; Failure; Fiber; Formulation; Goals; Gram-Negative Bacteria; In Vitro; Infection; Lead; Mass Spectrum Analysis; Measures; Metabolic; Metabolism; Modeling; Multi-Drug Resistance; Mus; Penetration; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase Transition; Process; Property; Rattus; Regimen; Research Institute; Rodent; Rodent Model; Safety; Services; Site; Solubility; Structure-Activity Relationship; System; Therapeutic; Therapeutic Index; Time; Toxic effect; Toxicology; absorption; animal facility; base; cost; drug development; drug discovery; efficacy evaluation; experience; in vitro Assay; in vivo; innovation; laser capture microdissection; lead optimization; novel therapeutics; pathogen; preclinical development; programs; public health research; residence; risk minimization; uptake

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. !

抽象的 1990年代后期进行的研究得出的结论是，较差的药代动力学（PK）和毒性是主要原因 药物开发中昂贵的晚期失败。抗生素临床前开发候选人必须具有 正确平衡效力，暴露（PK）和治疗指数（有效与有毒之间的可接受比率 浓度）。对于具有复杂和隔离的感染部位的感染疾病，组织分布 构成药物铅的另一个关键特征。滥用体外和啮齿动物模型的整合， 分布，新陈代谢和消除（ADME）以及体外毒性分析已大大降低了药物的属性 发现与发展。药理学核心的目的是评估这些特性 药物化学家进行的命中率和铅优化阶段支持五个财团 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（新泽西州纽瓦克）的区域生物疗法实验室，以协助组装团队开发 对高威胁细菌剂的治疗对策。 C核心负责人VéroniqueDartois博士拥有更多 抗感染剂的药物评估经验超过12年的经验。 为了支持命中率的计划，我们提出了一系列体外ADME分析和啮齿动力学的电池 研究目的是建立结构活动关系。结果整合到迭代中 药物化学弹性，直到化合物表现出理想的药代动力学，效力和毒性 属性，也称为铅。对于主要障碍是渗透化合物的选定项目 通过病原体的细胞壁和细胞内停留时间，我们开发了细菌的PK测定法 吸收，排出和代谢。对于铅优化程序，我们建议代谢物鉴定测定法， 剂量升级PK和啮齿动物的耐受性，通过常规质谱法和激光通过的组织分布 捕获微分解和体外安全筛选，以指导临床前开发的提名 候选人。我们将进行药代动力学 - 药力动力学（PK-PD）研究，以优化剂量和剂量 临床前开发化合物的方案。空心纤维系统将用于识别PK-PD驱动器 效率，并确定感染部位所需的浓度范围，以达到最大 总而言之，我们将与所有项目和所有核心互动，为每种药物提供必不可少的服务 发现阶段。基于ADME和毒理学概况的充分优先级和GO-NO/GO决定将 最小化药物发现过程中PK-和毒性相关属性的风险。 呢