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 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 抗生素临床前开发候选者必须具备以下条件： 效力、暴露（PK）和治疗指数（有效和毒性之间可接受的比例）的正确平衡 对于感染部位复杂且隐蔽的传染病，组织分布 构成药物先导物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）以及体外毒性测定，大大减少了药物的损耗 药理学核心的目标是评估这些特性。 药物化学家为支持五个联盟而进行的先导化合物和先导化合物优化阶段 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 的区域生物防护实验室（新泽西州纽瓦克）协助组建的团队开发 针对高威胁细菌制剂的治疗对策 核心 C 领导人 Véronique Dartois 博士有更多信息。 拥有12年以上抗感染药物药理评价经验。 为了支持先导化合物计划，我们提出了一系列体外 ADME 测定和啮齿动物药代动力学 以建立结构活动关系为目标的研究将结果整合到迭代中。 数轮药物化学，直到化合物表现出理想的药代动力学、效力和毒性 特性，也称为先导，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，我们开发了细菌内 PK 测定法 对于先导化合物优化计划，我们建议进行代谢物鉴定分析， 啮齿类动物的剂量递增 PK 和耐受性、通过传统质谱和激光进行的组织分布 捕获显微切割和体外安全筛选，以指导临床前开发的提名 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方案将用于识别 PK-PD 驱动因素。 功效，并确定感染部位所需的浓度范围，以达到最大效果 总之，我们将与所有项目和所有核心进行互动，以提供对每种药物至关重要的服务。 发现阶段将根据 ADME 和毒理学分析进行充分的优先排序和继续/不继续决策。 最大限度地降低药物发现过程后期与 PK 和毒性相关的损耗风险。 ！