Pharmacology Core

药理学核心

• 批准号: 10513919
• 负责人: Veronique Dartois
• 金额: $ 347.6万
• 依托单位: HACKENSACK UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10513919
• 关键词: 2019-nCoV; Active Biological Transport; Animal Model; Anti-Infective Agents; Antiviral Agents; Binding Proteins; Biological Assay; COVID-19; Cell Line; Cells; Chemicals; Chemistry; Clinical; Collaborations; Data; Dengue; Development; Dose; Drug Industry; Drug Kinetics; Drug or chemical Tissue Distribution; Drug usage; Equilibrium; Evaluation; Exons; FDA Emergency Use Authorization; Formulation; HIV; Hamsters; Health; Hepatitis C; Hydroxychloroquine; In Vitro; Infection; Lead; Left; Liquid substance; Lung; Measurement; Meridians; Metabolic; Metabolism; Modeling; Monitor; Mus; Nose; Oral; Outpatients; Permeability; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase Transition; Plasma; Plasma Proteins; Process; Prodrugs; Rodent; Route; Safety; Services; Site; Solubility; Structure-Activity Relationship; Testing; Therapeutic Index; Tissues; Toxic effect; Toxicology; Triage; Virus; Withdrawal; absorption; animal facility; candidate selection; chemical stability; drug candidate; drug development; drug discovery; drug distribution; efficacy evaluation; efficacy study; experience; in vitro activity; in vivo; indexing; innovation; lead candidate; lead optimization; metropolitan; novel; pandemic disease; preclinical development; programs; protein metabolism; respiratory; risk minimization; scaffold; small molecule; uptake; virology

ABSTRACT - Pharm Core 5 To be tested in efficacy studies and advance to preclinical development, small molecule antivirals must have the right balance of potency, exposure (pharmacokinetics, PK), and therapeutic index (acceptable ratio between efficacious and toxic concentrations). The Pharmacology Core will support advancement of promising hits and leads through tiered absorption, distribution, metabolism, and elimination (ADME) assessment and harmonized gating criteria, selecting compounds and chemical scaffolds with the essential attributes for efficacy studies and preclinical development. The Core will leverage a fully integrated analytical platform and state-of-the-art animal facility available at the Center for Discovery and Innovation, Hackensack Meridian Health (Nutley, NJ) to assist the assembled team. The Core Leader, Dr Véronique Dartois, has extensive experience in the pharmacological evaluation of anti-infective compounds, including 8 years supporting anti-Dengue drug discovery programs in the pharmaceutical industry. To support hit-to-lead programs, we will carry out physicochemical and in vitro PK profiling as well as basic formulation development and in vivo snapshot PK in mice via different routes of administration. The data will be used to establish structure-activity relationships, to nominate leads and guide compound progression towards efficacy evaluation, according to conventional phase transition criteria. To support lead optimization programs, we will perform safety screens, full mouse and hamster PK, tissue distribution in pulmonary fluid and nasal compartments, intracellular uptake, and prodrug conversion studies. In close collaboration with all Projects and the Animal Model Core, we will integrate (i) plasma and pulmonary PK, (ii) plasma protein binding, (iii) uptake in relevant cell lines to factor in active transport/efflux processes, and (iv) potency measurements, to calculate pharmacokinetic-pharmacodynamic indices in plasma and at the site of infection, and to propose doses for tolerability and efficacy studies. Plasma and tissue concentrations will be monitored during murine and hamster efficacy studies. Harmonized threshold metrics will guide lead optimization and go-no/go decisions to minimize the risk of PK- and toxicity-related attrition later in the drug development process.

摘要-Pharm Core 5 要在效率研究中进行测试并促进临床前发育，小分子抗病毒药必须具有 效力，暴露（药代动力学，PK）和治疗指数的正确平衡（可接受的比例 高效和有毒浓度）。药理学核心将支持诺言的进步，并 通过分层抽象，分布，代谢和进化（ADME）评估并进行协调 门控标准，选择具有效率研究基本属性的化合物和化学支架 临床前发展。核心将利用完全集成的分析平台和最先进的动物 Hackensack Meridian Health（Nutley，NJ）的发现与创新中心可用的设施可用 组装团队。核心负责人VéroniqueDartois博士在药理方面拥有丰富的经验 评估抗感染化合物，包括支持反登记药物发现计划的8年 制药行业。 为了支持命中率的计划，我们将进行身体和体外PK分析以及基本 通过不同的给药途径，小鼠中的形成发展和体内快照PK。数据将是 用于建立结构活动关系，提名铅并指导复合进展 根据常规相过渡标准，功效评估。支持潜在客户优化程序， 我们将执行安全屏幕，完整的小鼠和仓鼠PK，肺液和鼻腔中的组织分布 隔室，细胞内摄取和前药转换研究。与所有项目密切合作， 动物模型核心，我们将整合（i）等离子体和肺PK，（ii）血浆蛋白结合，（iii）吸收 在相关的细胞系中，以考虑主动传输/外排过程和（iv）效力测量值以计算 血浆和感染部位的药代动力学 - 药效指数，并提出剂量的剂量 耐受性和效率研究。在鼠和仓鼠期间将监测血浆和组织浓度 效率研究。统一的阈值指标将指导铅优化和不使用/执行决定以最小化 PK-和毒性相关的风险在药物开发过程的后期属性。