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 - 医药核心 5 为了在功效研究中进行测试并进入临床前开发，小分子抗病毒药物必须具有 效力、暴露量（药代动力学，PK）和治疗指数（之间可接受的比率）的正确平衡 有效和毒性浓度）。药理学核心将支持有希望的命中和进展。 通过分层吸收、分布、代谢和消除（ADME）评估和协调 门控标准，选择具有功效研究基本属性的化合物和化学支架 临床前开发。核心将利用完全集成的分析平台和最先进的动物。 哈肯萨克子午线健康中心（新泽西州纳特利）发现和创新中心提供设施来协助 核心领导者 Véronique Dartois 博士在药理学方面拥有丰富的经验。 抗感染化合物的评估，包括 8 年支持抗登革热药物发现计划 制药业。 为了支持先导化合物计划，我们将进行理化和体外 PK 分析以及基本分析 制剂开发和小鼠通过不同给药途径的体内快照 PK 数据将是。 用于建立结构-活性关系、提名先导化合物并指导化合物进展 根据传统的相变标准进行功效评估，以支持先导化合物优化计划， 我们将进行安全筛选、完整的小鼠和仓鼠 PK、肺液和鼻腔中的组织分布 与所有项目和药物密切合作进行隔室、细胞内摄取和前药转化研究。 在动物模型核心中，我们将整合 (i) 血浆和肺部 PK，(ii) 血浆蛋白结合，(iii) 摄取 在相关细胞系中考虑主动运输/流出过程，以及（iv）效力测量，以计算 血浆和感染部位的药代动力学-药效学指数，并建议剂量 将在小鼠和仓鼠期间监测血浆和组织浓度。 统一的阈值指标将指导先导化合物优化和继续/不继续决策，以最大限度地减少疗效。 药物开发过程后期出现 PK 和毒性相关损耗的风险。