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 为了在疗效研究中进行测试并推进临床前开发，小分子抗病毒药物必须具有 正确平衡效力、暴露量（药代动力学、PK）和治疗指数（可接受的比值） 有效浓度和毒性浓度）。药理学核心将支持有前途的命中的进步， 通过分层吸收、分布、代谢和消除（ADME）评估和协调 门控标准，选择具有有效性研究基本属性的化合物和化学支架， 临床前开发。核心将利用一个完全集成的分析平台和最先进的动物 Hackensack Meridian Health（Nutley，NJ）发现和创新中心提供的设施， 集合的团队。核心负责人Véronique Dartois博士在药理学领域拥有丰富的经验， 评估抗感染化合物，包括8年支持抗登革热药物发现计划， 制药业。 为了支持hit-to-lead项目，我们将进行理化和体外PK分析以及基础研究。 制剂开发和通过不同给药途径在小鼠中的体内快照PK。数据将 用于建立结构-活性关系，提名先导化合物并指导化合物的进展， 根据常规的相变标准进行疗效评价。为了支持潜在客户优化计划， 我们将进行安全性筛选、完整的小鼠和仓鼠PK、肺液和鼻腔中的组织分布， 室、细胞内摄取和前药转化研究。与所有项目密切合作， 在动物模型核心中，我们将整合（i）血浆和肺PK，（ii）血浆蛋白结合，（iii）摄取 在相关细胞系中，以考虑主动转运/外排过程，和（iv）效价测量，以计算 血浆中和感染部位的药代动力学-药效学指标，并建议用于 耐受性和功效研究。将在小鼠和仓鼠试验期间监测血浆和组织浓度。 功效研究。统一的阈值指标将指导潜在客户优化和go-no/go决策， 药物开发过程后期PK和毒性相关损耗的风险。