Pharmacology Core

摘要-医药核心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 效力、暴露(药代动力学，PK)和治疗指数(可接受的比率 有效浓度和毒性浓度)。药理学核心将支持有前景的HITS和 通过分级吸收、分配、代谢和消除(ADME)评估和协调的销售线索 配对标准，选择具有用于疗效研究的基本属性的化合物和化学支架 临床前发展。核心将利用一个完全集成的分析平台和最先进的动物 Hackensack子午线健康中心(新泽西州纳特利)提供的发现和创新中心设施可提供帮助 集结的团队。核心领导者Véronique Dartois博士在药理学方面拥有丰富的经验 抗感染化合物评价，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计划，我们将进行物理化学和体外PK分析以及基础 不同给药途径的小鼠配方研制和体内快照PK。数据将是 用于建立结构-活性关系，提名先导化合物并引导化合物朝着 疗效评价，按常规相变标准。为了支持Lead优化计划， 我们将进行安全筛选，全面的小鼠和仓鼠PK，组织在肺液和鼻腔中的分布 隔室、细胞内摄取和前药转化研究。与所有项目和 动物模型的核心，我们将整合(I)血浆和肺PK，(Ii)血浆蛋白结合，(Iii)摄取 在相关细胞系中考虑主动转运/外排过程，以及(Iv)效力测量，以计算 血浆和感染部位的药代动力学-药效学指标，并建议 耐受性和疗效研究。将在小鼠和仓鼠期间监测血浆和组织浓度 功效研究。协调的阈值指标将指导销售线索优化和通过/不通过决策，以最大限度地减少 在药物开发过程的后期，与PK和毒性相关的磨损的风险。

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.