Pharmaceutical Sciences Core

制药科学核心

• 批准号: 10671664
• 负责人: Vincent Jo Davisson
• 金额: $ 36.67万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10671664
• 关键词: Acceleration; Age; Animal Model; Biological Availability; Brain; Characteristics; Chemicals; Chemistry; Complementary Medicine; Cyanides; Decision Making; Development; Dose; Drug Kinetics; Ensure; Equilibrium; Evaluation; Excipients; Family suidae; Formulation; Goals; In Vitro; Investigational Drugs; Lead; Mammals; Metabolic; Metabolism; Methods; Modeling; Organ; Oryctolagus cuniculus; Peripheral; Permeability; Pharmaceutical Chemistry; Pharmaceutical Technology; Pharmacodynamics; Pharmacologic Substance; Pharmacology and Toxicology; Pharmacy (field); Process; Process Assessment; Prodrugs; Property; Qualifying; Rattus; Resources; Risk; Safety; Science; Site; Staging; Standardization; Testing; Tissues; Toxic effect; Toxicology; Translations; Triage; Universities; Variant; Zebrafish; analog; animal efficacy; candidate selection; chemical association; design; drug development; follow-up; glyoxylate; improved; in vivo; in vivo Model; lead candidate; lead optimization; meetings; metabolic phenotype; mouse model; new chemical entity; novel; porcine model; pre-clinical; process improvement; programs; screening; solid state

Abstract: The goal of the Pharmaceutical Sciences Core (PSC) is to provide drug development capabilities needed by the Center to enable the rapid translation of new chemical entities (NCEs) useful for cyanide countermeasures. The approach will be to add both capacity and capabilities in pharmacokinetics, toxicology, medicinal chemistry, and formulation through a collaborative team lead by Drs. V. J. Davisson and Gregory Knipp at Purdue University. The U54 program currently is able to use unbiased screening approaches in zebrafish to identify new chemical entities that show protection against cyanide toxicities. From the programs, there is capacity to conduct hit follow-up chemistry to qualification of new hit chemotypes. The PSC will critically evaluate and prioritize lead candidate compounds and formulations while executing hit-to-lead development studies. A focus of the U54 program moving forward is to establish, in addition to traditional scavengers, new metabolic modulators for tissue and organ protection against cyanide toxicity. While feasibility for translation to animal models is being demonstrated with hit compounds, barriers in meeting the product concept for relevant threat scenarios are significant. The PSC will provide capabilities for standardized in vivo pharmacology and toxicology support, pharmacokinetic assessment, physicochemical and solid-state property assessment and selection, preclinical formulation support that will accelerate translation and fulfill the program deliverables. A lead candidate staging process will be implemented to a) improve processes for assessment of the hit-to-leads and interface with in vivo models, b) improve the capacity to select compounds for lead development from the discovery group, c) provide entrée to lead compound efficacy and safety evaluation in mammalian models. In doing so, the PSC will impact decision making and resource management to enhance pharmaceutical strategies (developability properties) to enable more efficient transition from zebrafish to mammals.

摘要：药学核心(PSC)的目标是提供药物开发能力 该中心需要能够快速转化对氰化物有用的新化学物质(NCEs) 对策。该方法将增加药代动力学、毒理学、 药物化学和配方，由V.J.Davisson博士和Gregory博士领导的协作团队 普渡大学的克尼普。U54计划目前能够使用无偏见的筛查方法 斑马鱼，以确定新的化学实体，显示出保护免受氰化物毒性。从节目中， 有能力对新的HIT化学类型进行HIT后续化学鉴定。PSC将关键地 对候选化合物和配方进行评估和优先排序，同时执行命中到领先的开发 学习。U54计划向前推进的一个重点是，除了传统的清道夫之外，建立新的 用于保护组织和器官免受氰化物毒性的代谢调节剂。虽然将翻译为 动物模型正在使用Hit化合物进行演示，满足相关产品概念的障碍 威胁场景非常重要。PSC将提供标准化体内药理学和 毒理学支持、药代动力学评估、物理化学和固态性能评估以及 选择、临床前配方支持，以加快翻译速度并实现计划交付成果。一个 将实施领头羊候选人试运行流程，以a)改进从命中到领头羊的评估流程 以及与体内模型的接口，b)提高从 发现组，c)为领导化合物在哺乳动物模型中的有效性和安全性评估提供了入口。在……里面 这样做，PSC将影响决策和资源管理，以加强制药战略 (可开发性特性)，使斑马鱼能够更有效地过渡到哺乳动物。