Pharmaceutical Sciences Core

制药科学核心

• 批准号: 10426366
• 负责人: Vincent Jo Davisson
• 金额: $ 53.81万
• 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/10426366
• 关键词: Age; Animal Model; Biological Availability; Brain; Characteristics; Chemicals; Chemistry; 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; Rattus; Resources; Risk; Safety; Science; Site; Staging; Standardization; Structure; Testing; Tissues; Toxic effect; Toxicology; Translations; Triage; Universities; Variant; Zebrafish; analog; animal efficacy; base; 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; novel; porcine model; pre-clinical; 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：药物科学核心（PSC）的目标是提供药物开发能力 中心需要能够快速转化可用于氰化物的新化学实体（NCE） 对策将是增加药代动力学、毒理学、 由 V. J. Davisson 和 Gregory 博士领导的合作团队进行药物化学和配方设计。 普渡大学的 Knipp 表示，U54 项目目前能够使用公正的筛选方法。 斑马鱼识别出可防止氰化物毒性的新化学实体。 PSC 有能力对新的命中化学型进行后续化学鉴定。 在执行先导化合物开发的同时，评估并确定先导候选化合物和制剂的优先级 U54 计划前进的一个重点是除了传统的拾荒者之外，还建立新的拾荒者。 用于保护组织和器官免受氰化物毒性的代谢调节剂，同时具有转化为的可行性。 动物模型正在用热门化合物进行演示，在满足相关产品概念方面存在障碍 PSC 将提供标准化体内药理学和能力。 毒理学支持、药代动力学评估、理化和固态特性评估以及 选择、临床前制剂支持将加速转化并实现项目可交付成果。 将实施主要候选者分期流程，以 a) 改进对潜在客户的评估流程 以及与体内模型的接口，b) 提高​​从药物中选择用于先导开发的化合物的能力 发现小组，c) 提供在哺乳动物模型中评估先导化合物功效和安全性的入口。 这样做，PSC 将影响决策和资源管理，以增强制药战略 （可发展性）以实现从斑马鱼到哺乳动物的更有效过渡。