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.

翻译后摘要：药物科学核心（PSC）的目标是提供药物开发能力 该中心需要快速翻译对氰化物有用的新化学实体（NCE） 对策该方法将增加药代动力学，毒理学， 药物化学，并通过V.J.Davisson和Gregory博士领导的合作团队制定 普渡大学的学生。U54项目目前能够使用无偏筛选方法， 斑马鱼，以确定新的化学实体，显示对氰化物毒性的保护。从节目单上看， 有能力进行HIT后续化学以鉴定新的HIT化学型。PSC将严格 在执行“命中领先”开发的同时，评估并优先考虑领先候选化合物和制剂 问题研究U54计划的一个重点是，除了传统的清道夫， 用于保护组织和器官免受氰化物毒性的代谢调节剂。虽然翻译的可行性 动物模型正在证明与命中化合物，障碍，在满足相关的产品概念， 威胁情景是重要的。PSC将提供标准化体内药理学的能力， 毒理学支持、药代动力学评估、理化和固态性质评估，以及 选择、临床前制剂支持，将加速转化并实现项目交付成果。一 将实施潜在客户候选人阶段流程，以a）改进潜在客户评估流程 和与体内模型的接口，B）提高从体内模型中选择用于先导化合物开发的化合物的能力， 发现组，c）提供在哺乳动物模型中进行先导化合物功效和安全性评价的入口。在 这样，PSC将影响决策和资源管理，以加强制药战略 （可发育性特性）以使得能够更有效地从斑马鱼过渡到哺乳动物。