Medicinal Chemistry and Lead Development Core - SR

药物化学和先导化合物开发核心 - SR

• 批准号: 10580020
• 负责人: ASHISH KUMAR PATHAK
• 金额: $ 223.03万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-07 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580020
• 关键词: Alphavirus; Animals; Antiviral Agents; Automobile Driving; Biological; Biological Assay; Biological Availability; Chemistry; Collection; Computational Biology; Coronavirus Infections; Data; Data Storage and Retrieval; Decision Making; Development; Drug Design; Drug Kinetics; Evaluation; Excretory function; Flavivirus; Generations; Goals; Human Resources; In Vitro; Individual; Influenza; Informatics; Lead; Liver Microsomes; Metabolism; Microsomes; Modeling; Mus; Nucleosides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Plasma; Procedures; Process; Prodrugs; Property; Research; Research Project Grants; Retrieval; Role; Secure; Site; Solubility; Structure-Activity Relationship; Synthesis Chemistry; System; Testing; Therapeutic; Translational Research; Viral; Viral Physiology; Virus; Work; absorption; analog; anti-viral efficacy; biophysical properties; computational chemistry; cytotoxicity; data management; data sharing; design; drug candidate; drug development; drug discovery; drug-like compound; emerging pathogen; experimental study; in vivo; in vivo evaluation; informatics tool; inhibitor; iterative design; lead candidate; lead optimization; meter; new chemical entity; novel; process optimization; programs; scale up; structural biology; support tools; translational research program

The Medicinal Chemistry and Lead Development Core (MCLDC) is a key component of the Antiviral Drug Discovery and Development Center (AD3C) that will contribute to the goals of the overall Center of Excellence for Translational Research (CETR) program to develop new replication inhibitors and other broad-based therapeutics for the treatment of emerging pathogens through its interaction with each of the individual projects and cores. The MCLDC will provide a) synthetic chemistry, b) structure-activity relationship (SAR) data and analysis, c) lead optimization chemistry, d) bioanalytical assays, e) structural biology and computational support, and d) compound storage and data management. In this role, the MCLDC, in conjunction with the Assay Core, will be the central focus of the translational research component of the program. As such, the MCLDC will work closely with the Assay Core and each of the Research Project teams. As new chemical entities are designed and synthesized during the lead generation and optimization processes, the Assay Core will test these analogs in SAR-driving assays. Testing of compounds for drug-like properties such as microsomal stability and solubility; and in vitro Absorption, Distribution, Metabolism and Excretion (ADME) will be an integral part of SAR studies from the early developmental phase. Appropriate lead compounds will be provided to the various Research Project teams for advanced studies including efficacy, mechanism of action, and other experiments. The resulting data on lead compounds from the Assay Core and Research Projects will then be analyzed by the MCLDC to drive the iterative lead optimization and in vivo PK studies to completion, resulting in optimized leads with drug-like properties for animal studies. The lead candidates will have met the go/no go decision criteria set for activity, potency and drug-like properties. The goal for the end result of this process will be identification of novel optimized lead molecules that are appropriate for IND applications. The MCLDC will incorporate key personnel of other Cores and Research Project teams into the prioritization and decision–making procedures.

药物化学和铅开发核心（MCLDC）是抗病毒药物的关键组成部分 发现和开发中心（AD 3C），将有助于实现整个卓越中心的目标 转化研究（CETR）计划，以开发新的复制抑制剂和其他广泛的基础 通过其与每个单独项目的相互作用治疗新出现的病原体的疗法 和核心。MCLDC将提供a）合成化学，B）构效关系（SAR）数据， 分析，c）铅优化化学，d）生物分析测定，e）结构生物学和计算支持， 以及d）化合物存储和数据管理。在这一角色中，MCLDC与检测核心一起， 将是该计划的转化研究部分的中心焦点。因此，MCLDC将 与分析核心和每个研究项目团队密切合作。随着新的化学实体被设计出来 并在铅生成和优化过程中合成，检测核心将测试这些类似物 在SAR驱动分析中。测试化合物的药物样性质，如微粒体稳定性和溶解度; 体外吸收、分布、代谢和排泄（ADME）将是SAR研究的组成部分 从早期的发展阶段。适当的先导化合物将提供给各个研究机构， 高级研究项目组，包括功效、作用机制和其他实验。的 然后，将对来自试验核心和研究项目的铅化合物的结果数据进行分析， MCLDC推动迭代电极导线优化和体内PK研究完成，从而优化电极导线 用于动物研究的药物。主要候选人将满足通过/不通过决策标准集 活性、效力和类药物性质。这一进程的最终目标是确定 适合IND应用的新型优化先导分子。MCLDC将包含关键的 其他核心和研究项目团队的人员参与优先级排序和决策程序。