Advancing novel cyanide countermeasures

推进新型氰化物对策

• 批准号: 10241493
• 负责人: Calum A. MacRae
• 金额: $ 319.7万
• 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/10241493
• 关键词: Accidents; Achievement; Advanced Development; Antidotes; Clinic; Clinical; Combined Modality Therapy; Cyanides; Development; Dimethyl Sulfoxide; Elements; Family suidae; Formulation; Funding; Generations; Goals; Human; Industrialization; Injections; Investments; Lead; Metabolic; Metabolism; Modeling; Mus; Oryctolagus cuniculus; Pharmaceutical Chemistry; Pharmacology; Preclinical Testing; Readiness; Research; Research Personnel; Rewards; Science; Technology; Terrorism; Toxic effect; Toxicology; Translating; Translations; Work; Zebrafish; chemical threat; clinically relevant; design; drug development; drug discovery; glyoxylate; high throughput screening; in vivo; innovation; insight; meetings; member; metabolic poison; metabolomics; next generation; novel; product development; programs; small molecule libraries

The overarching objective of our proposed center is: · The delivery of cyanide countermeasure(s) that meet the BARDA definition of readiness for advanced development. In prior work within our consortium, we have discovered new compound classes that can counteract the effect of cyanide. Foremost among these are the multivalent cyanide scavenger hexachloroplatinate and the metabolic modulator glyoxylate, but several additional next-generation compounds are in the pipeline. These discoveries pave the way for development of cyanide countermeasures that are fundamentally different from existing countermeasures and have the potential to transform our ability to respond to cyanide exposures. This new U54 will focus on translating these discoveries into optimized, validated leads meeting the formal requirements for advanced development and clinical deployment. In addition to the delivery of these clinically relevant products, we will also contribute: · Fundamental insights into the full range of mechanisms of cyanide-induced lethality in vivo · Systematic exploration of the pharmacological manipulation of metabolism · Formal characterization of the core relationships between the different models in our platform and of the most efficient ways to move between these models in drug discovery and development, with the goal of developing a generalizable approach to metabolic poisons.

我们提议的中心的总体目标是： ·符合Barda关于准备就绪的定义的氰化物对策的交付 高级发展。在我们财团内的先前工作中，我们发现了新的化合物类 可以抵消氰化物的作用。其中最重要的是多价氰化物清道夫 六氯邮寄和代谢调节剂乙氧基化，但另外几种下一代化合物 在管道中。这些发现为开发氰化物对策铺平了道路 与现有的对策根本不同，并有可能改变我们的回应能力 暴露于氰化物。这个新的U54将专注于将这些发现转化为经过优化的，经过验证的潜在客户 满足对高级开发和临床部署的正式要求。 除了提供这些临床相关产品外，我们还将做出贡献： 对氰化物诱导的杀伤力的全部机制的基本见解 系统探索代谢的药物操纵 ·我们平台中不同模型与该核心关系的正式表征 在药物发现和开发中这些模型之间移动的最有效方法，目的是 开发一种可推广的代谢毒物的方法。