Validating promising drug candidates in mammalian models of CN poisoning

在U 54计划的这一部分中，将使用完善的小鼠和家兔氰化物中毒模型，在渐进性转化动物疗效研究中测试在项目1中描述的斑马鱼筛选中确定的有希望的候选药物，并通过项目2中的体内结构活性关系和药物化学研究进行推进。我们预计项目2每年将产生4-5种非常有前途的优化化合物。然后将在小鼠中测试这些候选物的体内功效和范围探索研究中的安全性。将在经过充分验证的氰化物气体吸入模型中检测疗效。我们预计，在每年测试的4-5种药物中，2-4种将在小鼠中显示出安全性和有效性方面的前景，然后将进行广泛监测的兔有效性研究，以确定生理效应和恢复率以及生存结果。这些药物将通过肌肉注射给小鼠和兔子服用，因为CounterACT项目主要感兴趣的是找到一种可以在现场快速给药的氰化物解毒剂。此外，还将通过吸入评估进展到兔模型的候选药物的疗效，因为吸入药物被迅速吸收，这是向大量人群给药的有效方法。我们预计，平均每年有一种药物将通过小鼠和家兔研究，并准备进行正式的毒理学和药代动力学研究。该项目的研究需要与项目2和代谢组学核心密切合作，但我们也将与项目1互动，以探索开发阶段的药物毒性机制，并验证易受氰化物毒性影响的特定人群的标志物。

In this component of the U54 program, promising drug candidates identified in the zebrafish screens described in Project 1 and advanced through in vivo structure activity relationship and medicinal chemistry studies in Project 2 will be tested in progressive translational animal efficacy studies using well-established mouse and rabbit models of cyanide poisoning. We anticipate that Project 2 will yield 4-5 highly promising optimized compounds each year. These candidates will then be tested in mice for in vivo efficacy and for safety in range finding studies. Efficacy will be tested in a well-validated cyanide gas inhalational model. We expect that of the 4-5 drugs tested each year, 2-4 will show promise in mice in terms of safety and efficacy, which will then progress to extensively monitored rabbit efficacy studies to determine physiologic effects, and rate of recovery in addition to survival outcomes. The drugs will be administered by intramuscular injection in both the mice and rabbits, since the CounterACT program is primarily interested in finding a cyanide antidote that could be given rapidly in the field. In addition, candidate drugs that progress to the rabbit model will also be assessed for efficacy via inhalation, since inhaled drugs are rapidly absorbed and this is an effective method to administer drugs to a large number of people. We anticipate that on average one drug per year will make it through the mouse and rabbit studies and be ready for formal toxicological and pharmacokinetic studies. The studies in this project require close collaboration with Project 2 and the Metabolomics Core, but we will also interact with Project 1 to explore mechanisms of drug toxicity during the development phase and to validate markers for specific populations vulnerable to cyanide toxicity.