Optimizing novel cyanide countermeasures

项目摘要 氰化物对人类健康构成重大威胁。如果没有有效且易于管理的解毒剂，通过工业事故或恐怖袭击大规模暴露于氰化物将产生破坏性影响。已经存在一些具有经证实的氰化物解毒活性的化合物，但它们的效力低且给药途径困难。仍然需要有效和高度有效的氰化物对策，并且能够发现具有新颖作用机制的真正新颖对策的方法特别有吸引力。拟议的卓越中心将发现和开发氰化物对策，这些对策是非常有效的，并通过新的机制发挥作用。项目1采用经过验证的大规模化学筛选来发现保护斑马鱼免受氰化物毒性的化合物。这些初始命中中的许多将不具有足够的效力或选择性以成为强的临床前药物先导。在项目2中，我们将使用药物化学方法来优化项目1中发现的命中的效力。然后将对优化的化合物进行分析，以确定其稳定性、生物利用度、毒性和代谢组学效应。这些实验将使我们能够将筛选命中转化为具有可接受的药代动力学特性和最小毒性的有效药物线索。最好的优化药物先导将交付给项目3，用于在哺乳动物中进行进一步的疗效测试。 具体而言，我们提出以下目标： 目标1.优化新型氰化物对策的效力。 目标2.分析优化的候选对策的药理学特性。 通过完成这些目标，我们将在项目1的高通量发现工作和项目3的经验证的功效模型之间提供重要的桥梁。本文概述的化合物优化方法利用了几种创新（体内SAR研究，高通量斑马鱼毒理学， 代谢组学），使这一过程比传统的药物开发途径更快，更具成本效益。总之，这些项目和核心将提供真正的新对策类，新的行动机制将改变我们应对氰化物威胁的能力。

Project summary Cyanide poses a significant threat to human health. Mass exposures to cyanide through industrial accidents or terror attacks would have devastating effects without effective and easily administered antidotes. A few compounds with proven cyanide antidotal activity already exist, but they suffer from low potency and difficult routes of administration. Potent and highly efficacious cyanide countermeasures are still needed, and methods that enable discovery of truly novel countermeasures with novel mechanisms of action are particularly attractive. The proposed center of excellence will discover and develop cyanide countermeasures that are highly potent and function through novel mechanisms. Project 1 employs a validated, large-scale chemical screen to discover compounds that protect zebrafish from cyanide toxicity. Many of these initial hits will not possess sufficient potency or selectivity to be strong preclinical drug leads. In Project 2, we will use medicinal chemistry methodologies to optimize the potency of the hits discovered in Project 1. Optimized compounds will then be profiled to determine their stability, bioavailability, toxicity, and metabolomic effects. These experiments will enable us to transform screening hits into potent drug leads with acceptable pharmacokinetic properties and minimal toxicities. The best of the optimized drug leads will be delivered to Project 3 for further efficacy testing in mammals. Specifically, we propose the following aims: Aim 1. To optimize the potency of novel cyanide countermeasures. Aim 2. To profile the pharmacological properties of optimized candidate countermeasures. By completing these aims, we will provide an essential bridge between the high-throughput discovery effort of Project 1 and the validated efficacy models of Project 3. The compound optimization process outlined herein takes advantage of several innovations (in vivo SAR studies, high-throughput zebrafish toxicology, metabolomics) to make the process much faster and more cost effective than the traditional drug development pathway. Together, the projects and cores will deliver truly new countermeasure classes with new mechanisms of action that transform our ability to respond to cyanide threats.