Countermeasures Against Chemical Threats: Countermeasures Against Cyanide

描述（由申请人提供）：尽管不同国家对氰化物中毒的特定解毒剂有不同的偏好，但美国30多年来的首选解毒剂一直是亚硝酸钠和硫代硫酸钠的组合，两者都是及时静脉给药。近年来，这已经补充了挥发性的亚硝酸戊酯，经鼻给药，具有血管扩张作用。然而，这些药物通常不仅作用缓慢，而且如果使用不当，可能会产生毒性和严重并发症。USAMRICD专家最近撰写的一篇关于氰化物的观点文章指出，在严重氰化物中毒中，快速干预是关键，治疗需要三分钟的解决方案，类似于神经毒剂解毒剂试剂盒（巴斯金等人，2004年）。有无毒剂可供受到威胁的军事人员或氰化物紧急情况的第一反应者服用，也是一种理想的要求。这些目标迄今尚未实现，目前的处理方式不适合军事环境，也不适合实际使用氰化物作为大规模危害平民的威胁剂。我们最近开发了（未发表）一系列原型氰化物解毒剂，释放底物的酶，3-巯基丙酮酸硫转移酶（3-MPST）在体内，从而提供了一个可行的替代方法解毒氰化物利用这种无处不在的细胞酶转化为无毒的硫氰酸盐。这里的基本原理是直接为这种酶提供其天然底物，从而绕过了从L-半胱氨酸的转氨作用内源性产生它的必要性，L-半胱氨酸是一种已知在组织中不太丰富的巯基氨基酸。我们还开发了一种独特的小鼠模型，最大限度地减少了大量动物的使用，用于评估亚致死剂量氰化物的毒性，这是非常适合评估我们的化合物的解毒功效。已经建立了我们的原型化合物在小鼠中保护免受氰化物毒性的概念证明，我们将同时a）扩展原型系列，并围绕这些系列设计和合成类似物以改善这些化合物的解毒功效、生物利用度和物理性质，B）抑制内源性抗氧化剂谷胱甘肽（作为其生物可利用形式;参见下文）在上述方案中评价这种抗氧化剂共同治疗是否会提高存活率并防止在急性氰化物中毒的长期存活者中看到的神经缺陷，和c）加速临床前研究（急性和长期毒性、ADME、其他动物模型等）对于那些已经证明具有保护作用的化合物，目标是在此授权期内向FDA提交IND申请。虽然我们系列的大多数化合物是快速作用的，但至少有一种原型（也许更多）是缓慢作用的（通过设计），但口服时完全保护;

DESCRIPTION (provided by applicant): Although different nations have variable preferences for specific antidotes against cyanide poisoning, the antidotes of choice in the U.S. for over 30 years have been the combination of sodium nitrite and sodium thiosulfate, both administered intravenously in timely sequence. In recent years, this has been supplemented with the volatile amyl nitrite given nasally for its vasodilatory effect. However, these agents are generally not only slow acting, but have potential for toxicity and serious complications if not used properly. A recent perspective article on cyanide, authored by experts at the USAMRICD, pointed out that in severe cyanide poisonings, rapid intervention is the key, and treatments require a three minute solution, akin to the nerve agent antidote kit (Baskin et al. 2004). The availability of non-toxic agents that could be taken prophylactically by military personnel on threatened exposure or by first responders to a cyanide emergency, also represents an ideal requirement. These goals have not yet been achieved to date, and the present treatment modalities are unsuitable in a military setting, or in the event of actual use of cyanide as a threat agent on a large scale against the civilian population. We have recently developed (unpublished) a series of prototype cyanide antidotes that release the substrate for the enzyme, 3-mercaptopyruvate sulfur-transferase (3-MPST) in vivo, thereby providing a viable alternative method for detoxifying cyanide by utilizing this ubiquitous cellular enzyme to convert cyanide to the non-toxic thiocyanate. The rationale here is to provide this enzyme with its natural substrate directly, thereby by-passing the necessity for generating it endogenously from the transamination of L-cysteine, a sulfhydryl amino acid known to be less abundant in tissues. We have also developed a unique mouse model-that minimizes the use of large numbers of animals-for assessing the toxicity of sub-lethal doses of cyanide, which is highly amenable for evaluating the antidotal efficacy of our compounds. Having already established proof of concept that our prototype compounds protect against cyanide toxicity in mice, we will simultaneously a) expand the prototype series, and design and synthesize analogs around these series to improve antidotal efficacy, bioavailability, and physical properties of these compounds, b) superimpose the endogenous antioxidant glutathione (as its bioavailable form; vide infra) in the above regimen to evaluate whether such antioxidant co-treatment would improve survivability and protect against the neurological deficits seen in long term survivors of acute cyanide intoxication, and c) accelerate preclinical studies (acute and long term toxicity, ADME, other animal models, etc.) for those compounds already demonstrated to be protective, with the goal of filing an IND application to the FDA well within this grant period. Although most of the compounds of our series are rapid acting, at least one prototype (perhaps more) is slower acting (by design), but fully protective when administered orally;