HNO-donating Prodrugs for Use as Pharmaceuticals and Biomedical Research Tools

描述（由申请人提供）：氰胺在美国以外的临床上用作酒精威慑药物。氨腈的生物活化产生代谢物硝酰基（HNO），其通过巯基修饰作为醛脱氢酶（AIDH）的抑制剂。血液乙醛水平的增加伴随着不愉快的症状，阻止继续使用酒精。氨腈在生物活性时也会产生氰化物，这限制了它在美国的临床批准。然而，与现有批准的酒精威慑剂相比，HNO供体的功效和较低的毒性表明HNO供体可能有助于改善酒精滥用的药物治疗。具有通式结构[RNHN（O）NO]-的伯胺二醇二氮烯鎓盐（NONOates）可以设计为NO或HNO供体。此外，这些化合物易于通过O2-衍生化与保护基团形成前药。本申请的重点是开发HNO供体NONOates，其可用作AIDH抑制剂，但与氰胺或双硫仑相比，副作用可能更少。本申请的具体目的是1）合成和表征一系列释放HNO的NONOates和前药，以及2）分析HNO供体NONOates抑制AIDH的药理学能力和潜在毒性。这些目标的完成将确定HNO捐赠NONOates是否可以作为治疗酒精中毒和酒精滥用的氰胺的可行替代品。硝酰基（HNO）是一种反应性的生理相关化合物，有可能对心力衰竭和酒精中毒等多种疾病产生积极影响。HNO是氰胺的活性代谢物，在美国以外用于治疗慢性酒精依赖。由于氰胺的有毒副产物，需要新的HNO供体化合物作为治疗酒精滥用的替代药理学试剂。

DESCRIPTION (provided by applicant): Cyanamide is used clinically outside the United States as an alcohol deterrent drug. Bioactivation of cyanamide produces the metabolite nitroxyl (HNO), which acts as an inhibitor of aldehyde dehydrogenase (AIDH) via thiol modification. The resulting increase in blood acetaldehyde levels are accompanied by unpleasant symptoms that discourage continued use of alcohol. That cyanamide also produces cyanide upon bioactiviaton has restricted clinical approval in the United States. However, the efficacy and lower toxicity compared to existing approved alcohol deterrent agents suggests that HNO donors may serve to improve pharmacotherapy of alcohol abuse. Primary amine diazeniumdiolates (NONOates) having the general structure [RNHN(O)NO]- can be designed to be either NO or HNO donors. Furthermore, these compounds are amenable to prodrug-formation via O2- derivatization with protecting groups. This application focuses on development of HNO-donating NONOates that can be used as AIDH inhibitors but with the potential for fewer side effects compared to cyanamide or disulfiram. The specific aims of this application are 1) to synthesize and characterize a series of HNO releasing NONOates and prodrugs and 2) to analyze the pharmacological proficiency for AIDH inhibition and potential toxicity of HNO-donating NONOates. Completion of these aims will establish whether HNO donating NONOates can function as viable alternatives to cyanamide in the treatment of alcoholism and alcohol abuse. Nitroxyl (HNO) is a reactive, physiologically-relevant compound that has potential to positively impact diseases as diverse as heart failure and alcoholism. HNO is the active metabolite of cyanamide, which is used outside the United States for the treatment of chronic alcohol dependence. Due to the toxic byproducts of cyanamide, new HNO-donating compounds are desired to serve as alternative pharmacological agents for the treatment of alcohol abuse.