HNO-donating Prodrugs for Use as Pharmaceuticals and Biomedical Research Tools
用作药物和生物医学研究工具的 HNO 供给前药
基本信息
- 批准号:7678195
- 负责人:
- 金额:$ 3.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-09-30 至 2011-09-29
- 项目状态:已结题
- 来源:
- 关键词:AcetaldehydeAdverse effectsAlcohol DeterrentsAlcohol abuseAlcohol consumptionAlcohol dependenceAlcoholismAminesBiological AssayBiomedical ResearchBloodCanadaCardiovascular DiseasesChemical AgentsChronicClinicalCollaborationsCollectionCyanamideCyanidesDataDevelopmentDiseaseDisulfiramEthanolEuropeExhibitsFaceFlushingGoalsHalf-LifeHeartHeart failureHepaticHepatotoxicityHypotensionIn VitroIndividualIschemiaJapanKansasLiverMedical centerModificationMusNitric OxideNitric Oxide DonorsNitrogen OxidesParentsPharmaceutical PreparationsPharmacologic SubstancePharmacology and ToxicologyPrevalenceProcessProdrugsProductionPropertyPsychiatric therapeutic procedureReperfusion TherapySalmonSeriesSickle Cell AnemiaSideStructureSulfhydryl CompoundsSymptomsTachycardiaTherapeuticToxic effectUnited StatesUniversitiesVertebral columnalcohol abstinencealcohol abuse pharmacotherapyalcohol abuse therapyalcoholism therapyaldehyde dehydrogenasesbasecatalasechemical synthesisdesigndiazeniumdiolatehydroxyureaimprovedin vivoinhibitor/antagonistnitroxylresearch studytool
项目摘要
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.
描述(由申请人提供):三聚氰胺在美国以外的临床上用作酒精威慑药物。氰胺的生物活化产生代谢物氮氧基(HNO),它通过硫醇修饰作为乙醛脱氢酶(AIDH)的抑制剂。由此导致的血液乙醛水平的增加伴随着令人不快的症状,这些症状阻碍了继续饮酒。氰胺在生物活性时也会产生氰化物,这限制了美国的临床批准。然而,与现有批准的酒精威慑药物相比,HNO捐赠者的有效性和毒性较低,这表明HNO捐赠者可能有助于改善酒精滥用的药物治疗。具有一般结构[RNHN(O)NO]-的伯胺重氮二醇酸盐(NONOates)可以被设计为NO或HNO供体。此外,这些化合物易于通过带有保护基团的O2-衍生化形成前药。本申请的重点是开发供HNO的NONOates,这种NONOates可用作AIDH抑制剂,但与三聚氰胺或二硫胺相比,副作用可能较少。本申请的具体目的是1)合成和表征一系列HNO释放的NONOates和前药,2)分析HNO供体NOates抑制AIDH的药理水平和潜在的毒性。完成这些目标将确定捐赠HNO的NONOates在治疗酒精中毒和酗酒方面是否可以作为三聚氰胺的可行替代品。硝基(HNO)是一种活性的、与生理相关的化合物,有可能对心力衰竭和酒精中毒等各种疾病产生积极影响。HNO是三聚氰胺的活性代谢物,在美国以外的地方用于治疗慢性酒精依赖。由于三聚氰胺的有毒副产物,人们希望新的HNO供体化合物作为治疗酒精滥用的替代药理药物。
项目成果
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