Iron Chelators Predicated on Desferrithiocin

以去铁硫辛为基础的铁螯合剂

• 批准号: 7340196
• 负责人: Raymond Joseph Bergeron
• 金额: $ 56.23万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7340196
• 关键词: Abbreviations; Acids; Adverse effects; Affect; Alkylation; Amines; Animal Model; Biological; Biological Factors; Canis familiaris; Capuchin Monkey; Cells; Chelating Activity; Chelating Agents; Chemistry; Classification; Clinical; Clinical Trials; Cooley' s anemia; Development; Doctor of Philosophy; Evaluation; Excretory function; Family; Florida; Heart; Hereditary hemochromatosis; In Vitro; Inherited; Injury; Iron; Iron Chelating Agents; Iron Overload; Kidney; Lead; Licensing; Liver; Longevity; Mammalian Cell; Mediating; Metals; Methods; Modeling; Molecular Weight; Organ; Pancreas; Parents; Patients; Phase; Physicians; Polyamines; Preparation; Primates; Prokaryotic Cells; Research; Research Personnel; Research Project Grants; Risk; Rodent; Sickle Cell Anemia; Siderophores; Spermidine; Streptomyces antibioticus; Structure; System; Testing; Time; Toxic effect; United States; Universities; Variant; Vertebral column; analog; base; beta Thalassemia; desferrithiocin; design; experience; human study; improved; in vivo; lipophilicity; norspermidine; novel; pharmacophore; pre-clinical; programs; targeted delivery; uptake; vector

DESCRIPTION (provided by applicant): The proposed research project will focus on the design, synthesis, evaluation, and development of targeted desferrithiocin analogues for the treatment of iron overload. Physicians have a pressing clinical need for new, more effective iron-chelating agents which selectively remove iron from the liver, heart, and pancreas, the organs at greatest risk of iron-induced injury in patients with thalassemia major, sickle cell disease, hereditary hemochromatosis and other forms of iron overload. Desferrithiocin (DFT), a natural product iron chelator (siderophore) isolated from Streptomyces antibioticus, is one of the most orally effective iron chelating agents yet identified but renal toxicity precludes its clinical use. Our systematic structure-activity studies have allowed the design and synthesis of analogues and derivatives, which retain the exceptional iron-chelating activity of DFT without adverse effects on the kidneys or other organs. Our lead compound, the orally active DFT analogue (S)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid [(S)-4'-(HO)-DADFT (28)], which is nearly three times as effective as sc DFO in the C. apella primate model, has been licensed to a commercial sponsor and currently is in Phase I/II clinical trials. We now hypothesize that the DFT platform can be structurally programmed to target delivery to organs at greatest risk of iron induced injury and to further enhance iron clearance. To test these hypotheses, our research plan has three specific aims: Aim 1: to design and synthesize partition-variant desferrithiocin analogues with enhanced access to organs vulnerable to iron-induced injury (eg, liver, heart, pancreas) and/or increased iron clearing efficiency; Aim 2: to design and synthesize polyamine-vectored desferrithiocin analogues that use the polyamine transport apparatus to gain entry into cells; and Aim 3: to assess these new desferrithiocin analogues in physiochemical, cellular and animal models to identify safe and effective compounds for GLP preclinical evaluation in preparation for human studies. The development of safe, effective, and well-tolerated iron-chelating agents based on DFT would be a major advance in the treatment of iron overload that would greatly enhance both the quality and length of life of affected patients in the United States and worldwide.

描述（由申请人提供）：拟议的研究项目将侧重于设计、合成、评价和开发用于治疗铁过载的靶向去铁硫菌素类似物。临床医生迫切需要新的、更有效的铁螯合剂，其选择性地从肝脏、心脏和胰腺中去除铁，这些器官在患有重型地中海贫血、镰状细胞病、遗传性血色素沉着症和其他形式的铁过载的患者中是铁诱导损伤的最大风险。去铁硫菌素（DFT）是从链霉菌（Streptomycessparticus）中分离的天然产物铁螯合剂（铁载体），是迄今为止发现的口服最有效的铁螯合剂之一，但其肾毒性妨碍了其临床应用。我们系统的结构-活性研究允许设计和合成类似物和衍生物，其保留DFT的特殊铁螯合活性，而不会对肾脏或其他器官产生不良影响。我们的先导化合物，口服活性DFT类似物（S）-2-（2，4-二羟基苯基）-4，5-二氢-4-甲基-4-噻唑羧酸[（S）-4 '-（HO）-DADFT（28）]，在C. apella灵长类动物模型，已被许可给商业赞助商，目前正在进行I/II期临床试验。我们现在假设DFT平台可以在结构上编程为靶向递送至铁诱导损伤风险最大的器官并进一步增强铁清除。为了验证这些假设，我们的研究计划有三个具体目标： 目标1：设计和合成分配变体去铁硫菌素类似物，其具有增强的对易受铁诱导的损伤的器官（例如，肝、心脏、胰腺）的接近和/或增加的铁清除效率; 目的二：设计并合成多胺载体的去铁硫菌素类似物，其利用多胺转运装置进入细胞; 目标3：在物理化学、细胞和动物模型中评估这些新型去铁硫菌素类似物，以识别安全有效的化合物，用于GLP临床前评价，为人体研究做准备。 基于DFT的安全、有效和耐受性良好的铁螯合剂的开发将是治疗铁过载的重大进展，这将大大提高美国和全球受影响患者的生活质量和寿命。