Iron Chelators Predicated on Desferrithiocin

以去铁硫辛为基础的铁螯合剂

• 批准号: 8081769
• 负责人: Raymond Joseph Bergeron
• 金额: $ 62.46万
• 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 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8081769
• 关键词: Abbreviations; Acids; Adverse effects; Affect; Alkylation; Amines; Animal Model; Biological; Biological Factors; Canis familiaris; Capuchin Monkey; Cell model; Cells; Chelating Activity; Chelating Agents; Chemistry; Clinical; Clinical Trials; Cooley' s anemia; Development; Eukaryota; Evaluation; Excretory function; Family; Florida; Heart; Hereditary hemochromatosis; Human; In Vitro; Injury; Iron; Iron Chelating Agents; Iron Overload; Kidney; Lead; Licensing; Liver; Longevity; Mammalian Cell; Mediating; Methods; Modeling; Molecular Weight; Organ; Pancreas; Parents; Patients; Phase; Physicians; Polyamines; Preparation; Primates; Prokaryotic Cells; Research; 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; desferrithiocin; design; experience; improved; in vivo; lipophilicity; metal chelator; norspermidine; novel; pharmacophore; preclinical evaluation; 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、评估和开发靶向去铁硫辛酸类似物，用于治疗铁超载。医生迫切需要新的、更有效的铁螯合剂，以选择性地去除肝脏、心脏和胰腺中的铁，这些器官在地中海贫血、镰状细胞病、遗传性血色素沉着症和其他形式的铁超载患者中具有最大的铁诱导损伤风险。去铁硫肽（DFT）是一种从链霉菌中分离出来的天然铁螯合剂（铁载体），是目前发现的最有效的口服铁螯合剂之一，但其肾毒性阻碍了其临床应用。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，这些类似物和衍生物保留了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。我们的先导化合物是口服活性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)]，其在无毛猿猴灵长类动物模型中的有效性几乎是sc DFO的三倍，已被授权给一家商业赞助商，目前正在进行I/II期临床试验。我们现在假设DFT平台可以在结构上进行编程，以靶向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：