Iron Chelators Predicated on Desferrithiocin

描述(由申请人提供)：建议的研究项目将集中于设计、合成、评估和开发用于治疗铁超载的靶向去铁硫蛋白类似物。临床医生迫切需要新的、更有效的铁络合剂，选择性地从肝脏、心脏和胰腺去除铁，这些器官在患有重型地中海贫血、镰状细胞病、遗传性血色病和其他形式的铁超载的患者中是铁诱导损伤的最高风险器官。去铁硫蛋白(DFT)是从抗生素链霉菌中分离出来的一种天然铁络合剂(铁载体)，是目前已知的最有效的口服铁络合剂之一，但由于肾脏毒性，其临床应用受到限制。我们的系统结构-活性研究使类似物和衍生物的设计和合成成为可能，这些类似物和衍生物保留了DFT的特殊铁络合活性，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-dihydroxyphenyl)-4，5-dihydro-4-methyl-4-thiazolecarboxylic酸[(S)-4‘-(HO)-DADFT(28)]，在隐孢子虫灵长类模型中的效果几乎是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，以靶向铁致损伤风险最高的器官，并进一步增强铁的清除。为了验证这些假设，我们的研究计划有三个具体目标： 目的1：设计和合成分区变异型去铁硫蛋白类似物，增强对铁损伤的易感器官(如肝脏、心脏、胰腺)和/或提高铁的清除效率； 目的2：设计和合成多胺载体去铁硫蛋白类似物，利用多胺转运器进入细胞； 目的：评估这些新的去铁硫蛋白类似物在理化、细胞和动物模型中的作用，以确定安全有效的化合物，用于GLP的临床前评估，为人类研究做准备。 基于DFT的安全、有效和耐受性良好的铁络合剂的开发将是铁超载治疗方面的重大进步，将极大地提高美国和世界各地受影响患者的质量和生命长度。

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.