ORAL IRON CHELATORS PREDICATED ON DESFERRITHIOCIN

描述：研究项目围绕系统设计， 杂环化合物的合成及其安全性和有效性评价 衍生物作为口服活性铁络合剂治疗慢性阻塞性肺疾病 铁超载。分离自S。 抗生素，已经表明母体化合物是一种非常有效的铁 螯合剂，但也有肾毒性。贝杰隆博士和他的同事们 确定了化合物中负责 感兴趣的三个主要性质：(1)铁的络合作用，(2) 肾毒性；(3)胃肠道吸收。这已经是 通过在动物体内设计、合成和评估 衍生品系列。至少有一种衍生品似乎是 具有口服活性，毒性低于母体化合物。其他化合物 可能具有将不同的配体结合在一起的优势，这将起作用 作为胃肠道的载体分子。在 拟议的研究，调查人员将把他们的努力延伸到设计 和合成杂环衍生物及其类似物，以提高 了解结构和活动关系，以确定 供进一步评估的候选化合物，并为这样的 化合物的安全性、有效性、特异性、药代动力学和 代谢，以及对动物体内组织铁处置的影响。这个 开发一种安全和口服有效的铁络合剂将是一个重要的 铁超载的治疗进展。

DESCRIPTION: The research project encompasses the systematic design, synthesis and evaluation of the safety and effectiveness of heterocyclic derivatives as orally active iron-chelating agents for the treatment of iron overload. Animal studies of a siderophore isolated from S. antibioticus, have shown the parent compound to be a very efficient iron chelator but also nephrotoxic. Dr. Bergeron and his co-workers have identified specific components of the compound that are responsible for the three major properties of interest: (1) chelation of iron, (2) nephrotoxicity, and (3) gastrointestinal absorption. This has been accomplished by designing, synthesizing and evaluating in animals a series of derivatives. At least one of the derivatives seems to be orally active and less toxic than the parent compound. Other compound may have the advantage of combining different ligands, which would act as a carrier molecular across the gastrointestinal tract. In the proposed studies, the investigators will extend their efforts to design and synthesis heterocyclic derivatives and analogues to improve the understanding of structure and activity relationships, to identify candidate compounds for further evaluation, and to define, for such compounds, their safety, efficiency, specificity, pharmacokinetics and metabolism, and effect on disposition of tissue iron in animals. The development of a safe and orally effective iron chelator would be a major advance in the treatment of iron overload.