ORAL IRON CHELATORS PREDICATED ON DESFERRITHIOCIN

基于去铁硫辛的口服铁螯合剂

• 批准号: 2654532
• 负责人: Raymond Joseph Bergeron
• 金额: $ 57.59万
• 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 2000-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2654532
• 关键词: Cebidae; Primates; Rodentias; analog; cerebrohepatorenal syndrome; chelating agents; disease /disorder model; drug design /synthesis /production; drug metabolism; drug screening /evaluation; gastrointestinal drug absorption; hydroxamate; iron; oral administration; renal toxin; siderophores

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.

项目描述：本研究项目包括系统设计， 杂环化合物的合成及安全性评价 作为口服活性铁螯合剂的衍生物 铁超载 从S. 阿提库斯，已经证明母体化合物是一种非常有效的铁 螯合剂，但也有肾毒性。 伯杰隆医生和他的同事 确定了化合物的特定成分， 感兴趣的三个主要性质：（1）铁的螯合，（2） 肾毒性;（3）胃肠道吸收。 这是 通过在动物身上设计、合成和评估来完成， 一系列衍生品。 至少有一个衍生品似乎是 口服活性和毒性低于母体化合物。 其它化合物 可能具有结合不同配体的优点， 作为载体分子穿过胃肠道。 在 研究人员将努力设计 和合成杂环衍生物和类似物，以改善 了解结构和活性关系，以确定 用于进一步评价的候选化合物，并定义， 化合物，其安全性、有效性、特异性、药代动力学和 代谢以及对动物组织铁处置的影响。 的 开发一种安全有效的口服铁螯合剂将是一个主要的 铁超载治疗的进展。