Therapeutic Multidentate Iron Sequestering Agents

描述（由申请人提供）：β地中海贫血、血色素沉着症或镰状细胞贫血导致的人体铁过载是一个严重的临床问题。铁螯合疗法是有效的，但开发容易获得的、口服活性的、有效的和无毒的螯合剂的目标已被证明是非常难以实现的。去铁胺（Desferal（r））是一种三异羟肟酸配体，在美国仍然是临床使用的铁螯合剂。Desferal（r）价格昂贵，在体内半衰期短，不能有效地从转铁蛋白中去除铁，必须定期、频繁地通过皮下或静脉途径给予，并且其使用可能导致显著的、不可逆的毒性。虽然有其他药物正在研究和开发作为Desferal（r）的潜在继任者，但还没有确定的螯合剂达到这一目标。该项目的目标是开发新的螯合剂，以满足这一需求。在前一段支持期间，与奥克兰儿童医院研究所（CHORI）和劳伦斯伯克利国家实验室（LBNL）的Patricia Durbin-Heavey博士合作，开发了新的配体系统和新的筛查方案。LBNL的放射性示踪剂小鼠模型被认为是准确和可靠的，并已被选为本项目的常规筛选方案。几个有前途的新的多齿配体已经开发的基础上继续假设，多齿，而不是二齿或三齿，羟基吡啶酮配体将是有效的口服螯合剂有效的浓度低于毒性水平。已经开发了一种动力学动物模型，用于这些药物的代谢，该模型准确地符合所观察到的行为。现在建议扩展这些动物研究，并将螯合剂开发到可以接受大规模测试的程度，最终目标是生产一种安全的口服活性铁螯合剂，以防止需要长期红细胞输注的患者铁蓄积的毒性。提出了几种新的配体类型，并对结构与功能的关系提出了具体的假设。

DESCRIPTION (provided by applicant): Human iron overload as a consequence of beta-thalassemia, hemochromatosis, or sickle cell anemia is a serious clinical problem. Iron chelation therapy is effective, but the goal of developing readily available, orally-active, effective and non-toxic sequestering agents have proven to be remarkably difficult to achieve. Desferrioxamine (Desferal(r)), a trihydroxamate ligand, remains the iron chelator of clinical use in the United States. Desferal(r) is expensive, has a short half-life in vivo, does not efficiently remove iron from transferrin, must be given on a regular, frequent basis by a subcutaneous or intravenous route, and its use can result in significant, irreversible toxicity. While there are other agents being investigated and developed as potential successors to Desferal(r), there is no established chelator that has yet met this target. The goal of this project is to develop new sequestering agents that would meet that need. In the previous period of support, in collaboration with the Children's Hospital of Oakland Research Institute (CHORI) and Dr. Patricia Durbin- Heavey at the Lawrence Berkeley National Laboratory (LBNL), both new ligand systems and new screening protocols have been developed. The radioactive tracer mouse model at LBNL has been found to be accurate and reliable and has been selected as this project's routine screening protocol. Several promising new multidentate ligands have been developed based on the continuing hypothesis that multidentate, rather than bidentate or tridentate, hydroxypyridonate ligands will be effective as oral chelating agents effective at concentrations below toxic levels. A kinetic animal model has been developed for the metabolism of these agents that accurately fits the observed behavior. It is now proposed to extend these animal studies and to develop the chelators to the point where they can be accepted for large-scale testing, with the ultimate goal being the production of a safe, orally-active iron chelating agent that will prevent the toxicity of iron accumulation in patients who require chronic red cell transfusions. Several new ligand types are proposed with specific hypotheses about structural function relationships.