Therapeutic Multidentate Iron Sequestering Agents

描述(由申请人提供)：由β-地中海贫血、血色素沉着或镰状细胞贫血引起的人类铁负荷过重是一个严重的临床问题。铁螯合疗法是有效的，但开发易于获得、口服有效、有效和无毒的隔离剂的目标被证明是非常困难的。去铁胺(Desferal(R))是一种三羟甲酸酯配体，在美国仍然是临床使用的铁络合剂。Desferal(R)价格昂贵，体内半衰期短，不能有效地去除转铁蛋白中的铁，必须定期、频繁地通过皮下或静脉途径给药，使用它可能会导致显著的、不可逆转的毒性。虽然还有其他试剂正在研究和开发，作为Desferal(R)的潜在继任者，但还没有一种既定的螯合剂达到这一目标。该项目的目标是开发新的隔离剂，以满足这一需求。在之前的支持期间，与奥克兰研究所儿童医院(CHORI)和劳伦斯伯克利国家实验室(LBNL)的Patricia Durbin-Heavey博士合作，开发了新的配基系统和新的筛选方案。LBNL的放射性示踪小鼠模型已被发现是准确和可靠的，并已被选为该项目的常规筛查方案。基于一种持续的假设，即多齿而不是双齿或三齿的羟基吡啶配体将作为口服螯合剂在低于毒性水平时有效，因此已经开发了几个有前景的新的多齿配体。已经开发了一个动力学动物模型来描述这些药物的代谢，该模型准确地符合观察到的行为。现在建议扩大这些动物研究，并开发能够接受大规模试验的螯合剂，最终目标是生产一种安全的、口服活性的铁络合剂，以防止需要慢性红细胞输注的患者体内铁积累的毒性。提出了几种新的配体类型，并提出了关于结构功能关系的具体假设。

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.