THERAPEUTIC MULTIDENTATE IRON SEQUESTERING AGENTS

说明(改编自应用程序) 预防输血引起的铁中毒的当前策略 含铁血黄素沉着症有许多局限性。去铁胺(Desferal)a 三羟甲酸，是最常用的铁络合剂。迪斯法尔，是 价格昂贵，在体内半衰期短，不能有效地去除体内的铁 转铁蛋白，必须定期、频繁地由皮下或 静脉注射及其使用可能导致显著的、不可逆转的毒性。 双齿二甲基-3-羟基吡啶-4-酮，称为L1、DMHP、CP20或 去铁酮，可以催化从转铁蛋白中除铁，并已被证明 口服时有效。然而，这种药剂的毒性结果是 部分原因是它的热力学不稳定和高浓度所需 取得治疗效果。 本申请描述了一项开发和评估一系列新铁的计划 口服时有效且不含 毒性。我们的假设是多齿的，而不是双齿的， 羟基吡哆酸酯配体将作为口服铁络合剂和 不会有毒性。我们的具体目标将是合成各种 多齿羟基吡啶酸酯配体，其结构设计为 它们可以在低浓度下将铁从转铁蛋白中脱除，具有较长的 体内半衰期，在以下情况下在治疗上有效地清除多余的铁 口服，无毒。使用了一些合成化学品 STEPS，一系列具有独特化学结构的新型铁络合物 有可能符合上述标准的建筑物，将会 合成的。脱铁的热力学稳定性和动力学 将测定每种化合物的人转铁蛋白。两铁超载 动物模型将被用来评估铁的毒性、生物途径 排泄物，以及从组织存储中去除铁的能力。 我们的最终目标是开发一种安全的、口服的、临床有效的 一种可防止铁蓄积毒性的铁络合剂 需要长期输注红细胞的患者。

DESCRIPTION (adapted from the application) Current strategies to prevent iron toxicity associated with transfusion induced hemosiderosis have a number of limitations. Desferrioxamine (Desferal) a tri-hydroxamate, is the most commonly used iron chelator. Desferal, 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. The bidentate dimethyl-3-hydroxypyridine-4-one, known as L1, DMHP, CP20 or Deferiprone, can catalyze iron removal from transferrin and has been shown to be effective when given orally. However, toxicity results with this agent, due in part to its thermodynamic instability and high concentration required to obtain a therapeutic effect. This application describes a plan to develop and evaluate a series of new iron chelating agents that are effective when administered orally and have no toxicity. Our hypothesis is that multidentate, rather than bidentate, hydroxypyridonate ligands will be effective as oral iron chelating agents and will not be toxic. Our specific aims will be to synthesize a variety of multidentate hydroxypyridonate ligands that are structurally designed so that they can decorporate iron from transferrin at low concentrations, have a long half-life in vivo, are therapeutically effective at removing excess iron when administered orally and are not toxic. Using a number of synthetic chemical steps, a series of novel iron chelating compounds with unique chemical structures, which have the potential to meet the above criteria, will be synthesized. The thermodynamics stability and kinetics of removal of iron from human transferrin will be determined for each compound. Two iron overloaded animal models will be used to evaluate toxicity, biological routes of iron excretion, and ability to remove iron from tissue stores. Our ultimate goal is to develop a safe, oral, clinically effective iron-chelating agent that will prevent the toxicity of iron accumulation in patients who require chronic red cell transfusions.