THERAPEUTIC MULTIDENTATE IRON SEQUESTERING AGENTS

描述（改编自应用程序） 预防输血引起的铁毒性的当前策略 含铁血黄素沉着症有许多局限性。去铁胺（Desferal）a 三异羟肟酸盐是最常用的铁螯合剂。德费拉尔群岛 昂贵，在体内半衰期短，不能有效地从体内去除铁， 转铁蛋白，必须给予定期，频繁的基础上，通过皮下注射或 静脉途径及其使用可导致显著的不可逆毒性。 双齿二甲基-3-羟基吡啶-4-酮，称为L1、DMHP、CP 20或 去铁酮可以催化从转铁蛋白中去除铁，并已被证明 口服时有效。然而，由于这种药剂的毒性， 这部分是由于其热力学不稳定性和 获得治疗效果。 本申请描述了一个计划，以开发和评估一系列新的铁 螯合剂在口服给药时是有效的， 毒性我们的假设是多齿的，而不是二齿的， 羟基吡啶酮配体作为口服铁螯合剂是有效的， 不会有毒。我们的具体目标将是综合各种 多齿羟基吡啶酮配体的结构设计， 它们可以在低浓度下从转铁蛋白中去除铁， 体内半衰期，在治疗上有效地去除过量的铁， 口服给药，无毒。使用大量的合成化学物质 步骤，一系列具有独特化学性质的新型铁螯合化合物， 有可能满足上述标准的结构，将 合成了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 动物模型将用于评估铁的毒性、生物途径 排泄和从组织储存中去除铁的能力。 我们的最终目标是开发一种安全、口服、临床有效的 铁螯合剂，这将防止铁积累的毒性， 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.