NEW PIH PRODRUG FOR CHELATION THERAPY OF IRON OVERLOAD

用于铁过载螯合疗法的新型 PIH 前药

• 批准号: 3502036
• 负责人: NEIL J LEWIS
• 金额: $ 5万
• 依托单位: JACOBUS PHARMACEUTICAL COMPANY, INC.
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-15 至 1992-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3502036
• 关键词: chelating agents; chelation therapy; dietary iron; drug administration rate /duration; drug adverse effect; drug design /synthesis /production; hydrazones; iron storage disorder; isoniazid; laboratory rat; nutrition related tag; pathogenic diet; prodrugs

The proposed research is designed to develop an improved synthetic method for the production of a new, more bioefficient derivative of pyridoxal isonicotinoyl hydrazone (PIH), an orally active iron chelator for the treatment of iron overload. In Phase I human trials, PIH (given orally in capsules containing the solid free base) produced an amount of iron excretion that would be clinically useful in the treatment of non- transfusion-dependent patients with iron-loading anemias. The bioefficiency of the free base formulation was much less than that expected from animal studies with PIH given in solution. Hypothesizing that the limited bioefficiency observed in the human studies was the result of the poor solubility of the free base form of PIH we have developed a pilot-scale synthesis for the production of a new derivative of PIH that is more than 200 fold more water soluble. This new PIH prodrug should substantially enhance bioefficiency and make the chelator clinically useful in the treatment of transfusion-dependent patients. The proposed Phase I SBIR project will develop a larger-scale method of synthesis of the new PIH prodrug that will permit the production of clinical supplies for further human trials during a Phase II project.

该研究旨在开发一种改进的合成 生产新的、更生物有效的 吡哆醛异烟酰腙（PIH），口服活性铁螯合剂 用于治疗铁超载。 在I期人体试验中，PIH（给予 在含有固体游离碱的胶囊中口服）产生一定量的 铁排泄，这将是临床上有用的治疗非- 铁负荷性贫血的输血依赖患者。 的 游离碱制剂的生物效率远低于 从PIH溶液给药的动物研究中预期。 的假设 在人类研究中观察到的有限生物效率是 由于PIH游离碱形式的溶解性差，我们得到了 开发了一种新衍生物的中试合成方法 比水溶性高出200倍以上。 这个新的PIH 前药应该大大提高生物效率， 临床上可用于治疗输血依赖性患者。 拟议的第一阶段SBIR项目将开发一种更大规模的方法， 合成新的PIH前药，这将允许生产 在第二阶段项目中用于进一步人体试验的临床用品。