NEW PIH PRODRUG FOR CHELATION THERAPY OF IRON OVERLOAD

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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.