This project seeks to develop oral iron chelating agents for the treatment of transfusional iron overload based on the promising results of the previous work on the 3-hydroxypyridin-4-ones. Initially the current lead compounds, which are more effective and less toxic than either 1,2-dimethyl-3-hydroxypyridin-4-one or desferrioxamine will be taken through subacute toxicity studies to Phase 1 clinical trials. It is likely that the structure of the current lead compounds can be modified in such a manner as to further improve their power to scavenge iron, while maintaining both a low toxicity and high oral activity. Towards this end, a program of directed synthesis of novel bidentate and hexadentate pyridinones will be guided by computer modelling and biochemical investigations. The most suitable compounds, as judged by physiochemical properties, will be screened using a hepatocyte culture system which gives information on both, iron mobilisation from cells, and cellular toxicity. An iron overloaded mouse model will be used to measure oral effectiveness and acute toxicity. The compounds with the most favourable toxicity/activity ratios will be selected for formal subacute toxicity studies prior to Phase 1 clinical trials. There is an urgent need to develop an oral iron chelator as desferrioxamine, the only established drug, is given by prolonged subcutaneous infusion. The hydroxypyridinones developed here, are the most promising approach to the treatment of iron overload associated with thalassaemia.
