OBJECTIVES: Desferrioxamine (DFO), deferiprone (DFP) and deferasirox (DFX) are iron chelators currently in clinical use for the treatment of iron overload. Due to difficulties with administration and associated side effects with these three molecules, the search continues for an efficient nontoxic orally active iron chelator. This communication describes the properties of one such candidate, 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1). METHODS: Physicochemical characterisation techniques, including partition coefficient, pKa values and logK values for iron(III). Iron scavenging assays, from iron citrate, nontransferrin bound iron and iron-loaded rats. Cytotoxicity studies using white cells, hepatocytes and cardiomyocytes. KEY FINDINGS: CM1 possesses high affinity and selectivity for iron(III) and a suitable partition coefficient to permeate membranes. CM1 forms a neutral 3 : 1 iron(III) complex under physiological conditions and so, it is predicted to be capable of entry into mammalian cells to scavenge excess intracellular iron and to efflux from cells as the neutral 3 : 1 complex. CM1 is demonstrated to be orally active and to possess a higher efficacy than DFP in rats. CM1 displays no toxicity to a range of cell types. CONCLUSION: The above promising studies will be extended to monitor the pharmacokinetics and metabolism of CM1. CM1 is an excellent candidate for phase 1 clinical trials.
OBJECTIVES:Desferrioxamine (DFO), deferiprone (DFP) and deferasirox (DFX) are iron chelators currently in clinical use for the treatment of iron overload. Due to difficulties with administration and associated side effects with these three molecules, the search continues for an efficient nontoxic orally active iron chelator. This communication describes the properties of one such candidate, 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1). METHODS: Physicochemical characterisation techniques, including partition coefficient, pKa values and logK values for iron(III). Iron scavenging assays, from iron citrate, nontransferrin bound iron and iron-loaded rats. Cytotoxicity studies using white cells, hepatocytes and cardiomyocytes. KEY FINDINGS:CM1 possesses high affinity and selectivity for iron(III) and a suitable partition coefficient to permeate membranes. CM1 forms a neutral 3 : 1 iron(III) complex under physiological conditions and so, it is predicted to be capable of entry into mammalian cells to scavenge excess intracellular iron and to efflux from cells as the neutral 3 : 1 complex. CM1 is demonstrated to be orally active and to possess a higher efficacy than DFP in rats. CM1 displays no toxicity to a range of cell types. CONCLUSION: The above promising studies will be extended to monitor the pharmacokinetics and metabolism of CM1. CM1 is an excellent candidate for phase 1 clinical trials.