STRUCTURE ACTIVITY RELATIONSHIPS AFFECTING THE ABILITY OF MONOANIONIC3-HYDROXYPYRID-4-ONES TO MOBILIZE IRON/

Current attempts to remove iron from individuals suffering from iron o verload have encountered difficulty due to the toxicity of the adminis tered chelating agent. In a search for iron chelators of potentially r educed toxicity, nine monoanionic compounds have been examined. To det ermine the chemical features which govern their ability to induce the excretion of iron, the compounds were administered to female Sprague-D awley rats. All carboxylate derivatives were tested for biliary excret ion following iv injection, as well as for urinary excretion following iv or po injection. Sulfonate derivatives were tested for biliary and urinary excretion as well, but only one representative compound was t ested po. The biological activity of the new pyridinones was compared to that of 1,2-dimethyl-3-hydroxypyrid-4-one, L1, which served as the standard. While none of the chelators was able to surpass L1 in both u rinary and biliary iron excretion, all of the chelators at least equal ed L1 in one of these two areas following iv administration. Two deriv atives surpassed the standard in mobilizing iron into the bile, and al l others were statistically equivalent. In terms of urinary excretion, two compounds were equivalent to L1 after iv administration, although none of the compounds equaled L1 when administered orally. The struct ure of hydroxy-2-methyl-4-oxo-1-pyridyl)methanecarboxylic acid was det ermined by X-ray diffraction, as this compound showed higher activity than previously reported by other investigators. We speculate that the se chelators utilize organ-specific, monoanionic transport systems in the liver and kidneys to mobilize iron and that their toxicity may be substantially less than that of their neutral analogs.