Synthesis, Physicochemical Properties, and Evaluation ofN-Substituted-2-alkyl-3-hydroxy-4(1H)-pyridinones

Abstract

The synthesis of a range of 3-hydroxy-4(1H)-pyridinones with potential for the chelation of iron(III) is described. The pK_a values of respective ligands and the stability constants of their iron(III) complexes are presented. The distribution coefficient values of a range of 48 hydroxypyridinones and their corresponding iron(III) complexes between 1-octanol and MOPS buffer (pH 7.4) are reported. The range of log D_complex values covers 7 orders of magnitude. The results suggest the existence of a biphasic relationship between the distribution coefficient values of the chelator and the corresponding iron(III) complexes. For ligands with a log D_ligand = −1, a linear relationship exists with a value of the slope 2.53, whereas with ligands with a log D_ligand < −1, a linear relationship exists with a slope of 0.49. The reduced slope for the more hydrophilic molecules of the series offers some advantage for this type of hydroxypyridinone as the distribution coefficients for such complexes do not change so rapidly with increasing ligand hydrophilicity. The ability of selected 3-hydroxypyridinones to facilitate the excretion of iron in bile was investigated in non-iron-overloaded, bile duct-cannulated rats and in a [⁵⁹Fe]ferritin-loaded rat model. Both systems compare the ability of chelators to remove iron from the liver, the prime target organ in thalassemia. The N-(hydroxyalkyl)-3-hydroxypyridin-4-ones are demonstrated to be orally active under the in vivo conditions adopted. Thus both 1-(hydroxyalkyl)- and 1-(carboxyalkyl)pyridinones are able to remove iron from the liver. Although 1-(carboxyalkyl)hydroxypyridinones are active, they do not demonstrate any clear advantage over Deferiprone (1,2-dimethyl-3-hydroxypyridin-4-one). Indeed 1-(hydroxyalkyl)hydroxypyridinones which are known to be rapidly converted to 1-(carboxyalkyl)hydroxypyridinones are also marginally superior to Deferiprone. In contrast, 2-ethyl-1-(2‘-hydroxyethyl)-3-hydroxypyridin-4-one, which is not metabolized to the corresponding (carboxyalkyl)hydroxypyridinone, was found to be superior to Deferiprone and therefore deserves further consideration as an orally active iron chelator with potential for the treatment of iron overload associated with transfusion-dependent thalassemia.