N-Arylamine derivatives of 3-hydroxy-4-pyridinones: solution studies and bioevaluation in view of Al-detoxification roles.

A study of a series of bifunctional 3-hydroxy-4-pyridinone derivatives, containing side-chains with various alkyl-aryl-amine-amides as extra-functional groups, was conducted to assess the relevance of those groups to the Al-chelating affinity, the lipo-hydrophilic balance of the compounds, and 67Ga biodistribution in mice, in view of their potential use as Al-decorporating agents; the results were compared with those for the drug Deferriprone. Their acid-base properties and Al-chelating affinity in aqueous solution were studied by potentiometric techniques. These ligands form very stable tris-chelated Al complexes and the non-chelating extra-groups are only responsible for small differences in the complex stability (DeltapAl< or =1.2). At physiological pH the major ligand/complex species have different charges, because of the different extent of protonation of the ligands. The introduction of the different groups induces a well-balanced stepwise-like lipo-hydrophilic character (-0.2 < log D(oct./water) < +1.1). The effect of each ligand on the biodistribution of 67Ga in overloaded mice is rapid blood clearance for all of them, but with different biodistribution patterns, namely excretion pathways and brain uptake/clearance, thus suggesting potential different clinical use.