Structure-activity investigation of the inhibition of 3-hydroxypyridin-4-ones on mammalian tyrosine hydroxylase

3-Hydroxypyridin-4-ones are currently one of the main candidates for the development of orally active iron chelators. Small bidentate ligands lend to inhibit iron-containing metalloenzymes and therefore can cause undesirable side effects. A range of 3-hydroxypyridin-4-ones with different R-2 substitutents was selected for the investigation of the structure-activity relationship between the chemical nature of the ligand and the inhibition of mammalian tyrosine: hydroxylase. Results indicated that lipophilicity was the dominant factor in controlling the ability of this class of chelator to inhibit mammalian tyrosine hydroxylase. Ligands with hydrophilic R-2 substitutents tended to be weak inhibitors. No significant correlation was found in this study between iron-binding affinity, extended R-2 chain length, and enzyme inhibitory activity. In contrast, both the LogP values of the entire molecule and of the R-2 segment correlated well with inhibitory activity. (C) 2001 Elsevier Science Inc. All rights reserved.