Synthesis of 2-amido-3-hydroxypyridin-4(1H)-ones: Novel iron chelators with enhanced pFe(3+) values

The synthesis of a range of 2-amido-3-hydroxypyridin-4-ones as bidentate ir on(III) chelators with potential for oral administration is described. The pKa values of the ligands together with the stability constants of their ir on(III) complexes have been determined. Results indicate that the introduct ion of an amido substituent at the 2-position leads to an appreciable enhan cement of the pFe(3+) values. The ability of these novel 3-hydroxypyridin-4 -ones to facilitate the iron excretion in bile was investigated using a Fe- 59-ferritin loaded rat model. The optimal effect was observed with the N-me thyl amido derivative 15b, which has an associated pFe(3+) value of 21.7, m ore than two orders of magnitude higher than that of deferiprone (1,2-dimet hyl-3-hydroxypyridin-4-one) 1a (pFe(3+) = 19.4). Dose response studies sugg est that chelators with high pFe(3+) values scavenge iron more effectively at lower doses when compared with simple dialkyl substituted hydroxypyridin ones. (C) 2001 Elsevier Science Ltd. All rights reserved.