Synthesis, physicochemical properties and biological evaluation of ester prodrugs of 3-hydroxypyridin-4-ones: design of orally active chelators with clinical potential

The synthesis of a range of hydrophobic ester prodrugs of 3-hydroxypyridin- 4-ones with potential for oral administration is described. The distributio n coefficient values of a range of these ester prodrugs and the correspondi ng alcohols in 1-octanol and MOPS buffer FH 7.4 are presented together with their rates of hydrolysis at pH 2, pH 7.4, in rat blood and liver homogena te. In vivo iron mobilisation efficacy of the pivaloyl and benzoyl prodrugs has been compared with their parent drugs using a Fe-59-ferritin loaded ra t model. Both classes of prodrug enhanced the ability of the parent hydroxy pyridinone to facilitate the excretion of Fe-59. The influence of the pival oyl function was more marked than that of the benzoyl function. The optimal effect was observed with 1-[2'-(pivaloyloxy)ethyl]-2-methyl-3-hydroxy-4(1H )-pyridinone 25. However, not all the prodrugs provide increased efficacy w hich suggests that lipophilicity is not the only factor which influences th e drug efficacy. The metabolism of the compound may have a dominating influ ence on the overall efficacy. (C) Elsevier, Paris.