Synthesis, physicochemical properties and biological evaluation of aromatic ester prodrugs of 1-(2'-hydroxyethyl)-2-ethyl-3-hydroxypyridin-4-one (CP102): orally active iron chelators with clinical potential.

Abstract

The synthesis of seven aromatic ester derivatives of 1-(2'-hydroxyethyl)-2-ethyl-3-hydroxypyridin-4-one is described. These ester prodrugs have been designed to target iron chelators to the liver, the major iron storage organ. In principle this should improve chelation efficacy and minimize toxicity. The distribution coefficients of these ester prodrugs between 1-octanol and MOPS buffer pH 7.4 were measured together with their rates of hydrolysis at pH 2 and pH 7.4, in rat blood and liver homogenate. Esters with heteroaromatic acid moieties were found to be less stable than benzoyl analogues. The in-vivo iron mobilisation efficacy of these ester prodrugs has been compared with that of the parent drug using a 59Fe-ferritin loaded rat model. Many prodrugs were found to enhance the ability of the parent hydroxypyridinone to facilitate 59Fe excretion. However, not all prodrugs provided increased efficacy, demonstrating that lipophilicity is not the only factor which influences drug efficacy. Furthermore, no clear correlation between efficacy and susceptibility to hydrolysis was detected. The picolinic and nicotinic ester derivatives appear to offer the best potential as prodrugs as they have a relatively low LogP value and yet lead to enhanced efficacy over the parent hydroxypyridinone.