Extensive structure activity relationship (SAR) studies focused on the
desferrithiocin [DFT, (S)-4,5-dihydro-2-(3-hydroxy-2-pyridinyl)-4-methyl-4-thiazolecarboxylic
acid] pharmacophore have led to three different DFT analogs being evaluated clinically for the treatment of
iron overload diseases, for example,
thalassemia. The SAR work revealed that the lipophilicity of a
ligand, as determined by its partition between octanol and water, logP(app), could have a profound effect on the
drug's
iron clearing efficiency (
ICE), organ distribution, and toxicity profile. While within a given structural family the more lipophilic a
chelator the better the
ICE, unfortunately, the more lipophilic
ligands are often more toxic. Thus, a balance between lipophilicity,
ICE, and toxicity must be achieved. In the current study, we introduce the concept of 'metabolically programmed'
iron chelators, that is, highly lipophilic, orally absorbable, effective deferration agents which, once absorbed, are quickly converted to their nontoxic, hydrophilic counterparts.