Evaluation of the desferrithiocin pharmacophore as a vector for hydroxamates

A series of (S)-desmethyldesferrithiocin (DMDFT, 1) hydroxamates and a bis-salicyl polyether hydroxamate are evaluated for their iron-clearing properties in rodents; some of these are further assessed in primates. These hydroxamates include (S)-desmethyldesferrithiocin, N-methylhydroxamate (2); (S)-desmethyldesferrithiocin, N-[5-(acetylhydroxyamino)pentyl]hydroxamate (3); desmethyldesferrithiocin, N-benzylhydroxamate (4); (S,S)-N(1), N(8)-bis[4,5-dihydro-2-(3-hydroxy-2-pyridinyl)-4-thiazoyl]-N(1), N(8)-dihydroxy-3,6-dioxa-1,8-octanediamine (5); and N(1), N(8)-bis(2-hydroxybenzoyl)-N(1),N(8)-dihydroxy-3,6-dioxa-1, 8-octanediamine (6). The ligands are evaluated when given both orally (po) and subcutaneously (sc) in the bile-duct-cannulated rodent model. In iron-overloaded primates, ligands 1-4 are assessed when administered po and sc. The efficiencies of the hydroxamates are shown to vary considerably; giving the compounds sc consistently resulted in greater chelating efficiency in vivo. After oral administration in the primate, compound 3, a pentacoordinate unsymmetrical dihydroxamate, produces iron excretion sufficient to warrant further preclinical evaluation both as a potential orally active iron-chelating agent and as a parenteral iron chelator. The increased iron clearance of several of these ligands when administered sc versus po also underscores the idea that parenteral administration is a reasonable alternative to a less efficient, orally active device which would require large and frequent doses.