The synthesis and iron-clearing properties of the naphthyldesferrithiocins 2-(2'-hydroxynaphth-1'-yl)-delta2-thiazoline-(4R)-carboxylic acid, 2-(2'-hydroxynaphth-1'-yl)-delta2-thiazoline-(4S)-carboxylic acid, 2-(3'-hydroxynaphth-2'-yl)-delta2-thiazoline-(4R)-carboxylic acid, and 2-(3'-hydroxynaphth-2'-yl)-delta2-thiazoline-(4S)-carboxylic acid are described. While the bile duct-cannulated rat model clearly demonstrates that the 3'-hydroxynaphthyl-2'-yl compounds are orally active iron-clearing agents and the corresponding 2'-hydroxynaphthyl-1'-yl compounds are not, in the primate model none of the benz-fused desazadesferrithiocin analogues are active. Oral versus subcutaneous administration of these ligands strongly suggests that metabolism is a key issue in their iron-clearing properties and that these benz-fused desferrithiocins are not good candidates for orally active iron-clearing drugs.

The iron clearance properties, toxicity, and pharmacokinetics of (R)- and (S)-desmethyldesferrithiocin (DMDFT) are described. The studies were performed in rodent and primate models. While both enantiomers were found to be effective iron chelators with minimal toxicity in the rodents, only (S)-DMDFT was able to induce the clearance of any iron in the primates. In addition, two out of nine of the monkeys given (R)-DMDFT died within 24 h of drug administration. The reason for the differences in iron clearance properties and the apparent toxicity of the (R)-enantiomer in the primates is likely related to the disparities in the pharmacokinetics of the two analogues. The pharmacokinetic data suggest enantioselectivity in renal clearance of the desferrithiocins and their iron complexes with (S)-DMDFT clearance 3.5 times greater than that of (R)-DMDFT, and FeIII [(S)-DMDFT]2 clearance 6.8 times greater than that of FeIII [R-DMDFT]2. In all primates studied FeIII [(R)-DMDFT]2 in the plasma exceeded 25 mg/L (50 microM) for several hours and remained above 10 mg/L (20 microM) at 8 h while levels of FeIII [(S)-DMDFT]2 never exceeded 50 microM and were at or below the limits of detection 8 h post-injection.