New chelating agents suitable for the treatment of iron overload

The requirements for chelating agents that are possible substitutes for des ferriferrioxamine-B (DFO) are reviewed, and the candidates that have been c arried the farthest with animal tests and clinical trials are briefly descr ibed. The ligands that have not been studied thoroughly but which look prom ising on the basis of initial screening tests, are also discussed. Of the l igands that satisfy the thermodynamic stability requirements, many have to be eliminated for biomedical reasons, such as toxicity, method of administr ation, and bioavailability. In some cases, possibly effective drugs have no t been explored because they have not yet been given the attention warrante d by preliminary tests. Thus, mono(o-hydroxybenzyl)ethylenediaminetriacetic acid, which tested well in the mouse screen, has not been further investig ated. Also, N, N'-bis(pyridoxyl)ethylenediamine-N, N'-diacetic acid (PLED), which has been shown to be effective and low in toxicity, should be subjec ted to more extensive tests. Several promising new ligands have recently be en synthesized and deserve further investigation. Thus, N,N'-bis(6-methyl-3 -hydroxy-2-pyridylmethyl)ethylenediamine-N,N'-diacetic acid (EDDA-MeHP), wh ich has the same functional groups as PLED but seems to be somewhat superio r in Fe(III) affinity, is a promising candidate for Fe(III) removal. Also, N,N'-di(o-hydroxy-phenyl)ethylenediamine-N,N'-diacetic acid (HPED), which h as the same functional donor groups as HBED, and has high affinity for Fe(I II), needs further exploration. A number of other new ligands deserving fur ther study will be described: N,N',N "-tris(3-hydroxy-6-methyl-2-pyridylmet hyl)-1,4,7-triazanonane (TACN-MeHP), which has the highest affinity for Fe( III) of any ligand, natural or synthetic; TACN-Me2HB, an analog of TACN-MeH P with hydroxybenzyl groups in place of hydroxypyridyl donors (and is consi derably more hydrophobic than TACN-MeHP); and a hexadentate ligand containi ng three hydroxypyridinone moieties which should overcome the dilution prob lem (low stability at high dilution) encountered with 1,2-dimethyl-3-hydrox y-4-pyridinone (L1). Other ligands which may possibly serve as drugs for tr eatment of iron overload are also described. (C) 1999 Elsevier Science S.A. All rights reserved.