The development of iron chelating drugs.
Studies over the past few years have shown that it is possible to develop iron chelating agents that are active when given by mouth. Such compounds need to have a high binding constant for Fe(III) and an intermediate water and lipid solubility of both the unliganded compound and the iron complex with a Kpart of 0.2-1 for the free ligand. Hexadentate ligands would be preferable to bidentate compounds but no suitable compounds are available. In order to evaluate such compounds, simple cellular and animal screening models have been set up in a number of laboratories, and the potential of a new compound can be determined in a few weeks. Several groups have produced candidate compounds which are in various stages of development. DF is the established iron chelating drug, and the production of an orally active pro-drug must be high on the list of further developments, although this approach has so far not produced any useful compounds. It would appear that, at present, none of the other available hydroxamates will be sufficiently orally active or non-toxic to replace DF. Similarly, none of the available catecholates is promising enough to warrant further development at present. Among the amino carboxylates, although specificity may be a problem, the ester derivatives of HBED appear promising but have not yet been fully evaluated; this needs to be done before this group is discarded. Among the aryl hydrazones, PIH has reached the stage where it has been given to humans, but it may not be sufficiently active to be clinically useful. In this group there are several further compounds under development. PIB and a number of other derivatives need careful investigation before they are discarded, while pyridoxal-2-pyrimidyl-ethoxycarbonyl methbromide (PPEM) is in the early stages of animal testing and appears quite promising. Too little is known about the more recently synthesized hexadentate compounds based on the pyridoxal moieties, such as PLED, to judge whether this is a promising approach. Unfortunately, the naturally occurring siderophore, desferrithiocin, has proved too toxic for further development. Finally, a number of hydroxypyridin-4-ones have been synthesized and there are several that appear to be promising. CP20 (L1), the methyl derivative, has been given to humans, while at least two compounds with greater activity and relatively lower animal toxicity are close to being introduced. This group of compounds lends itself to the synthesis of a large number of derivatives with defined properties.(ABSTRACT TRUNCATED AT 400 WORDS)
Porter
J B
JB
Huehns
E R
ER
Hider
R C
RC
D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D006801:Humans; D007502:Iron Chelating Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D014018:Tissue Distribution
D007502:Iron Chelating Agents