Elsevier

Transfusion Science

Volume 23, Issue 3, December 2000, Pages 201-209
Transfusion Science

The design and properties of 3-hydroxypyridin-4-one iron chelators with high pFe3+ values

https://doi.org/10.1016/S0955-3886(00)00090-4Get rights and content

Introduction

Transfusion-dependent patients such as those suffering from β-thalassaemia develop a fatal secondary haemosiderosis and consequently, a selective iron chelator must be used to relieve such iron overload. Desferrioxamine-B (DFO) (1), the most widely used iron chelator in haematology over the past 30 years, has a major disadvantage of being orally inactive [1]. Consequently, the successful design of an orally active, non-toxic, selective iron chelator has been a much sought after goal for medicinal chemists for the past 25 years. In designing iron chelators for clinical application, metal selectivity and ligand–metal complex stability are of paramount importance [2]. A suitable comparator for ligands is the pFe3+ value, defined as the negative logarithm of the concentration of the free iron(III) in solution [3], [4]. The comparison of ligands using this parameter is useful, since pFe3+, unlike the corresponding stability constants, takes into account the effects of ligand basicity, denticity and degree of protonation, as well as differences in metal–ligand stoichiometries. Chelators with high pFe3+ values are predicted not only to scavenge iron more effectively at low ligand concentrations, but also dissociate less readily and therefore form lower concentrations of the partially coordinated complexes.

Over the past 20 years the Kings College group has simultaneously monitored three different parameters in an attempt to design useful iron chelators. These are (a) bioavailability, (b) selectivity and affinity for iron, and (c) disposition and toxicity. Although an ideal orally active, non-toxic, iron chelator has yet to be identified, we believe that we are well on the way to solving the problem. 3-Hydroxypyridin-4-ones (HPOs) (2) (Table 1) are currently one of the main candidates for the development of orally active iron chelators. Indeed, the 1,2-dimethyl derivative (deferiprone, CP20) is the only orally active iron chelator currently available for clinical use (marketed by Apotex, Toronto, Canada as Ferriprox™). In order to improve chelation efficacy and minimise toxicity, a series of novel hydroxypyridinones possessing high pFe3+ values are currently under development. In this review, the critical parameters in chelator design will be discussed and recent developments centred on hydroxypyridinone chelators described.

Section snippets

Bioavailability

The term bioavailability is not synonymous with absorption. It is possible to design pharmaceuticals which are efficiently absorbed from the gastrointestinal tract (GIT) and yet possess low bioavailability [5]. One such compound is β-propranalol, of which over 80% of an oral dose is absorbed in humans and yet it has a bioavailability of <5%. Bioavailability is defined as the percentage of absorbed dose which reaches the systemic blood circulation. If a compound is efficiently eliminated by

Tridentate chelators

The majority of tridentate ligands which possess a high affinity for iron(III) possess a nitrogen ligand, which is necessary to create the optimum stereochemistry [21]. Thus desferrithiocin (8) which forms a stable 2:1 complex with iron(III) also possesses appreciable affinity for iron(II), copper(II) and zinc(II) [22]. Variants of desferrithiocin have been investigated, but to date no suitable candidates have been identified for the replacement of DFO [23], mainly because of the adverse

Acknowledgements

The research project was supported by Apotex Research Inc., Canada and Biomed EC grant BMH4-CT97-2149.

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