Institute of Pharmaceutical Science
King’s College London
Patients with chronic refractory anemias receiving regular blood transfusions accumulate iron with potential damage to the liver, endocrine system and heart. The body has no mechanism for the active excretion of iron so each unit of blood adds 200-250mg iron to the body’s iron burden. Initially this excess iron is stored in the macrophages of the reticuloendothelial system but as the load increases and the saturation of plasma transferrin reaches 100% or more, the excess iron is deposited into the parenchymal cells of these organs. Thalassemia major (TM), in which there is an inherited failure to synthesise the beta globin chain of haemoglobin, is the most common transfusion dependent iron loading disease worldwide, and in which most trials of iron chelation drugs have been performed. Moreover in TM there is inappropriately increased absorption of dietary iron due to a low plasma hepcidin concentration. Without iron chelation therapy, mean survival from birth in TM was 12-17 years (Borgna-Pignatti, 2004), death occurring mainly from cardiac failure or arrhythmia. In 1976 Propper, Nathan and colleagues introduced the first effective iron chelation therapy, daily subcutaneous infusions of deferoxamine (DFO) (Propper, Shurin & Nathan, 1976). Subcutaneous infusions of DFO improved the life expectancy of those who could comply with the demanding routine of self -administered infusions over 12 hours for at least 5 days each week. Failure of compliance, side effects, hypersensitivity and the high cost of the drug, pump, needles and tubing precluded most of the worlds TM patients from receiving adequate chelation therapy and they continued to die prematurely (Modell et al, 2000). The need for an orally active, iron chelating drug was widely recognised and a large number of potential compounds were tested in cell cultures and in animals. Many chemists were searching for such molecules including Ray Bergeron, Bob Grady, Arthur Martell, Colin Pitt, Prem Ponka and Ken Raymond.
In 1977 I spent a sabbatical period in the Department of Biochemistry, Berkeley with Professor J. B. Neilands. Joe Neilands was the father figure in the field of siderophores (powerful iron chelators secreted by many bacteria and fungi) and had identified both the first hydroxamate – and first catechol-based siderophore. While working with the Neilands group, I became aware of studies by Ken Raymond in the Chemistry Department at Berkeley, some of which were directed at designing orally active iron chelators for the treatment of thalassemia. His candidates were modelled on catechol – containing siderophores. Based on my experience with membrane permeability, I realised that it was unlikely that any of Raymond’s candidate molecules would be sufficiently highly orally active, to be effective in the treatment of TM.
After returning to London, I identified hydroxypyridinones as possible substitutes for the catechol moiety in Raymond’s compounds, the major reason being that the resulting iron complexes would possess no net charge, in contrast to the 3– charge, typical of catechol siderophore iron complexes. Neutral molecules permeate biological membranes much more readily than charged molecules. At the time there was little work reported on hydroxypyridinones and no iron chelation data was available. I approached the British Technology Group (BTG) for funding and they provided a grant which was sufficient to undertake some preliminary experiments. George Kontoghiorghes was appointed as a PhD student and started to study hydroxypyridinones and hydroxypyrones. Many of these compounds were found to bind iron tightly and relatively selectively. Some of them were found to facilitate the movement of iron through cell membranes. With continued funding from BTG we collaborated with Ernest Huehns and John Porter (UCL) in order to test six compounds for oral activity in mice. We discovered that the 3-hydroxypyridin-4-one (L1) possessed extremely high oral bioavailability, leading to efficient iron excretion. (Hider, Kontoghiorghes and Silver, 1982). The UCL/Essex group, then synthesised a range of 3-hydroxypyridin-4-ones to undertake a structure/activity study (Porter et al, 1988) and to initiate preliminary toxicity investigations. (Porter et al, 1991)
In 1986 there was a Ciba-Geigy Funded Meeting where the general opinion prevailed that the chance of finding a drug which is both active orally and not toxic when administered at 1g dose per day was extremely low. Several compounds had been identified which both bound iron tightly and entered cells rapidly, but without exception they were found to be toxic. The take away message was that a nontoxic oral iron chelator may never be identified. However the following year there was a “Workshop on the Development of Oral Iron Chelating Agents” in Herakleion, Crete which was sponsored both by Ciba-Geigy and BTG. More optimism was expressed at this meeting in presentations by Chaim Hershko (Diethyl HBED), Gary Brittenham (PIH derivatives) and George Kontoghiorghes and myself (Hydroxypyridinones) – may be the identification of a relatively nontoxic orally active iron chelator would be possible.
Back in London there was heated discussion as to whether or not we should prepare 1,2-dimethyl 3-hydroxypyridin-4-one (L1, CP20) for clinical studies or wait until we had completed investigation of the 3-hydroxypyridin-4-one analogues, thereby enabling us to select the most efficient, least toxic chelator. George Kontoghiorghes wanted to concentrate on L1, and to introduce it into clinical studies as quickly as possible. The rest of the UCL/Essex group considered this to be premature. As a result, Kontoghiorghes approached Victor Hoffbrand who at The Royal Free Hospital (RFH) was faced with many referred TM patients who had failed subcutaneous DFO therapy and were at risk of dying. After further animal studies, clinical trials began at the RFH in 1987 with L1 (subsequently named deferiprone).(Kontoghiorges et al, 1987) Thus deferiprone became the first orally active iron chelator to be successfully used in man.
There have been many controversies and important milestones centred on the use of deferiprone since 1987. I will mention two important developments that have occurred over this period.
The onset of the successful monitoring of iron in myocardial tissue by Anderson and Pennell (Anderson et al, 2004; Pennell et al, 2006) has led to the identification of deferiprone as being the most efficient chelator to remove iron from the heart. (Pennell et al, 2013). The mode of action is probably as indicated in figure 1, that is the noncharged nature of both the ligand and the iron complex permit both species to penetrate membranes by nonfacilated diffusion; ie the precise design feature which led to the identification of hydroxypyridinones in 1979-80.
There is now increasing evidence that elevated levels of iron in certain brain regions are associated with symptoms of neurodegeneration. (Crichton,Ward and Hider,2017). Currently a Phase 2 clinical trial based on the application of deferiprone to remove inappropriately accumulated brain iron is taking place in many European centres. Devos et al, 2014)
It is surprising to me that deferiprone, which is such a small molecule, possesses this considerable potential as a therapeutic agent.
Anderson, U., Westwood, M.A., et al. Brit. J. Haematol. 127 (2004) 348.
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