A Dose Escalation Study of the Pharmacokinetics, Safety &amp; Efficacy of Deferitrin, an Oral Iron Chelator in Beta Thalassaemia Patients.

Galanello, Renzo; Forni, Gian Luca; Jones, A. R.; Kelly, Andrew B.; Willemsen, Annelieke E.C.A.B.; He, Xuexin; Johnston, Amanda; Fuller, David E.; Donovan, Joanne M.; Piga, Antonio

doi:10.1182/blood.v110.11.2669.2669

Cited by 6 publications

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“…However, when the ligand was given b.i.d., patients presented with elevated BUN and SCr, and the trials were discontinued. 165 The problem then became how to solve the renal toxicity problem when the chelator was administered b.i.d.…”

Section: Discussionmentioning

confidence: 99%

“…The initial outcome revealed that removal of the DFT aromatic nitrogen and introduction of a hydroxyl at either the aromatic 4′ or 3′ position of DADFT ( 4 ) led to ligands with remarkably reduced toxicity in rodents and good ICE in primates. In fact, deferitrin ( 26 ) was taken into human clinical trials by Genzyme. , Initial results were very promising when the drug was given s.i.d. However, when the ligand was given b.i.d., patients presented with elevated BUN and SCr, and the trials were discontinued .…”

Section: Discussionmentioning

confidence: 99%

“…However, when the drug was given twice daily (b.i.d.) at a dose of 12.5 mg/kg (25 mg/kg/day), unacceptable renal toxicity was observed in three patients after only 4–5 weeks of treatment, and the study was terminated . The directive then became to engineer a ligand that would not cause any nephrotoxicity even when it was given b.i.d.…”

Section: Dft: Structure–activity Studiesmentioning

confidence: 99%

“…at doses of 5, 10, or 15 mg/kg/day, administering the drug b.i.d. at 12.5 mg/kg/dose (25 mg/kg/day) was associated with unacceptable renal toxicity. , Because of the apparent increase in renal toxicity observed in patients treated with 26 b.i.d. versus s.i.d., we elected to determine if this damage could be reproduced in the rodents.…”

Section: Reengineering (S)-4′-(ho)-dadft (26)mentioning

confidence: 99%

“…Recall that the major hurdle in exploiting the DFT pharmacophore, e.g., deferitrin ( 26 ), as an orally active iron chelator was its nephrotoxicity. , Iron chelator-induced proximal tubule damage is not uncommon. In fact, one of the problems associated with a currently accepted iron-overload treatment, Exjade, is proximal tubule-derived renal damage. , Therefore, a series of toxicity studies focusing on 44 ’s impact on renal function was carried out in rats.…”

Section: Synthesis and Biological Evaluation Of (S)-45-dihydro-2-[2-h...mentioning

confidence: 99%

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Desferrithiocin: A Search for Clinically Effective Iron Chelators

et al. 2014

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The successful search for orally active iron chelators to treat transfusional iron-overload diseases, e.g., thalassemia, is overviewed. The critical role of iron in nature as a redox engine is first described, as well as how primitive life forms and humans manage the metal. The problems that derive when iron homeostasis in humans is disrupted and the mechanism of the ensuing damage, uncontrolled Fenton chemistry, are discussed. The solution to the problem, chelator-mediated iron removal, is clear. Design options for the assembly of ligands that sequester and decorporate iron are reviewed, along with the shortcomings of the currently available therapeutics. The rationale for choosing desferrithiocin, a natural product iron chelator (a siderophore), as a platform for structure–activity relationship studies in the search for an orally active iron chelator is thoroughly developed. The study provides an excellent example of how to systematically reengineer a pharmacophore in order to overcome toxicological problems while maintaining iron clearing efficacy and has led to three ligands being evaluated in human clinical trials.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Dft: Structure–activity Studiesmentioning

confidence: 99%

Section: Reengineering (S)-4′-(ho)-dadft (26)mentioning

confidence: 99%

Section: Synthesis and Biological Evaluation Of (S)-45-dihydro-2-[2-h...mentioning

confidence: 99%

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Desferrithiocin: A Search for Clinically Effective Iron Chelators

et al. 2014

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Substituent Effects on Desferrithiocin and Desferrithiocin Analogue Iron-Clearing and Toxicity Profiles

et al. 2012

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Desferrithiocin (DFT, 1) is a very efficient iron chelator when given orally. However, it is severely nephrotoxic. Structure-activity studies with 1 demonstrated that removal of the aromatic nitrogen to provide desazadesferrithiocin (DADFT, 2) and introduction of either a hydroxyl group or a polyether fragment onto the aromatic ring resulted in orally active iron chelators that were much less toxic than 1. The purpose of the current study was to determine if a comparable reduction in renal toxicity could be achieved by performing the same structural manipulations on 1 itself. Accordingly, three DFT analogues were synthesized. Iron clearing efficiency and ferrokinetics were evaluated in rats and primates; toxicity assessments were carried out in rodents. The resulting DFT ligands demonstrated a reduction in toxicity that was equivalent to that of the DADFT analogues and presented with excellent iron clearing properties.

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Design, Synthesis, and Testing of Non-Nephrotoxic Desazadesferrithiocin Polyether Analogues

Bergeron

Wiegand²,

McManis³

et al. 2008

J. Med. Chem.

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A series of iron-clearing efficiencies (ICEs), ferrokinetics, and toxicity studies for (S)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid (deferitrin, 1), (S)-4,5-dihydro-2-[2-hydroxy-4-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid (2) and (S)-4,5-dihydro-2-[2-hydroxy-3-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid (3) are reported. The ICEs in rodents are shown to be dose-dependent and saturable for ligands 2 and 3 and superior to 1. Both polyether analogues in subcutaneous (sc) versus oral (po) administration in rodents and primates demonstrated excellent bioavailability. Finally, in a series of toxicity studies of ligands 1-3, the dosing regimen was shown to have a profound effect in animals treated with ligand 1. When ligand 1 was given at doses of 237 µmol/kg/day twice a day (b.i.d.), there was serious proximal tubule damage versus 474 µmol/kg/day once daily (s.i.d.). With 2 and 3, in iron-overloaded and/or non-iron-loaded rodents, kidney histopathologies remained normal.Although iron comprises 5% of the earth's crust, living systems have great difficulty in accessing and managing this vital micronutrient. The low solubility of Fe(III) hydroxide (K sp = 1 × 10 −39 ), 1 the predominant form of the metal in the biosphere, has led to the development of sophisticated iron storage and transport systems in nature. Microorganisms utilize low molecular weight, virtually ferric ion-specific ligands, siderophores 2-6 higher eukaryotes tend to employ proteins to transport and store iron (e.g., transferrin and ferritin, respectively). [7][8][9] Humans absorb and excrete only about 1 mg of the metal daily; there is no effective mechanism for the excretion of excess iron. 10 In humans, nontransferrin-bound plasma iron, a heterogeneous pool of the metal in the circulation, unmanaged iron, seems to be a principal source of iron-mediated organ damage. Introduction of excess iron into this closed system, whether derived from transfused red blood cells [11][12][13] or from increased absorption of dietary iron, 14,15 leads to a build up of the metal in the liver, heart, pancreas, and elsewhere. Such iron accumulation eventually produces (i) liver disease that may progress to cirrhosis, [16][17][18] (ii) diabetes related both to iron-induced decreases in pancreatic β-cell secretion 19,20 and increases in hepatic insulin resistance, and (iii) heart disease, still the leading cause of death in thalassemia major [21][22][23] and related forms of transfusional iron overload.The toxicity associated with excess iron, whether a systemic or a focal problem, derives from its interaction with reactive oxygen species, for instance, endogenous hydrogen peroxide (H 2 O 2 ). [24][25][26][27] In the presence of Fe(II), H 2 O 2 is reduced to the hydroxyl radical (HO • ), a very reactive species, and HO − , a process known as the Fenton reaction. The Fe(III) liberated can NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript be reduced back to Fe(II) via ...

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A Dose Escalation Study of the Pharmacokinetics, Safety & Efficacy of Deferitrin, an Oral Iron Chelator in Beta Thalassaemia Patients.

Cited by 6 publications

References 0 publications

Desferrithiocin: A Search for Clinically Effective Iron Chelators

Desferrithiocin: A Search for Clinically Effective Iron Chelators

Substituent Effects on Desferrithiocin and Desferrithiocin Analogue Iron-Clearing and Toxicity Profiles

Design, Synthesis, and Testing of Non-Nephrotoxic Desazadesferrithiocin Polyether Analogues

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