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

Abstract

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 ...

A phase 1 dose-escalation study: safety, tolerability, and pharmacokinetics of FBS0701, a novel oral iron chelator for the treatment of transfusional iron overload

“…5 The data in this study suggest that the fraction of the oral dose of FBS0701 not bound to iron is largely excreted renally whereas the drug:iron complex is likely to be excreted predominantly via the biliary route.…”

“…[2][3][4] FBS0701 was selected for clinical development on the basis of its primary pharmacological and pharmacokinetic properties and the toxicity profile, all of which suggested that FBS0701 might offer significant clinical advantages for patients with iron overload as compared to currently available therapies. 5 Extensive preclinical toxicological studies of FBS0701 consistently demonstrated a higher no-observableadverse-effect level (NOAEL) compared to deferasirox (ExJade ® , Novartis) suggesting a favorable clinical safety profile especially with respect to nephrotoxicity. 6,7 In this study, we report the results of the first multi-dose exposure of FBS0701 in iron-overloaded patients.…”

How I treat transfusional iron overload

“…In preclinical studies, FBS0701 bound Fe(III) with very high affinity and selectivity and demonstrated a Ͼ 4-fold higher no-observable-adverse-effect level compared with DFX, suggesting a favorable clinical safety profile, especially with respect to gastrointestinal and renal toxicity. 88 Multidose safety and pharmacokinetic studies in iron-overloaded patients established the acute safety of FBS0701 and the feasibility of once-a-day dosing, 89 and a phase 2 study has now been reported confirming these observations. 90 …”

Antimalarial Iron Chelator FBS0701 Blocks Transmission by Plasmodium falciparum Gametocyte Activation Inhibition

“…The error bars represent the standard error of the mean. addition, FBS0701 is more efficient at chelating iron in mice and monkeys than is DFO (29,30). Moreover, Ferrer et al (22) showed that FBS0701 can chelate and remove intracellular erythrocytic iron.…”