Desferrithiocin analogue iron chelators: iron clearing efficiency, tissue distribution, and renal toxicity

Abstract

The current solution to iron-mediated damage in transfusional iron overload disorders is decorporation of excess unmanaged metal, chelation therapy. The clinical development of the tridentate chelator deferitrin (1, Table 1) was halted due to nephrotoxicity. It was then shown by replacing the 4'-(HO) of 1 with a 3,6,9-trioxadecyloxy group, the nephrotoxicity could be ameliorated. Further structure-activity relationship studies have established that the length and the position of the polyether backbone controlled: (1) the ligand's iron clearing efficiency (ICE), (2) chelator tissue distribution, (3) biliary ferrokinetics, and (4) tissue iron reduction. The current investigation compares the ICE and tissue distribution of a series of (S)-4,5-dihydro-2-[2-hydroxy-4-(polyether)phenyl]-4-methyl-4-thiazolecarboxylic acids (Table 1, 3-5) and the (S)-4,5-dihydro-2-[2-hydroxy-3-(polyether)phenyl]-4-methyl-4-thiazolecarboxylic acids (Table 1, 8-10). The three most effective polyether analogues, in terms of performance ratio (PR), defined as mean ICE(primate)/ICE(rodent), are 3 (PR 1.1), 8, (PR 1.5), and 9, now in human trials, (PR 2.2). At the onset of the clinical trial on 9, no data were available for ligand 3 or 8. This is unfortunate, as 3 has many advantages over 9, e.g., the ICE of 3 in rats is 2.5-fold greater than that of 9 and analogue 3 achieves very high levels in the liver, pancreas, and heart, the organs most affected by iron overload. Finally, the impact of 3 on the urinary excretion of kidney injury molecule-1 (Kim-1), an early diagnostic biomarker for monitoring acute kidney toxicity, has been carried out in rats; no evidence of nephrotoxicity was found. Overall, the results suggest that 3 would be a far superior clinical candidate to 9.

Figure 1

Structures of iron chelators that are now in use or that have been clinically evaluated: desferrioxamine B mesylate (DFO), 1,2-dimethyl-3-hydroxypyridin-4-one (deferiprone, L1), 4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]benzoic acid (deferasirox, Exjade), and the desferrithiocin [(S)-4,5-dihydro-2-(3-hydroxy-2-pyridinyl)-4-methyl-4-thiazolecarboxylic acid (DFT)] analogue (S)-4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methyl-4-thiazolecarboxylic acid, deferitrin (1).

Figure 2

Dose-response curves for compounds 1, 3, 4, and 9 administered p.o. to bile duct-cannulated rats. The ICE data, expressed as a percentage, (y-axis) for ligands 1, 4, and 9 are from Bergeron et al. 2008.

Figure 3

Tissue distribution in the liver, heart, plasma, pancreas, and kidney of rats treated with DADFT analogues 1, 3, 4, 8, and 9 given s.c. at a dose of 300 μmol/kg. The concentrations (y-axis) are reported as nmol compound per g wet weight of tissue, or as μM (plasma). For all time points, n = 3. The data for ligands 1, 4 and 9 are from Bergeron et al. 2006, , .

Figure 4

Tissue distribution in liver, heart, plasma, pancreas, and kidney of rats treated with DADFT analogues 1, 3, 4, and 9 given p.o. at a dose of 300 μmol/kg. The concentrations (y-axis) are reported as nmol compound per g wet weight of tissue, or as μM (plasma). For all time points, n = 3. The data for ligands 1, 4, and 9 are from Bergeron et al. 2008.

Figure 5

Urinary Kim-1 excretion, expressed as Kim-1 (ng/kg/24 h), for group: A) untreated age-matched control rats; B) rats treated with 3 p.o. once daily at a dose of 170.7 μmol/kg/d × 28 d; C) rats given Exjade p.o. once daily at a dose of 384 μmol/kg/d; D) rats given 3 p.o. once daily at a dose of 384 μmol/kg/d × 10 d; E) rats given deferitrin (1) p.o. twice daily at a dose of 237 μmol/kg/dose (474 μmol/kg/d) × 7 d, and F) rats given 3 p.o. twice daily at a dose of 237 μmol/kg/dose (474 μmol/kg/d) × 7 d. Note that none of the rats survived the planned 10-d exposure to Exjade. For groups A–D and F, n = 5; group E, n = 3.

Scheme 1

Synthesis of (S)-4,5-Dihydro-2-[2-hydroxy-3-(3,6-dioxaheptyloxy)phenyl]-4-methyl-4- thiazolecarboxylic Acid (8) and (S)-4,5-Dihydro-2-[2-hydroxy-3-(3,6,9,12-tetraoxatridecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic Acid (10)^{a a}Reagents and conditions: (a) 60% NaH (2.0 equiv), DMSO, CH₃[O(CH₂)₂]₂OTs (12, 1.0 equiv), 71% (13) or CH₃[O(CH₂)₂]₄OTs (14, 1.0 equiv), 70% (15); (b) CH₃OH (aq), pH 6, 70 ºC, 24 h, 93% (8) or 85% (10).