caa a22 4500 445322004 CHVBK 20180317142707.0 cr unu---uuuuu 170323e20110401xx s 000 0 eng 10.1007/s10534-010-9389-y doi (NATIONALLICENCE)springer-10.1007/s10534-010-9389-y Desferrithiocin analogue iron chelators: iron clearing efficiency, tissue distribution, and renal toxicity [Elektronische Daten] [Raymond Bergeron, Jan Wiegand, Neelam Bharti, James McManis, Shailendra Singh] 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, Table1) 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 (Table1, 3-5) and the (S)-4,5-dihydro-2-[2-hydroxy-3-(polyether)phenyl]-4-methyl-4-thiazolecarboxylic acids (Table1, 8-10). The three most effective polyether analogues, in terms of performance ratio (PR), defined as mean ICEprimate/ICErodent, 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. Springer Science+Business Media, LLC., 2010 Iron chelator nationallicence Desazadesferrithiocin polyether analogues nationallicence Tissue distribution nationallicence Nephrotoxicity nationallicence Urinary biomarker nationallicence Kidney injury molecule-1 (Kim-1) nationallicence Bergeron Raymond Department of Medicinal Chemistry, University of Florida, JHMHC, Box 100485, 32610-0485, Gainesville, FL, USA aut Wiegand Jan Department of Medicinal Chemistry, University of Florida, JHMHC, Box 100485, 32610-0485, Gainesville, FL, USA aut Bharti Neelam Department of Medicinal Chemistry, University of Florida, JHMHC, Box 100485, 32610-0485, Gainesville, FL, USA aut McManis James Department of Medicinal Chemistry, University of Florida, JHMHC, Box 100485, 32610-0485, Gainesville, FL, USA aut Singh Shailendra Department of Medicinal Chemistry, University of Florida, JHMHC, Box 100485, 32610-0485, Gainesville, FL, USA aut BioMetals Springer Netherlands 24/2(2011-04-01), 239-258 0966-0844 24:2<239 2011 24 10534 https://doi.org/10.1007/s10534-010-9389-y text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10534-010-9389-y text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Bergeron Raymond Department of Medicinal Chemistry, University of Florida, JHMHC, Box 100485, 32610-0485, Gainesville, FL, USA aut NATIONALLICENCE 700 1- Wiegand Jan Department of Medicinal Chemistry, University of Florida, JHMHC, Box 100485, 32610-0485, Gainesville, FL, USA aut NATIONALLICENCE 700 1- Bharti Neelam Department of Medicinal Chemistry, University of Florida, JHMHC, Box 100485, 32610-0485, Gainesville, FL, USA aut NATIONALLICENCE 700 1- McManis James Department of Medicinal Chemistry, University of Florida, JHMHC, Box 100485, 32610-0485, Gainesville, FL, USA aut NATIONALLICENCE 700 1- Singh Shailendra Department of Medicinal Chemistry, University of Florida, JHMHC, Box 100485, 32610-0485, Gainesville, FL, USA aut NATIONALLICENCE 773 0- BioMetals Springer Netherlands 24/2(2011-04-01), 239-258 0966-0844 24:2<239 2011 24 10534 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer