Design, synthesis, and testing of non-nephrotoxic desazadesferrithiocin polyether analogues
Design, synthesis, and testing of non-nephrotoxic desazadesferrithiocin polyether analogues
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DOI：
10.1021/jm800154m
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发表时间：
2008-07-10
影响因子：
7.3
通讯作者：
Singh, Shailendra
中科院分区：
文献类型：
--
作者：
Bergeron, Raymond J.;Wiegand, Jan;Singh, Shailendra
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)phenyll-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 I was given at doses of 237 mu mol/kg/day twice a day (b.i.d.), there was serious proximal tubule damage versus 474,mu mol/kg/day once daily (s.i.d.). With 2 and 3, in iron-overloaded and/or non-iron-loaded rodents, kidney histopathologies remained normal.
