1067643-01-9Relevant academic research and scientific papers
Desferrithiocin analogues and nephrotoxicity
Bergeron, Raymond J.,Wiegand, Jan,McManis, James S.,Bharti, Neelam,Singh, Shailendra
experimental part, p. 5993 - 6004 (2009/10/01)
The syntheses of a series of 4′-O-alkylated (S)-4,5-dihydro-2-(2,4- dihydroxyphenyl)-4-methyl-4-thiazolecarboxylic acid and 5′-O-alkylated (S)-4,5-dihydro-2-(2,5-dihydroxyphenyl)-4-methyl-4-thiazolecarboxylic acid ligands are described. Their partition between octanol and water, log P app, is determined, along with their iron-clearing efficiency (ICE) in both non-iron-overloaded, bile duct-cannulated rodents and in iron-overloaded primates. The ligand-promoted biliary ferrokinetics in rats are described for each of the chelators. Plots of log Papp versus ICE in a rodent model for both the 4′-O-alkylated 2,4-dihydroxy and 5′-O-alkylated 2,5-dihydroxy series produced an inverse parabola plot with r2 values of 0.97 and 0.81, respectively. The plots indicate an optimum log P app/ICE relationship. Because of the nature of the data spread in the 4′-O-alkylated 2,4-dihydroxy series, it will be used to help assess the origin of nephrotoxicity in desferrithiocin analogues: is toxicity simply related to lipophilicity, ICE, or a combination of these properties?
