Desferrithiocin analogues and nephrotoxicity.
The syntheses of a series of 4'-O-alkylated ( S)-4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methyl-4-thiazole-carboxylic 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 P(app) 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 r(2) 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?
Bergeron
Raymond J
RJ
Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610-0485, USA. rayb@ufl.edu
Wiegand
Jan
J
McManis
James S
JS
Bharti
Neelam
N
Singh
Shailendra
S
D000284:Administration, Oral; D000818:Animals; D002428:Cebus; D004095:Dihydropyridines / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000737:chemistry; D004195:Disease Models, Animal; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000737:chemistry; D019190:Iron Overload / Q000188:drug therapy / Q000378:metabolism*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D008055:Lipids / Q000737:chemistry; D008297:Male; D008968:Molecular Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013844:Thiazoles / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000737:chemistry; D014867:Water / Q000737:chemistry
D004095:Dihydropyridines; D007502:Iron Chelating Agents; D008024:Ligands; D008055:Lipids; D013844:Thiazoles; D014867:Water; D007501:Iron; C050223:desferrithiocin
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