Design, synthesis, and testing of non-nephrotoxic desazadesferrithiocin polyether analogues.
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)phenyl]-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 1 was given at doses of 237 micromol/kg/day twice a day (b.i.d.), there was serious proximal tubule damage versus 474 micromol/kg/day once daily (s.i.d.). With 2 and 3, in iron-overloaded and/or non-iron-loaded rodents, kidney histopathologies remained normal.
Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610-0485, USA. rayb@ufl.edu
Raymond J
RJ
Bergeron
Jan
J
Wiegand
James S
JS
McManis
Neelam
N
Bharti
Shailendra
S
Singh
D000818:Animals; D001659:Biliary Tract / Q000187:drug effects / Q000378:metabolism; D002521:Cercopithecus; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004986:Ether / Q000737:chemistry*; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects; D007700:Kinetics; D008297:Male; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D004095:Dihydropyridines; D007502:Iron Chelating Agents; D013844:Thiazoles; C477594:desazadesferrithiocin; D004986:Ether; D007501:Iron