desferrithiocin and Disease-Models--Animal

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?

Topics: Administration, Oral; Animals; Cebus; Dihydropyridines; Disease Models, Animal; Drug Design; Drug Evaluation, Preclinical; Iron; Iron Chelating Agents; Iron Overload; Kidney Diseases; Ligands; Lipids; Male; Molecular Conformation; Rats; Rats, Sprague-Dawley; Stereoisomerism; Thiazoles; Water

Iron contributes significantly to the formation of reactive oxygen species via the Fenton reaction. Therefore, we assessed whether a series of desferrithiocin analogs, both carboxylic acids and hydroxamates, could (1) either promote or diminish the iron-mediated oxidation of ascorbate, (2) quench a model radical species, 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+), and (3) when applied topically, prevent acetic acid-induced colitis in rats. Surprisingly, most of the desferrithiocin analogs inhibited the Fenton reaction to an approximately equivalent degree; however, substantial differences were observed in the capacity of the analogs to scavenge the model radical cation. Four carboxylic acid desferrithiocin analogs and their respective N-methylhydroxamates were tested along with desferrioxamine and Rowasa, a currently accepted topical therapeutic agent for inflammatory bowel disease (IBD), in a rodent model of acetic acid-induced colitis. The colonic damage was quantitated by two independent measurements. Although neither radical scavenging nor prevention of Fenton chemistry was a definitive predictor of in vivo efficacy, the overall trend is that desferrithiocin analogs substituted with an N-methylhydroxamate in the place of the carboxylic acid are both better free radical scavengers and more active against acetic acid-induced colitis. These results represent an intriguing alternative avenue to the development of improved IBD therapeutic agents.

Topics: Acetic Acid; Animals; Colitis; Dihydropyridines; Disease Models, Animal; Drug Interactions; Intestinal Mucosa; Male; Random Allocation; Rats; Rats, Sprague-Dawley; Reference Values; Sensitivity and Specificity; Thiazoles

Recent studies have demonstrated that parenteral deferroxamine can prolong life in patients with iron overload. We have developed a non-human primate model of iron overload and have accurately determined negative iron balance in parenteral and oral studies of deferroxamine and a new chelator, desferrithiocin. Cebus monkeys were loaded with iron dextran (10 mg/kg twice weekly) until their serum contained a transferrin saturation greater than 75%, and (in two animals) liver biopsies showed iron loading. When complete iron balance studies were performed at this time, basal iron balance was -53 +/- 11 micrograms (N = 4), providing a low background for provocative studies. Iron balance was determined for intramuscular (N = 2) and oral (N = 3) deferroxamine, as well as intramuscular (N = 1) and oral (N = 4) desferrithiocin. The pattern of iron excretion after parenteral deferroxamine strongly resembled that of the iron-loaded, transfused human. Desferrithiocin was found to have significant activity as an oral chelator. This Cebus monkey model accurately determines negative iron balance and readily permits precise comparison of iron chelators given parenterally or orally. This model may offer an important step between rodent and human trials of promising new iron chelators.

Topics: Administration, Oral; Animals; Cebus; Deferoxamine; Dihydropyridines; Disease Models, Animal; Injections, Intramuscular; Iron; Iron Chelating Agents; Thiazoles