title: Desazadesmethyldesferrithiocin analogues as orally effective iron chelators.
abstract: Further structure-activity studies of desferrithiocin analogues are carried out. (S)-Desazadesmethyldesferrithiocin, 2-(2-hydroxyphenyl)-Delta2-thiazoline-4(S)-carboxylic acid, serves as the principal framework in the current paper. Desazadesmethyldesferrithiocin can be structurally altered with facility, and data are already available on its iron-clearing properties and toxicity parameters. Four different kinds of structural modifications of this framework are undertaken: introduction of hydroxy, carboxy, or methoxy groups on the aromatic ring; alteration of the thiazoline ring; increasing the distance between the ligand donor atoms; and benz-fusion of the aromatic rings. The structural modifications described are shown to have a tremendous impact on both the iron clearance and toxicity profiles of the desazadesmethyldesferrithiocin molecule. All of the compounds are assessed in a bile-duct-cannulated rodent model to determine iron clearance efficiency. Ligands which demonstrate an efficiency of greater than 2% are carried forward to the iron-overloaded primate for iron-clearing measurements. Ligands with efficiencies greater than 3% in the primate are then evaluated in a formal toxicity study in rodents. On the basis of the results of the present work, 2-(2, 4-dihydroxyphenyl)-Delta2-thiazoline-4(S)-carboxylic acid is a promising candidate for clinical evaluation.
authors.affiliation: Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610-0485, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Bergeron
authors.forename: J
authors.initials: J
authors.lastname: Wiegand
authors.forename: W R
authors.initials: WR
authors.lastname: Weimar
authors.forename: J R
authors.initials: JR
authors.lastname: Vinson
authors.forename: J
authors.initials: J
authors.lastname: Bussenius
authors.forename: G W
authors.initials: GW
authors.lastname: Yao
authors.forename: J S
authors.initials: JS
authors.lastname: McManis
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001646:Bile / Q000737:chemistry; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D002428:Cebus; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D007501:Iron / Q000032:analysis / Q000652:urine; D007502:Iron Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D019190:Iron Overload / Q000188:drug therapy; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity
chemical_list: C116990:2-(2,4-dihydroxyphenyl)-delta(2)-thiazoline-4-carboxylic acid; D002264:Carboxylic Acids; D007502:Iron Chelating Agents; D013844:Thiazoles; D007501:Iron