title: Metabolically programmed iron chelators.
abstract: Extensive structure activity relationship (SAR) studies focused on the desferrithiocin [DFT, (S)-4,5-dihydro-2-(3-hydroxy-2-pyridinyl)-4-methyl-4-thiazolecarboxylic acid] pharmacophore have led to three different DFT analogs being evaluated clinically for the treatment of iron overload diseases, for example, thalassemia. The SAR work revealed that the lipophilicity of a ligand, as determined by its partition between octanol and water, logP(app), could have a profound effect on the drug's iron clearing efficiency (ICE), organ distribution, and toxicity profile. While within a given structural family the more lipophilic a chelator the better the ICE, unfortunately, the more lipophilic ligands are often more toxic. Thus, a balance between lipophilicity, ICE, and toxicity must be achieved. In the current study, we introduce the concept of 'metabolically programmed' iron chelators, that is, highly lipophilic, orally absorbable, effective deferration agents which, once absorbed, are quickly converted to their nontoxic, hydrophilic counterparts.
authors.affiliation: JHMHC, Department of Medicinal Chemistry, University of Florida, Box 100485, Gainesville, FL 32610-0485, United States. Electronic address: rayb@ufl.edu.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Bergeron
authors.affiliation: JHMHC, Department of Medicinal Chemistry, University of Florida, Box 100485, Gainesville, FL 32610-0485, United States.
authors.forename: Neelam
authors.initials: N
authors.lastname: Bharti
authors.affiliation: JHMHC, Department of Medicinal Chemistry, University of Florida, Box 100485, Gainesville, FL 32610-0485, United States.
authors.forename: James S
authors.initials: JS
authors.lastname: McManis
authors.affiliation: JHMHC, Department of Medicinal Chemistry, University of Florida, Box 100485, Gainesville, FL 32610-0485, United States.
authors.forename: Jan
authors.initials: J
authors.lastname: Wiegand
mesh_terms: D015195:Drug Design; D007501:Iron / Q000737:chemistry*; D007502:Iron Chelating Agents / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D007502:Iron Chelating Agents; D007501:Iron
keywords: Metabolically programmed iron chelators