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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.
AuthorsRaymond J Bergeron, Neelam Bharti, James S McManis, Jan Wiegand
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 23 Issue 17 Pg. 5954-71 (Sep 01 2015) ISSN: 1464-3391 [Electronic] England
PMID26231739 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 Elsevier Ltd. All rights reserved.
Chemical References
  • Iron Chelating Agents
  • Iron
Topics
  • Drug Design
  • Iron (chemistry)
  • Iron Chelating Agents (chemistry)
  • Structure-Activity Relationship

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