Metabolically programmed iron chelators.
Metabolically programmed iron chelators.
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DOI：
10.1016/j.bmc.2015.06.059
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发表时间：
2015-09-01
影响因子：
3.5
通讯作者：
Wiegand J
中科院分区：
文献类型：
--
作者：
Bergeron RJ;Bharti N;McManis JS;Wiegand J
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 analogues being evaluated clinically for the treatment of iron overload diseases, e.g., thalassemia. The SAR work revealed that the lipophilicity of a ligand, as determined by its partition between octanol and water, log Papp, 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, i.e., highly lipophilic, orally absorbable, effective deferration agents which, once absorbed, are quickly converted to their nontoxic, hydrophilic counterparts.
