Bergeron Raymond J, Wiegand Jan, McManis James S, Vinson John R T, Yao Hua, Bharti Neelam, Rocca James R
Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610-0485, USA.
J Med Chem. 2006 May 4;49(9):2772-83. doi: 10.1021/jm0508944.
Previous studies revealed that within a family of ligands the more lipophilic chelators have better iron-clearing efficiency. The larger the log P(app) value of the compound, the better the iron-clearing efficiency. What is also clear from the data is that although the relative effects of log P(app) changes are essentially the same through different families, there are differences in absolute value between families. However, there also exists a second, albeit somewhat more disturbing, relationship. In all sets of ligands, the most lipophilic chelator is always the most toxic. The current study focuses on designing ligands that balance the lipophilicity/toxicity problem while iron-clearing efficiency is maintained. Earlier studies with (S)-4,5-dihydro-2-(2-hydroxy-4-methoxyphenyl)-4-methyl-4-thiazolecarboxylic acid [(S)-4'-(CH(3)O)-DADFT, 6] indicated that this methyl ether was a ligand with excellent iron-clearing efficiency in both rodents and primates; however, it was too toxic. On the basis of this finding, a less lipophilic, more water-soluble ligand than 6 was assembled, (S)-4,5-dihydro-2-[2-hydroxy-4-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-4'-(HO)-DADFT-PE, 11], a polyether analogue, along with its ethyl and isopropyl esters. The parent polyether and its isopropyl and ethyl esters were all shown to be highly efficient iron chelators in both rodents and primates. A comparison of 11 in rodents with the desferrithiocin analogue (S)-4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methyl-4-thiazolecarboxylic acid [(S)-4'-(HO)-DADFT, 1] revealed the polyether to be more tolerable, achieving higher concentrations in the liver and significantly lower concentrations in the kidney. The lower renal drug levels are in keeping with the profound difference in the architectural changes seen in the kidney of rodents given 1 versus those treated with 11.
先前的研究表明，在一族配体中，亲脂性更强的螯合剂具有更好的铁清除效率。化合物的log P(app)值越大，铁清除效率越高。从数据中还可以清楚地看出，尽管log P(app)变化的相对影响在不同族中基本相同，但各族之间的绝对值存在差异。然而，还存在第二种关系，尽管有点令人不安。在所有配体组中，亲脂性最强的螯合剂总是毒性最大的。当前的研究重点是设计在保持铁清除效率的同时平衡亲脂性/毒性问题的配体。早期对(S)-4,5-二氢-2-(2-羟基-4-甲氧基苯基)-4-甲基-4-噻唑羧酸[(S)-4'-(CH(3)O)-DADFT, 6]的研究表明，这种甲醚在啮齿动物和灵长类动物中都是具有出色铁清除效率的配体；然而，它毒性太大。基于这一发现，合成了一种比6亲脂性更低、水溶性更高的配体，(S)-4,5-二氢-2-[2-羟基-4-(3,6,9-三氧杂癸氧基)苯基]-4-甲基-4-噻唑羧酸[(S)-4'-(HO)-DADFT-PE, 11]，一种聚醚类似物，以及它的乙酯和异丙酯。母体聚醚及其异丙酯和乙酯在啮齿动物和灵长类动物中均显示为高效的铁螯合剂。将11在啮齿动物中与去铁胺类似物(S)-4,5-二氢-2-(2,4-二羟基苯基)-4-甲基-4-噻唑羧酸[(S)-4'-(HO)-DADFT, 1]进行比较，发现聚醚更具耐受性，在肝脏中的浓度更高，而在肾脏中的浓度显著更低。肾脏中较低的药物水平与给予1的啮齿动物肾脏中所见的结构变化与给予11的啮齿动物肾脏中所见的结构变化之间的巨大差异一致。
