Faller B, Spanka C, Sergejew T, Tschinke V
Research Department, Novartis Pharma AG, WKL-122.P.33, CH-4002 Basel, Switzerland.
J Med Chem. 2000 Apr 20;43(8):1467-75. doi: 10.1021/jm990261n.
Physicochemical analysis and Monte Carlo simulations were used to identify structural features which prevent oral absorption of HBED, a potent iron chelator. In water the dominant conformations of HBED involve the hydrophobic collapse of the two aromatic rings. These conformations are favored in polar media because they expose the polar phenolic hydroxy groups to the solvent and partially shield the nonpolar aromatic rings. In a less polar solvent such as chloroform, a symmetrical H-bond network between the carboxylates and the amines dominates the conformational space. This leads to the exposure of the phenolic hydroxy groups to the solvent, which is unfavorable for solvation. The low solubility of HBED in nonpolar solvents was confirmed experimentally by determination of the partition coefficients in octanol, chloroform, and cyclohexane and may explain the poor membrane permeability of this compound. The high conformational stability which disfavors partitioning into phospholipids is mainly due to the symmetrical H-bond network. Potentiometric titrations of a monoester of HBED in MeOH/water indicate that the protonation sequence was changed compared to that of the parent compound, suggesting that the symmetrical H-bond network was disrupted. Conformational analysis in chloroform confirmed that, in contrast to HBED, no symmetric interaction between the carboxylate and the nitrogen amines is possible in the half-ester and a variety of conformations which allow partial shielding of the polar phenolic OH groups are energetically possible. This theoretical model predicting a better solubility of the half-esters in nonpolar solvents was supported by the large increase in the partition coefficients in octanol, chloroform, and cyclohexane measured experimentally. The high absorbability predicted by physicochemical and computer simulation methods was corroborated by in vivo experiments in marmoset monkeys where the monoethyl ester derivative of HBED was well-absorbed orally while the parent compound was nearly ineffective in the same model.
采用物理化学分析和蒙特卡罗模拟来确定阻碍强效铁螯合剂HBED口服吸收的结构特征。在水中，HBED的主要构象涉及两个芳香环的疏水塌缩。这些构象在极性介质中更受青睐，因为它们使极性酚羟基暴露于溶剂中，并部分屏蔽非极性芳香环。在极性较小的溶剂如氯仿中，羧酸盐和胺之间的对称氢键网络主导了构象空间。这导致酚羟基暴露于溶剂中，不利于溶剂化。通过测定HBED在辛醇、氯仿和环己烷中的分配系数，实验证实了其在非极性溶剂中的低溶解度，这可能解释了该化合物较差的膜通透性。不利于分配到磷脂中的高构象稳定性主要归因于对称氢键网络。HBED单酯在甲醇/水中的电位滴定表明，与母体化合物相比，质子化顺序发生了变化，这表明对称氢键网络被破坏。氯仿中的构象分析证实，与HBED不同，半酯中羧酸盐和氮胺之间不可能存在对称相互作用，并且存在多种构象，这些构象能使极性酚羟基部分被屏蔽，在能量上是可行的。通过实验测得的辛醇、氯仿和环己烷中分配系数的大幅增加，支持了该理论模型预测的半酯在非极性溶剂中具有更好的溶解度。物理化学和计算机模拟方法预测的高吸收性在狨猴体内实验中得到了证实，在该实验中，HBED的单乙酯衍生物口服吸收良好，而母体化合物在同一模型中几乎无效。
