Mn(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin, (H₂O)MnTnHex-2-PyP⁵⁺ (MnHex) carrying long hexyl chains, is a lipophilic mimic of superoxide dismutase (SOD) and a redox-active drug candidate. MnHex crosses the blood–brain barrier, and improved neurologic outcome and decreased infarct size and inflammation in a rat middle cerebral artery occlusion (MCAO) ischemic stroke model. Yet, the dose and the therapeutic efficacy of Mn porphyrin were limited by an adverse effect of arterial hypotension. An equally lipophilic Fe analog, (OH)FeTnHex-2-PyP⁴⁺ (FeHex), is as redox-active and potent SOD mimic in vitro. With different coordination geometry of the metal site, FeHex has one hydroxo (OH) ligand (instead of water) bound to the Fe center in the axial position. It has ~2 orders of magnitude higher efficacy than MnHex in an SOD-deficient E. coli model of oxidative stress. In vivo, it does not cause arterial hypotension and is less toxic to mice. We thus evaluated FeHex versus MnHex in a rodent MCAO model. We first performed short- and long-term pharmacokinetics (PK) of both porphyrins in the plasma, brain, and liver of rats and mice. Given that damage to the brain during stroke occurs very rapidly, fast delivery of a sufficient dose of drug is important. Therefore, we aimed to demonstrate if, and how fast after reperfusion, Fe porphyrin reaches the brain relative to the Mn analog. A markedly different plasma half-life was found with FeHex (~23 h) than with MnHex (~1.4 h), which resulted in a more than 2-fold higher plasma exposure (AUC) in a 7-day twice-daily treatment of rats. The increased plasma half-life is explained by the much lower liver retention of FeHex than typically found in Mn analogs. In the brain, a 3-day mouse PK study showed similar levels of MnHex and FeHex. The same result was obtained in a 7-day rat PK study, despite the higher plasma exposure of FeHex. Importantly, in a short-term PK study with treatment starting 2 h post MCAO, both Fe- and Mn- analogs distributed at a higher level to the injured brain hemisphere, with a more pronounced effect observed with FeHex. While a 3-day mouse MCAO study suggested the efficacy of Fe porphyrin, in a 7-day rat MCAO study, Mn-, but not Fe porphyrin, was efficacious. The observed lack of FeHex efficacy was discussed in terms of significant differences in the chemistry of Fe vs the Mn center of metalloporphyrin; relative to MnHex, FeHex has the propensity for axial coordination, which in vivo would preclude the reactivity of the Fe center towards small reactive species.

中文翻译：

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啮齿动物缺血性中风（MCAO）模型中基于铁卟啉的SOD模拟和氧化还原活性化合物（OH）FeTnHex-2-PyP4 +：与Mn类似物（H2O）MnTnHex-2-PyP5 +相比，功效和药代动力学。

Mn（III）介孔四（Nn-己基吡啶-2-基）卟啉（H ₂ O）MnTnHex-2-PyP ⁵⁺（MnHex）带有长己基链，是超氧化物歧化酶（SOD）和具有氧化还原活性的候选药物。MnHex跨血脑屏障，在大鼠大脑中动脉闭塞（MCAO）缺血性中风模型中改善了神经系统结局，并减少了梗塞面积和炎症。然而，锰卟啉的剂量和治疗功效受到动脉低血压的不利影响。亲脂性相同的Fe类似物（OH）FeTnHex-2-PyP ⁴⁺（FeHex），在体外具有氧化还原活性和有效的SOD模仿作用。在金属位点的配位几何结构不同的情况下，FeHex在轴向位置具有一个与Fe中心键合的羟基（OH）配体（而不是水）。在缺乏SOD的氧化应激大肠杆菌模型中，它的功效比MnHex高约2个数量级。在体内，它不会引起动脉低血压，并且对小鼠的毒性较小。因此，我们评估了FeHex与啮齿动物MCAO模型中的MnHex。我们首先对大鼠和小鼠的血浆，大脑和肝脏中的卟啉进行了短期和长期药代动力学（PK）。鉴于中风期间对大脑的损害发生得非常迅速，因此快速递送足够剂量的药物非常重要。因此，我们旨在证明相对于Mn类似物，铁卟啉是否以及在再灌注后多快到达大脑。发现FeHex（〜23 h）与MnHex（〜1.4 h）的血浆半衰期明显不同，这导致在每天7天，每天两次的治疗中，血浆暴露（AUC）超过2倍以上。大鼠。血浆半衰期延长的原因是FeHex的肝脏保留率比Mn类似物低得多。在大脑中，为期3天的小鼠PK研究显示MnHex和FeHex的水平相似。尽管FeHex的血浆暴露量较高，但在为期7天的大鼠PK研究中也获得了相同的结果。重要的是，在MCAO后2小时开始的短期PK研究中，Fe和Mn类似物均以较高的水平分布在受伤的脑半球，而FeHex的作用更为明显。一项为期3天的小鼠MCAO研究表明铁卟啉的疗效，但在为期7天的大鼠MCAO研究中，Mn-而不是Fe卟啉是有效的。根据铁化学性质的显着差异讨论了观察到的FeHex功效不足 一项为期3天的小鼠MCAO研究表明了铁卟啉的功效，而在7天的大鼠MCAO研究中，Mn-而不是Fe卟啉是有效的。根据铁化学性质的显着差异讨论了观察到的FeHex功效不足 一项为期3天的小鼠MCAO研究表明了铁卟啉的功效，而在7天的大鼠MCAO研究中，Mn-而不是Fe卟啉是有效的。根据铁化学性质的显着差异讨论了观察到的FeHex功效不足 对金属卟啉的锰中心; 相对于MnHex，FeHex具有轴向配位的倾向，这将在体内排除Fe中心对小的反应物种的反应性。