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Pharmacokinetic Evaluation of Brain Penetrating Morpholine-3-hydroxy-2-pyridine Oxime as an Antidote for Nerve Agent Poisoning.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-02-27 , DOI: 10.1021/acschemneuro.0c00032 Tamara Zorbaz 1 , Petra Mišetić 2 , Nicolas Probst 3 , Suzana Žunec 1 , Antonio Zandona 1 , Gordana Mendaš 1 , Vedran Micek 1 , Nikolina Maček Hrvat 1 , Maja Katalinić 1 , Anissa Braïki 3 , Ludovic Jean 3 , Pierre-Yves Renard 3 , Vesna Gabelica Marković 4 , Zrinka Kovarik 1
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-02-27 , DOI: 10.1021/acschemneuro.0c00032 Tamara Zorbaz 1 , Petra Mišetić 2 , Nicolas Probst 3 , Suzana Žunec 1 , Antonio Zandona 1 , Gordana Mendaš 1 , Vedran Micek 1 , Nikolina Maček Hrvat 1 , Maja Katalinić 1 , Anissa Braïki 3 , Ludovic Jean 3 , Pierre-Yves Renard 3 , Vesna Gabelica Marković 4 , Zrinka Kovarik 1
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Nerve agents, the deadliest chemical warfare agents, are potent inhibitors of acetylcholinesterase (AChE) and cause rapid cholinergic crisis with serious symptoms of poisoning. Oxime reactivators of AChE are used in medical practice in treatment of nerve agent poisoning, but the search for novel improved reactivators with central activity is an ongoing pursuit. Among the numerous oximes synthesized, in vitro reactivation is a standard approach in biological evaluation with little attention given to the pharmacokinetic properties of the compounds. This study reports a comprehensive physicochemical, pharmacokinetic, and safety profiling of five 3-hydroxy-2-pyridine aldoximes, which were recently shown to be potent AChE reactivators. The oxime JR595 was singled out as highly metabolically stable in human liver microsomes and non-cytotoxic oxime for SH-SY5Y neuroblastoma and 1321N1 astrocytoma cell lines and its pharmacokinetic profile was determined after intramuscular administration in mice. JR595 was rapidly absorbed into blood after 15 min with simultaneous distribution to the brain at up to about 40% of its blood concentration; however, it was eliminated both from the brain and blood within an hour. In addition, the MDCKII-MDR1 cell line assay showed that oxime JR595 was not a P-glycoprotein efflux pump substrate. Furthermore, preliminary antidotal study against multiple LD50 doses of VX and sarin in mice showed the potential of JR595 to provide desirable therapeutic outcomes with future improvements in its circulation time.
中文翻译：
穿透性吗啉-3-羟基-2-吡啶肟作为神经毒剂解毒剂的药代动力学评价。
神经药是最致命的化学战剂，是乙酰胆碱酯酶（AChE）的有效抑制剂，可引起严重的中毒症状，引起快速的胆碱能危象。在医学实践中，AChE的肟活化剂被用于治疗神经毒剂中毒，但是寻找具有中枢活性的新型改良的活化剂仍是一项持续的追求。在合成的众多肟中，体外再活化是生物学评估中的标准方法，很少关注化合物的药代动力学特性。这项研究报告了五种3-羟基-2-吡啶醛醛肟的综合物理化学，药代动力学和安全性分析，最近发现它们是有效的AChE活化剂。肟JR595在人肝微粒体中具有高代谢稳定性，对SH-SY5Y神经母细胞瘤和1321N1星形细胞瘤细胞系具有非细胞毒性肟，并在小鼠体内肌肉注射后确定了其药代动力学特征。15分钟后，JR595被迅速吸收到血液中，并同时以高达其血液浓度的40％分布到大脑；但是，它在一小时内就从大脑和血液中消除了。另外，MDCKII-MDR1细胞系分析表明肟JR595不是P-糖蛋白外排泵底物。此外，针对小鼠的多种LD50剂量的VX和沙林蛋白的初步解毒研究表明，JR595可以提供理想的治疗效果，并有可能改善其循环时间。
更新日期：2020-03-12
中文翻译：
穿透性吗啉-3-羟基-2-吡啶肟作为神经毒剂解毒剂的药代动力学评价。
神经药是最致命的化学战剂，是乙酰胆碱酯酶（AChE）的有效抑制剂，可引起严重的中毒症状，引起快速的胆碱能危象。在医学实践中，AChE的肟活化剂被用于治疗神经毒剂中毒，但是寻找具有中枢活性的新型改良的活化剂仍是一项持续的追求。在合成的众多肟中，体外再活化是生物学评估中的标准方法，很少关注化合物的药代动力学特性。这项研究报告了五种3-羟基-2-吡啶醛醛肟的综合物理化学，药代动力学和安全性分析，最近发现它们是有效的AChE活化剂。肟JR595在人肝微粒体中具有高代谢稳定性，对SH-SY5Y神经母细胞瘤和1321N1星形细胞瘤细胞系具有非细胞毒性肟，并在小鼠体内肌肉注射后确定了其药代动力学特征。15分钟后，JR595被迅速吸收到血液中，并同时以高达其血液浓度的40％分布到大脑；但是，它在一小时内就从大脑和血液中消除了。另外，MDCKII-MDR1细胞系分析表明肟JR595不是P-糖蛋白外排泵底物。此外，针对小鼠的多种LD50剂量的VX和沙林蛋白的初步解毒研究表明，JR595可以提供理想的治疗效果，并有可能改善其循环时间。
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