Efficacy of novel phenoxyalkyl pyridinium oximes as brain-penetrating reactivators of cholinesterase inhibited by surrogates of sarin and VX
Efficacy of novel phenoxyalkyl pyridinium oximes as brain-penetrating reactivators of cholinesterase inhibited by surrogates of sarin and VX
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DOI：
10.1016/j.cbi.2016.07.004
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发表时间：
2016-11-25
影响因子：
5.1
通讯作者：
Ross, Matthew K.
中科院分区：
文献类型：
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作者：
Chambers, Janice E.;Chambers, Howard W.;Ross, Matthew K.
吡啶肟类化合物具有很强的亲核性，是有机磷抑制的胆碱酯酶(ChE)的有效复活剂。然而，目前的肟类再活化剂在穿越血脑屏障和重新激活完整生物体中的脑胆碱酯酶方面无效。我们的实验室已经开发了一系列取代的苯氧基烷基吡啶肟(美国专利9,227,937 B2)，目的是识别有效穿越血脑屏障的复活剂。该系列中的前35个被发现与在牛脑制剂中被沙林替代物(邻苯二甲酰亚胺基异丙基甲基磷酸盐，PIMP)或VX替代物(硝基苯乙基甲基膦，NEMP)抑制的ChE复活剂具有类似的体外效果，正如以前在大鼠脑标本中观察到的那样。其中一些新的肟类化合物已经显示出能够降低使用高亚致死剂量的沙林替代品(硝基苯基异丙基甲基磷酸盐，NIMP)或VX替代品NEMP治疗的大鼠大脑中ChE抑制水平。在给药后2小时，再激活水平高达35%，而目前批准的治疗药物2-PAM在大脑ChE抑制方面没有减少。此外，有证据表明，几种更有效的新型肟类药物可以减轻癫痫样行为，但不包括2-PAM。因此，这些新的肟类已经证明了能够重新激活来自两个物种的大脑制剂中被抑制的胆碱酯酶，体内数据支持它们进入大脑并提供治疗作用的能力。这些新的肟类化合物有可能被开发成神经毒剂治疗的改进解毒剂。(C)2016爱思唯尔爱尔兰有限公司。保留所有权利。
Pyridinium oximes are strong nucleophiles and many are effective reactivators of organophosphate-inhibited cholinesterase (ChE). However, the current oxime reactivators are ineffective at crossing the blood-brain barrier and reactivating brain ChE in the intact organism. Our laboratories have developed a series of substituted phenoxyalkyl pyridinium oximes (US patent 9,227,937 B2) with the goal of identifying reactivators effective in crossing the blood-brain barrier. The first 35 of the series were found to have similar in vitro efficacy as reactivators of ChE inhibited by a sarin surrogate (phthalimidyl isopropyl methylphosphonate, PIMP) or a VX surrogate (nitrophenyl ethyl methylphosphonate, NEMP) in bovine brain preparations as previously observed in rat brain preparations. A number of these novel oximes have shown the ability to decrease the level of ChE inhibition in the brains of rats treated with a high sublethal dosage of either a sarin surrogate (nitrophenyl isopropyl methylphosphonate, NIMP) or the VX surrogate NEMP. Levels of reactivation at 2 h after oxime administration were up to 35% while the currently approved therapeutic, 2-PAM, yielded no reduction in brain ChE inhibition. In addition, there was evidence of attenuation of seizure-like behavior with several of the more effective novel oximes, but not 2-PAM. Therefore these novel oximes have demonstrated an ability to reactivate inhibited ChE in brain preparations from two species and in vivo data support their ability to enter the brain and provide a therapeutic action. These novel oximes have the potential to be developed into improved antidotes for nerve agent therapy. (C) 2016 Elsevier Ireland Ltd. All rights reserved.