Refined uncharged Bis-Oximes for Rapid CNS Reactivation of OP-Inhibited hAChE.

用于OP抑制的HAChE的CNS快速重新激活的精制不带电荷的二-肟。 项目摘要。有机磷(OP)的重新激活抑制了乙酰胆碱酯酶 抗OP解毒剂(AChE)是治疗神经性毒剂或OP中毒的唯一真正药物 接触杀虫剂。目前批准的和正在试验的大多数抗OP解毒剂是 攻击和去除与其共价连接的OP的磷原子的亲核醛肟 酸痛活性丝氨酸。 改善目前OP中毒解毒治疗的一个重要途径是通过创造 在外周组织和中枢神经系统中，重新激活的解毒剂将达到被抑制的AChE， 目前批准的解毒剂不能进入的地方。 我们在体外设计并表征了七个改进的无电荷LG双肟。 一种新型支架的解毒剂，对沙林、环沙林、VX和对氧磷有更好的再激活作用 对HAChE的抑制作用强于RS194B。 LG双肟支架的独特的新特征是可电离的环胺和 醛肟基团允许单一化合物在多达16种不同的离子形式之间保持平衡 在亲核反应性和构象上。 我们现在建议探索并从结构上优化这种新的解毒剂支架，基于我们的 尚未发表的LG双肟和最快吡啶类化合物的X射线结构模板 BIS-OMM4。模板将由非弹性中子散射(INS)数据提供信息。我们会 在体外测试精制化合物对OP-HAChE偶联物的再激活效力 评估小鼠中最有希望的复活剂的初始PK谱。BEST CREED的互动 患有AChE的候选人将接受X光和INS检查。

Refined uncharged bis-oximes for rapid CNS reactivation of OP-inhibited hAChE. Project Summary. Reactivation of organophosphate (OP) inhibited acetylcholinesterase (AChE) by anti-OP antidotes is the only true remedy for OP intoxication in nerve agent or OP pesticide exposure. Most of currently approved and experimental anti-OP antidotes are nucleophilic aldoximes that attack and remove phosphorus atom of OPs covalently attached to the AChE active serine. One significant way of improving current antidotal treatment of OP intoxication is by creation of reactivating antidotes that will reach inhibited AChE in peripheral tissue but also in the CNS, where currently approved antidotes cannot enter. We have designed and characterized in vitro seven improved uncharged LG bis-oxime antidotes of a novel scaffold, with better reactivation of sarin, cyclosarin, VX and paraoxon inhibited hAChE than RS194B. The uniquely novel feature of the LG bis-oxime scaffold is that ionizable cyclic amines and aldoxime groups allow single compound to equilibrate between up to sixteen ionic forms differing in nucleophilic reactivity and in conformation. We now propose to explore and structurally optimize this new antidote scaffold, based on our yet unpublished X-ray structural templates of both LG bis-oximes and of the fastest pyridinium bis-oxime MMB4. Templates will be informed by inelastic neutron scattering (INS) data. We will test refined compounds for reactivation potency against OP-hAChE conjugates in vitro and will evaluate the initial PK profile of most promissing reactivators in mice. Interaction of best refined candidates with AChE will be explored by X-ray and INS.