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

用于快速 CNS 重新激活 OP 抑制的 hAChE 的精制不带电双肟。

• 批准号: 10582723
• 负责人: Zoran Radic
• 金额: $ 19.27万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582723
• 关键词: Acetylcholinesterase; Address; Antidotes; Central Nervous System; Chemical Weapons; Complex; Data; Development; Dose; Evaluation; Generations; Human; In Vitro; Individual; Intoxication; Molecular Conformation; Mus; Neutrons; Organophosphates; Oximes; Oxygen; Paraoxon; Peripheral; Pesticides; Phosphorus; Recovery; Reporting; Roentgen Rays; Sarin; Security; Serine; Structure; Testing; Tissues; Treatment Efficacy; arm; blood-brain barrier penetration; cyclic amine; cyclosarin; design; efficacy testing; flexibility; improved; in vitro testing; in vivo; nerve agent; nonhuman primate; novel; pesticide exposure; phosphoramidate; prevent; scaffold

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 We now propose to explore and structurally optimize this new antidote scaffold, based on our yet unpublished X-ray structural templates of both LG bis-oximes and of the fastest pyridinium bis-oxime MMB4.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.

精制的不带电荷的双肟，用于OP抑制的hAChE的快速CNS再活化。 项目摘要。有机磷（OP）抑制乙酰胆碱酯酶的再活化 （乙酰胆碱酯酶）的抗OP解毒剂是唯一真正的补救措施OP中毒的神经毒剂或OP 农药暴露大多数目前批准的和实验性的抗OP解毒剂是 亲核醛肟攻击并除去共价连接到 乙酰胆碱酯酶活性丝氨酸。 改善目前OP中毒解毒治疗的一个重要方法是创造 重新激活解毒剂，将达到抑制乙酰胆碱酯酶在外周组织，但也在中枢神经系统， 目前批准的解毒剂不能进入 我们设计并在体外表征了七种改进的不带电LG双肟 一种新型支架的解毒剂，对沙林、环沙林、VX和对氧磷具有更好的再活化作用 对hAChE的抑制作用优于RS 194 B。 LG双肟支架的独特新颖特征是可电离的环胺和 醛肟基团允许单个化合物在多达16种不同的离子形式之间平衡， 亲核反应性和构象。 我们现在建议探索和结构优化这种新的解毒剂支架，基于我们的 LG双肟和最快的吡啶鎓的尚未发表的X射线结构模板 双肟MMB 4.模板将由非弹性中子散射（INS）数据提供信息。我们将 在体外测试精制化合物对OP-hAChE缀合物的再活化效力， 评价小鼠中最有希望的再激活剂的初始PK特征。最佳精炼的相互作用 AChE患者将接受X线和INS检查。