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 We now propose to explore and structurally optimize this new antidote scaffold, based on our yet unpublished X-ray structural templates of both LG bis-oximes and of the fastest pyridinium bis-oxime MMB4.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

精制的未加成双氧化物，用于op抑制的Hache快速CNS重新激活。 项目摘要。有机磷酸盐（OP）抑制乙酰胆碱酯酶的重生 （ACHE）通过抗OP解毒剂是神经剂或OP中OP中毒的唯一真正疗法 农药暴露。当前大多数批准和实验性抗OP解毒剂是 亲核藻类攻击和去除行动的磷原子，共价附着在 ACHE活性丝氨酸。 改善当前对OP中毒的解毒疗法的一种重要方法是创建 重新激活的解毒剂将在周围组织中抑制ACHE，但也会在中枢神经系统中抑制ACHE 目前批准的解毒剂无法输入。 我们已经设计和表征了体外七个改进的未充电LG BIS-OXIME 新型脚手架的解毒剂，沙林，环糖素，VX和paraoxon更好地重新激活 抑制Hache比RS194B。 LG Bis-Oxime支架的独特新颖特征是可电离的环状胺和 藻类组允许单个化合物在多达16个离子形式之间平衡不同 在亲核反应性和构象中。 现在，我们建议根据我们的 但未发表的LG BIS-OXIMES和最快的吡啶菌的未发表的X射线结构模板 BIS-OXIME MMB4。模板将通过非弹性中子散射（INS）数据告知。我们将 测试精制化合物在体外针对OP-HACHE偶联物的重新激活效力，并将 评估小鼠中大多数备用重新激活器的初始PK分布。最佳精制的相互作用 X射线和INS将探索患有疼痛的候选人。