Optimization of Substituted Phenoxyalkyl Pyridinium Oximes as Therapies for Organophosphate Poisoning

7. 项目总结/摘要 许多有机磷酸酯 (OP) 抗胆碱酯酶药物（例如神经毒剂）具有剧毒。恐怖分子 涉及 OP 的行动或事故可能会导致大规模人员伤亡，并具有潜在的高致死率。的 目前的治疗方法包括毒蕈碱受体拮抗剂阿托品和肟再激活剂 抑制乙酰胆碱酯酶（美国为 2-PAM）。然而，2-PAM 并不总是能有效拯救生命 无法有效穿透血脑屏障，因此 2-PAM 可能使受害者得不到很好的保护。一个改进的 需要肟治疗来抵消神经毒剂的杀伤力并协助神经保护，以便两者 生命和大脑功能可能得以保留。我们的实验室已经发明了一个平台，并获得了专利和许可 取代的苯氧基烷基吡啶鎓肟比 2-PAM 表现出更好的生存功效，并且与 2-PAM 不同 PAM，暴露于高水平高剂量的大鼠中癫痫样行为和神经病理学迹象的减弱 相关神经毒剂替代物。对雄性豚鼠进行的针对沙林毒气的有限研究也显示了其功效。 通过我们当前的 CounterACT 先导物鉴定 U01，有效化合物（“活性物质”）已被 被下调为先导药物和替代药物，Oxime 20 被提议作为活性药物 成分（API）。拟议的项目将建立在目前的生存功效、药代动力学和 API 的基础上 大鼠的毒性信息。最初，将开发 API 的优质载体，作为更好的溶剂 亲脂性 API。药效学目标（目标 1）将确定大鼠（雌雄）是否需要较低剂量的 该 API 将有效促进致死剂量的沙林替代品（硝基苯基异丙酯）的存活率 膦酸甲酯，NIMP； G 剂化学）和 VX 替代物（硝基苯基乙基甲基膦酸酯， NEMP； V剂化学）单独或与2-PAM组合。药代动力学 (PK) 目标（目标 2）将 确定新载体中 API 的 PK、血浆蛋白结合和肝微粒体代谢 两种性别的老鼠，并将引入对更大的非啮齿动物测试物种——哥廷根迷你猪的研究，两者 性别。肟毒性目标（目标 3）将调查 API 的总体病理剂量反应、 对两种性别的大鼠和小型猪的组织病理学、临床化学和血液学不良结果 确定最大耐受剂量和未观察到不良反应水平，以及体外遗传毒性 以及 CYP 和转运蛋白的药物相互作用。化学目标（目标 4）将支持之前的 3 个目标 通过提供 NIMP、NEMP 和 API 的合成，生产具有改进溶剂的新型车辆 特性，评估 API 稳定性，并为制造和化学制造提供初步计划 控制。所有研究都将是非 GLP 的，并将遵循 FDA IND 前会议的指导。首要的 该先导物优化项目的目标是提供优化的药理学和毒理学信息 我们的两个物种的两性的铅肟将为 API 进入高级开发做好准备 争取 FDA 批准。

7. Project Summary/Abstract Many of the organophosphate (OP) anticholinesterases, such as nerve agents, are highly toxic. Terrorist actions or accidents involving OPs could lead to mass casualties with potentially high levels of lethality. The current therapy consists of the muscarinic receptor antagonist atropine and an oxime reactivator of the inhibited acetylcholinesterase (2-PAM in the US). However, 2-PAM is not always effective at saving lives and cannot effectively penetrate the blood brain barrier, so 2-PAM can leave victims poorly protected. An improved oxime therapeutic is needed to counteract nerve agent lethality and assist with neuroprotection, so that both life and brain function may be preserved. Our laboratories have invented, patented and licensed a platform of substituted phenoxyalkyl pyridinium oximes that have shown better survival efficacy than 2-PAM and, unlike 2- PAM, attenuation of signs of seizure-like behavior and neuropathology in rats exposed to high levels of highly relevant nerve agent surrogates. Limited studies in male guinea pigs against sarin have also shown efficacy. With our current CounterACT Lead Identification U01 the efficacious compounds (the “actives”) have been down-selected to a lead and an alternate, with Oxime 20 being proposed as the Active Pharmaceutical Ingredient (API). The proposed project will build on the present survival efficacy, pharmacokinetic and API toxicity information in rats. Initially a superior vehicle for the API will be developed as a better solvent for the lipophilic API. A pharmacodynamic aim (Aim 1) will determine in rats (both sexes) whether a lower dosage of the API will be effective in promoting survival of lethal dosages of a sarin surrogate (nitrophenyl isopropyl methylphosphonate, NIMP; a G agent chemistry) and a VX surrogate (nitrophenyl ethyl methylphosphonate, NEMP; a V agent chemistry) alone or in combination with 2-PAM. A pharmacokinetic (PK) aim (Aim 2) will determine the PK of the API in the new vehicle, plasma protein binding and hepatic microsomal metabolism in rats of both sexes and will introduce studies of a larger non-rodent test species, the Gottingen minipig, both sexes. An oxime toxicity aim (Aim 3) will investigate dose responses of the API for gross pathological, histopathological, clinical chemistry and hematology adverse results in rats and minipigs of both sexes to identify a Maximum Tolerated Dosage and a No Observed Adverse Effect Level, as well as in vitro genotoxicity and drug-drug interactions for CYPs and transporters. A chemistry aim (Aim 4) will support the previous 3 aims by providing the synthesis of NIMP, NEMP and the API, produce a new vehicle with improved solvent properties, evaluate API stability, and provide initial plans for manufacturing and Chemical Manufacturing Controls. All studies will be non-GLP and will follow FDA guidance from pre-IND meetings. The overarching goal of this Lead Optimization project is to provide optimized pharmacological and toxicological information on our lead oxime in both sexes of two species that will prepare the API to move into advanced development toward FDA approval.