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Optimization of Substituted Phenoxyalkyl Pyridinium Oximes as Therapies for Organophosphate Poisoning

取代苯氧基烷基吡啶鎓肟治疗有机磷中毒的优化

基本信息

批准号：
10660985
负责人：
Janice Elaine Chambers
金额：
$ 67.29万
依托单位：
MISSISSIPPI STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10660985
关键词：
Accidents Acetylcholinesterase Advanced Development Affinity Animals Antidotes Atropine Attenuated Behavior Binding Proteins Brain Cavia Chemicals Chemistry Cholinesterase Inhibitors Clinical Chemistry Consultations Convulsions Data Development Dose Drug Interactions Drug Kinetics Evaluation Exposure to Future Goals Hematology Hepatic Human In Vitro Intellectual Property Laboratories Laboratory Animals Lead Legal patent Licensing Licensure Life Metabolism Methods Microsomes Miniature Swine Muscarinic Acetylcholine Receptor No-Observed-Adverse-Effect Level Organophosphates Oximes Pathologic Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Pharmacology Pharmacology and Toxicology Plasma Plasma Proteins Poison Poisoning Probability Property Property Rights Qualifying Rattus Recurrence Research Safety Sarin Seizures Series Solubility Solvents Specific qualifier value Testing Therapeutic Toxic effect Toxicology Tremor active method animal poison antagonist attenuation blood-brain barrier penetration commercialization dosage efficacy testing experimental study genotoxicity improved in vivo invention lead optimization lipophilicity male manufacture mass casualty meetings methylphosphonate nerve agent neuropathology neuroprotection novel organophosphate poisoning pharmacologic pre-Investigational New Drug meeting preservation respiratory response scale up sex

项目摘要

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.

7.项目摘要/摘要许多有机磷(OP)抗胆碱酯酶，如神经毒剂，都是剧毒的。恐怖分子涉及行动的行动或事故可能导致大规模伤亡，具有潜在的高致命性。这个目前的治疗方法包括毒扁豆碱受体拮抗剂阿托品和一种肟类复活剂抑制乙酰胆碱酯酶(美国的2-PAM)。然而，2-PAM并不总是有效的拯救生命和不能有效地穿透血脑屏障，因此2-PAM会使受害者受到较差的保护。一种改进的需要羟肟疗法来抵消神经毒剂的致命性，并帮助神经保护，以便两者生命和大脑功能可能会得到保护。我们的实验室已经发明、专利和许可了一个平台取代苯氧基烷基吡啶肟，已显示出比2-PAM更好的生存效率，并与2-PAM不同- PAM、高剂量高剂量染毒鼠癫痫样行为和神经病理学的减弱相关的神经毒剂代用品。在雄性豚鼠身上进行的针对沙林的有限研究也显示了有效性。在我们目前的中和铅鉴定U01中，有效化合物(活性物质)已经被从下到下选择一个先导和一个替补，并建议将肟酮20作为活性药物原料(原料药)。拟议的项目将建立在目前的生存效率、药代动力学和原料药的基础上。大鼠的毒性信息。最初，将开发一种用于空气污染防治的高级工具，作为更好的溶剂亲脂性原料药。一个药效学目标(目标1)将确定在大鼠(无论性别)中是否有较低剂量的原料药将有效地促进致命剂量的沙林替代品(硝基苯基异丙基)的存活甲基磷酸盐，NIMP；G试剂化学)和VX替代物(硝基苯乙基甲基磷酸盐， NEMP；V试剂化学)单独或与2-PAM结合。药代动力学(PK)目标(目标2)将测定原料药在新载体中的PK、血浆蛋白结合力和肝微粒体代谢并将引入一种更大的非啮齿动物试验物种--哥廷根小型猪的研究，两者都性别。肟毒性目标(目标3)将调查原料药对大体病理的剂量反应，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量和未观察到的不良反应水平以及体外遗传毒性以及细胞色素P450和转运蛋白的药物-药物相互作用。化学目标(目标4)将支持前面的3个目标通过提供NIMP、NEMP和原料药的合成，生产出具有改进的溶剂的新车属性，评估原料药的稳定性，并提供制造和化学制造的初步计划控制。所有研究都将是非GLP的，并将遵循FDA在IND前会议上的指导。最重要的是此铅优化项目的目标是提供优化的药理学和毒理学信息我们在两性两个物种中的铅肟将为原料药进入高级开发做好准备接近FDA的批准。