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/摘要许多有机磷酸盐（OP）抗胆碱酯酶，例如神经剂，都是剧毒的。恐怖分子涉及的行动或事故可能会导致大规模伤亡，潜在的杀伤力可能很高。这当前的疗法由毒蕈碱受体拮抗剂阿托品和氧化物重新激活剂组成抑制乙酰胆碱酯酶（美国2-PAM）。但是，2-PAM并不总是有效地挽救生命，并且无法有效地穿透血脑屏障，因此2-PAM可以使可怕的受到严格的保护。改进需要摄影治疗以抵消神经剂的致死性并有助于神经保护，因此可以保留生活和大脑功能。我们的实验室发明，专利和许可取代的苯氧基烷基吡啶量比2-PAM表现出更好的生存效率，与2--不同 PAM，暴露于高水平的大鼠中癫痫发作行为和神经病理学的迹象的衰减相关的神经毒剂代理。在针对沙林的雄性豚鼠的研究有限也显示出有效性。使用我们当前的抵抗铅识别U01，有效化合物（“活性”）已经向下选择的铅和替代方案，将Oxime 20作为活性药物提出成分（API）。拟议的项目将基于当前的生存效率，药代动力学和API 大鼠的毒性信息。最初，将开发API的超级工具作为更好的解决方案亲脂性API。药效目标（AIM 1）将在大鼠（两性）中确定是否较低剂量 API将有效地促进sarin替代物（硝基苯基）致死剂量的存活率甲膦酸盐，NIMP； G剂化学）和VX替代物（亚硝基苯基甲基膦酸乙酯， nemp; v代理化学）单独或与2-PAM结合使用。药代动力学（PK）AIM（AIM 2）将确定新车辆中API的PK，等离子体蛋白结合和肝微粒体代谢中的PK 两性的大鼠，将引入对较大的非塑料测试物种的研究，性别。氧毒性目的（AIM 3）将研究API的剂量反应，以使病理总体病理，性别病理学，临床化学和血液学不良导致两性的大鼠和小鼠确定最大耐受剂量和无观察到的不良影响水平以及体外遗传毒性和CYP和转运蛋白的药物相互作用。化学目标（AIM 4）将支持前3个目标通过提供NIMP，NEMP和API的合成，生产具有改进溶液的新车辆属性，评估API稳定性并为制造和化学制造提供初始计划控件。所有研究将是非GLP，并将遵循预先会议的FDA指导。总体该铅优化项目的目标是提供优化的药物和毒理学信息我们在两个物种的两个性别中的铅氧，它们将使API准备进入先进的发展迈向FDA批准。