Identification of Novel Brain-penetrating Phenoxyalkyl Pyridinium Oxime Countermeasures

新型脑穿透性苯氧基烷基吡啶肟对策的鉴定

• 批准号: 9928535
• 负责人: Janice Elaine Chambers
• 金额: $ 4.32万
• 依托单位: MISSISSIPPI STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9928535
• 关键词: Accidents; Acetylcholinesterase; Adolescent; Adult; Advanced Development; Animals; Atropine; Attenuated; Behavior; Binding Proteins; Blood - brain barrier anatomy; Brain; Brain Injuries; Bronchoconstriction; Budgets; Butyrylcholinesterase; Cavia; Cessation of life; Chemicals; Chemistry; Child; Cholinesterase Inhibitors; Data; Drug Kinetics; Erythrocytes; Event; Exposure to; Female; Future; Generations; Glutamates; Goals; Human; In Vitro; Insecticides; Laboratories; Lead; Legal patent; Life; Metabolism; Microsomes; Muscarinic Acetylcholine Receptor; Nature; Nervous System Trauma; Neuraxis; Organophosphates; Oximes; Paraoxon; Parathion; Permeability; Pharmacodynamics; Plasma; Plasma Proteins; Poisoning; Property; Rattus; Research; Respiratory Muscles; Safety; Sarin; Savings; Seizures; Series; Spasm; Specificity; Survivors; Terrorism; Testing; Therapeutic; Time; Toxic effect; Treatment Efficacy; Tremor; Violence; acute toxicity; attenuation; base; cholinergic; comparative efficacy; cytotoxicity; dosage; drug development; efficacy testing; genotoxicity; improved; in vivo; juvenile animal; lead optimization; male; mass casualty; methylphosphonate; nerve agent; neuropathology; novel; off-patent; preservation; prevent; respiratory; safety study; sex

7. Project Summary/Abstract Many of the organophosphate (OP) anticholinesterases are highly toxic and have been developed as either nerve agents or insecticides. Prolonged acetylcholinesterase (AChE) inhibition results in glutamate-induced seizures with subsequent permanent brain damage. Some OPs are relatively easy to synthesize and could become threat agents of great concern from potential terrorist action where the specific OP employed might not be immediately known. Terrorist actions or accidents could lead to mass casualties in adults and children of both sexes. The current therapy consists of the muscarinic receptor antagonist atropine and an oxime reactivator of the inhibited AChE (2-PAM in the US). However 2-PAM is not broad-spectrum and cannot effectively penetrate the blood brain barrier, so it would leave victims poorly protected against some OP chemistries and would not attenuate the hypercholinergic activity in the brain and resultant brain damage. Therefore an improved oxime therapeutic is needed which can counteract both nerve agent and insecticidal chemistries and can restore brain cholinergic function to attenuate or prevent long-term central nervous system damage, so that both life and brain function may be preserved. Our laboratories have invented and patented (US Patent 9,277,937) a platform of substituted phenoxyalkyl pyridinium oximes that have shown broader based survival efficacy than 2-PAM and also attenuation of signs of seizure-like behavior and neuropathology in male rats exposed to high levels of both nerve agent and insecticidal chemistries. Limited studies in male guinea pigs against sarin have also showed efficacy. Only limited preliminary information exists at present with respect to the novel oximes' pharmacokinetics and no information exists on their therapeutic efficacy in female or juvenile animals. Preliminary data indicate that combinations of a novel oxime and 2-PAM are more efficacious than the single oximes. A combination of these two or combinations of two novel oximes with different specificities for nerve agent and insecticidal chemistries could provide a broader spectrum of efficacy than single oximes and provide a more effective therapeutic in the event of mass casualties induced by an unidentified OP. Therefore this application proposes the generation of additional efficacy data against a highly relevant sarin surrogate (nitrophenyl isopropyl methylphosphonate, NIMP) and paraoxon (PXN; the active metabolite of the insecticide parathion) in adult female and juvenile (both sexes) rats, on our three most efficacious novel oximes and combinations of two oximes. Initial pharmacokinetic and initial oxime toxicity data will be generated. Lastly efficacy tests will be performed in male and female adult guinea pigs with sarin and VX. The goal of this Lead Identification project is to down-select to a lead and an alternate novel oxime or novel oxime binary combination that will be ready to enter into optimization studies through a subsequent Lead Optimization U01 project, that will move the novel oximes into advanced development toward FDA approval.

7.项目总结/摘要 许多有机磷（OP）抗胆碱酯酶是高毒性的，并已被开发为 神经毒剂或杀虫剂。长时间的乙酰胆碱酯酶（AChE）抑制导致谷氨酸诱导的 癫痫发作并导致永久性脑损伤一些OP相对容易合成， 成为潜在恐怖行动的重大威胁因素，其中所采用的具体行动可能 不能立即知道。恐怖主义行动或事故可能导致成人和儿童的大规模伤亡 男女都是目前的治疗包括毒蕈碱受体拮抗剂阿托品和肟 被抑制的AChE的再活化剂（在美国为2-PAM）。然而，2-PAM不是广谱的，不能 有效地穿透血脑屏障，所以它会让受害者对一些OP的保护很差 化学物质，并且不会减弱脑中的高胆碱能活性和由此产生的脑损伤。 因此，需要一种改进的肟治疗剂，其可以对抗神经毒剂和杀虫剂 化学和可以恢复大脑胆碱能功能，以减轻或防止长期中枢神经系统 这样，生命和大脑功能都可以得到保护。我们的实验室发明了 (US专利9，277，937）的取代的苯氧基烷基吡啶鎓肟的平台， 比2-PAM的生存疗效更好，并且还能减轻神经病变样行为和神经病理学体征 雄性大鼠暴露于高水平的神经毒剂和杀虫剂化学品。男性研究有限 豚鼠对沙林毒气的抵抗也显示出有效性。目前只有有限的初步资料， 关于新型肟类药物的药代动力学，没有关于其在女性中治疗效果的信息 或幼年动物。初步数据表明，一种新的肟和2-PAM的组合更多 比单一肟更有效。这两种肟的组合或两种新肟的组合， 神经毒剂和杀虫化学品的不同特异性可以提供更广泛的功效 并在由一种或多种肟类化合物引起的大规模伤亡事件中提供更有效的治疗。 因此，本申请建议生成针对高度不确定性的 相关沙林替代物（甲基膦酸硝基苯基异丙酯，NIMP）和对氧磷（PXN;活性 在成年雌性和幼年（两种性别）大鼠中，对我们三种最常见的 有效的新肟和两种肟的组合。初始药代动力学和初始肟毒性数据 将被生成。最后，将在雄性和雌性成年豚鼠中进行沙林和 VX.该铅识别项目的目标是向下选择一种铅和一种替代的新型肟或 新的肟二元组合，将准备进入优化研究，通过随后的铅 优化U 01项目，该项目将使新型肟进入FDA批准的高级开发阶段。