A Vitamin K analog countermeasure for organophosphate poisoning

维生素 K 类似物治疗有机磷中毒的对策

基本信息

批准号：
10602913
负责人：
SHERINE S CHAN
金额：
$ 29.83万
依托单位：
NEUROENE THERAPEUTICS INC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-18 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10602913
关键词：
Acetylcholine Acetylcholinesterase Acute Adjuvant Animal Model Anticonvulsants Atropine Authorization documentation Benzodiazepines Brain Caring Chemical Warfare Agents Chemical Weapons Chemicals Chronic Clinical Cognitive Complex Dose Dose Limiting Drug usage Dryness Emergency treatment Ensure Enzyme Inhibition Epilepsy Event Frequencies Funding GABA Receptor Health Isoflurophate Lead Life Maximum Tolerated Dose Measures Membrane Potentials Midazolam Mitochondria Modeling Molecular Target Mus Muscarinic Acetylcholine Receptor National Institute of Allergy and Infectious Disease Neurologic Neurons Ohio Oral Organ Organophosphates Outcome Oxidative Stress Parkinson Disease Pathway interactions Patients Penetration Pesticides Pharmaceutical Preparations Poisoning Posture Production Property Rattus Research Rodent Security Seizures Site Soman Status Epilepticus Temperature Testing Therapeutic Time Toxic effect United States United States National Institutes of Health Universities Utah Vitamin K Work analog authority chemical countermeasure clinical candidate drug candidate fluorophosphate gamma-Aminobutyric Acid improved long-term sequelae mitochondrial dysfunction mitochondrial membrane nerve agent neuroprotection novel organophosphate poisoning prevent programs public health emergency research and development screening program sedative side effect standard care standard of care vitamin analog

项目摘要

Abstract Neuroene Therapeutics has discovered a novel class of well-tolerated, brain-penetrating, non-sedating compounds that are small analogs of Vitamin K (VK) that mimic the form of VK needed for mitochondrial and neurological health. Our VK analogs are effective in several animal models of pharmacoresistant seizures and Parkinson's disease. Our lead antiseizure drug (ASD) candidate is fast-acting, has broad-spectrum antiseizure activity in several pharmacoresistant seizure models, and is mitochondrial protective. Neuroene's clinical candidate has great potential as a fast-acting rescue agent and long-term chronic therapeutic. VK analogs are very stable in dry form at room temperature, allowing for long shelf life for stockpiling in the event of a public health emergency or bio-incident. Organophosphate agents (OPs) are used widely as pesticides, but are also potent nerve agents for chemical warfare. Foreign adversaries have stockpiles of chemical weapons and have used these agents in the past. OPs irreversibly inhibit the enzyme acetylcholinesterase. However, they have also been shown to inhibit other pathways at low doses where acetylcholinesterase is not inhibited. Oxidative stress and mitochondrial dysfunction occur at low OP doses, and it has been shown that OP compounds induce changes in mitochondrial membrane potential and inhibit mitochondrial complexes needed for ATP production. While there are several treatments for OP exposure, most have undesirable side effects and/or have a very narrow window to administer their drug. Whereas Neuroene's clinical candidate protects against mitochondrial dysfunction, a major toxicity of OP exposure, and does not target the mechanisms of the standard of care treatments. Neuroene's clinical candidate has excellent tolerability in mice, and naturally occurring VK has no upper dose limit/maximum tolerated dose. Neuroene's clinical candidate could represent a potentially superior alternative to the standard of care for OP exposure, or as an adjuvant to the standard treatment of care, by targeting an additional mechanism of action for OP-poisoning. Aim 1. Determine the PK properties of Neuroene's clinical candidate, safe dosing range and maximum tolerated dose in rats. Aim 2. Determine the ability of Neuroene's clinical candidate to ameliorate diisopropyl fluorophosphate (DFP) SE in rats. Aim 3. Determine the ability of Neuroene's clinical candidate to ameliorate soman poisoning in rats. Neuroene's clinical candidate is fast-acting, broad- spectrum, and protects mitochondria. This compound could immediately stabilize and override cascading effects due to poisoning by OPs. If successful, Neuroene's drug could be a dual-purpose ASD for acute settings and to reduce long-term sequela associated with OP poisoning. Neuroene's clinical candidate could be made widely available commercially to improve the United States' health security posture due our commercial indications for pharmacoresistant seizures, while being available during a public health emergency or bio-incident

抽象的 Neuroene Therapeutics 发现了一类新型的耐受性良好、具有脑穿透性、非镇静作用的药物维生素 K (VK) 的小类似物，模仿线粒体和线粒体所需的 VK 形式。神经系统健康。我们的 VK 类似物在多种耐药性癫痫动物模型中有效帕金森病。我们的主要抗癫痫药物 (ASD) 候选药物起效快，具有广谱抗癫痫作用在几种耐药性癫痫模型中具有活性，并且具有线粒体保护作用。 Neurone的临床候选人作为快速作用的救援剂和长期慢性治疗剂具有巨大的潜力。 VK 类似物是在室温下以干燥形式非常稳定，可在公共场合储存较长的保质期卫生紧急情况或生物事件。有机磷制剂 (OP) 广泛用作杀虫剂，但也是化学物质的强效神经毒剂战争。外国对手拥有化学武器库存，并且过去曾使用过这些制剂。 OP 不可逆地抑制乙酰胆碱酯酶。然而，它们也被证明可以抑制其他低剂量时乙酰胆碱酯酶不被抑制的途径。氧化应激和线粒体低 OP 剂量时会发生功能障碍，并且已经表明 OP 化合物会引起线粒体变化膜电位并抑制 ATP 产生所需的线粒体复合物。虽然有几个 OP 暴露的治疗方法，大多数都有不良副作用和/或给药窗口非常窄他们的药物。虽然 Neuroene 的临床候选药物可以防止线粒体功能障碍，但线粒体功能障碍是线粒体的主要毒性。 OP 暴露，并不针对标准护理治疗的机制。 Neurone的临床候选药物在小鼠中具有出色的耐受性，天然存在的 VK 没有剂量上限/最大剂量耐受剂量。 Neuroene 的临床候选药物可能是标准药物的潜在更好替代品 OP 暴露的护理，或作为标准护理治疗的辅助手段，通过针对额外的 OP中毒的作用机制。目标 1. 确定 Neuroene 临床候选药物的 PK 特性，大鼠的安全剂量范围和最大耐受剂量。目标 2. 确定 Neuroene 的临床能力改善大鼠氟磷酸二异丙酯 (DFP) SE 的候选药物。目标 3. 确定 Neuroene 的能力改善大鼠梭曼中毒的临床候选者。 Neuroene 的临床候选药物起效快、作用广泛谱，并保护线粒体。这种化合物可以立即稳定并克服级联效应由于OP中毒。如果成功，Neuroene 的药物可能成为一种双用途 ASD，用于急性情况和减少与 OP 中毒相关的长期后遗症。 Neuroene 的临床候选药物可以广泛应用由于我们的商业适应症，可在商业上改善美国的健康安全状况耐药性癫痫发作，同时在公共卫生紧急情况或生物事件期间可用