A Vitamin K analog countermeasure for organophosphate poisoning

摘要 Neuroene Treateutics公司发现了一种耐受性良好、穿透性好、非镇静的新型药物 是维生素K(VK)的小类似物，它模仿线粒体和 神经健康。我们的VK类似物在几种耐药癫痫动物模型中有效 帕金森氏症。我们的主要抗癫痫药物(ASD)是快速起效的，具有广谱抗癫痫作用 在几种耐药癫痫模型中具有活性，并具有线粒体保护作用。神经烯临床 候选作为一种快速有效的救援剂和长期的慢性治疗药物具有很大的潜力。VK类比是 在室温下干燥状态下非常稳定，允许在公共环境下储存较长的货架期 卫生突发事件或生物事件。 有机磷农药被广泛用作农药，但也是一种强有力的化学神经毒剂。 战争。外国对手拥有化学武器库存，并在过去使用过这些毒剂。运营部 不可逆地抑制乙酰胆碱酯酶。然而，它们也被证明抑制了其他 低剂量乙酰胆碱酯酶不受抑制的途径。氧化应激与线粒体 在低剂量OP时会出现功能障碍，已有研究表明OP化合物可引起线粒体的改变 膜电位并抑制产生ATP所需的线粒体复合体。虽然有几个 对于OP暴露的治疗，大多数都有不良副作用和/或窗口很窄 他们的毒品。尽管Neuroene的临床候选药物可以预防线粒体功能障碍，但它的主要毒性是 OP暴露，并且没有针对护理治疗标准的机制。神经烯临床 候选在小鼠中具有极好的耐受性，自然发生的VK没有上限/最大剂量 耐受剂量。Neuroene的临床候选药物可能代表着一种潜在的优于标准的替代方案 作为对OP暴露的护理，或作为标准护理治疗的辅助，通过针对额外的 OP中毒的作用机制。目的1.确定临床候选药物Neuroene的PK特性， 大鼠的安全剂量范围和最大耐受量。目的2.测定神经烯类的临床应用能力 改善大鼠二异丙基氟磷酸盐(DFP)SE的候选药物。目的3.测定神经烯的能力 临床候选改善大鼠梭曼中毒。Neuroene的临床候选药物是快速、广泛的- 光谱，并保护线粒体。这种化合物可以立即稳定并克服级联效应 因为行动组下毒。如果成功，Neuroene的药物可能成为一种两用的ASD，用于急性环境和 减少与OP中毒相关的长期后遗症。神经烯的临床候选药物可能会被广泛应用 商业上可用于改善美国的健康安全状况，因为我们的商业标志 在公共卫生紧急情况或生物事件期间可用的抗药性癫痫

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