Optimization of EP2 Antagonists for Post-Seizure Cognitive Deficits

条款摘要 癫痫是继中风、阿尔茨海默病和偏头痛之后第四大最常见的神经系统疾病， 伴随着认知缺陷认知共病大大降低了患有糖尿病的人的生活质量 癫痫虽然有一些抗癫痫药物是可用的，没有批准的药物减轻认知 问题或疾病的进展。炎症是包括癫痫在内的所有慢性疾病的组成部分， 并且是包括环氧合酶-2（考克斯-2）在内的几种广泛信号级联的结果。我们有 表明前列腺素E2的EP 2受体的激活是血脑屏障渗漏的原因， 大多数炎症反应、神经元损伤和认知缺陷都是由乳腺癌引起的考克斯-2 脑内感应我们已经合成并测试了超过500种化合物作为竞争性拮抗剂， 人EP 2受体，并在三只动物中证明了两种研究先导化合物体内功效 癫痫模型在最近的一个UG 3项目中，我们调查了领先的EP 2上的候选开发活动 拮抗剂BPN 30343（TG 11 -77.HCl）。然而，它在ADMET检测中显示出两个缺点。所以我们 我现在建议进行额外的发现阶段先导化合物优化研究，以确定一种EP 2拮抗剂 候选人，以促进为IND使能研究。在具体目标1（UG 3）中，我们将测试最近合成的13种新的 用于关键ADMET试验的EP 2拮抗剂，以选择最多3种在犬中具有必要药代动力学的化合物。 如果在目标1中发现缺陷，我们将在目标2（UH 3阶段）中对备用EP 2进行电极导线优化研究 拮抗剂支架开发3种新的化合物用于功效和临床前测试。在目标3中，我们确认 在癫痫持续状态大鼠模型中的先导EP 2拮抗剂的功效，并鉴定允许我们 在大鼠和犬中进行DRF药代动力学和DRF毒代动力学研究。UH 3阶段的可交付成果 是一种开发候选化合物及其备用化合物，用于临床试验假设EP 2受体 癫痫发作后的调节可以为癫痫的主要合并症之一提供第一预防性治疗。

Lay Summary Epilepsy, the 4th most prevalent neurological disorder after stroke, Alzheimer’s and migraine, is often accompanied by cognitive deficits. Cognitive comorbidities substantially reduce quality of life in people with epilepsy. Although a number of anti-seizure drugs are available, no approved drugs mitigate either the cognition problems or progression of the disease. Inflammation is a component of all chronic diseases including epilepsy, and is the consequence of several broad signaling cascades including cyclooxygenase-2 (COX-2). We have shown that activation of the EP2 receptor for prostaglandin E2 is responsible for blood-brain barrier leakage and much of the inflammatory reaction, neuronal injury and cognitive deficit that follows seizure-provoked COX-2 induction in brain. We have earlier synthesized and tested >500 compounds as competitive antagonists of the human EP2 receptor, and demonstrated in vivo efficacy with two research lead compounds in three animal models of epilepsy. In a recent UG3 project, we investigated the candidate development activities on a lead EP2 antagonist BPN30343 (TG11-77.HCl). However, it showed two weaknesses in ADMET assays. Therefore, we now propose to conduct additional discovery phase lead-optimization studies to identify an EP2 antagonist candidate to promote for IND-enabling studies. In specific aim 1 (UG3), we will test recently synthesized 13 novel EP2 antagonists for key ADMET tests to select up to 3 compounds that have requisite pharmacokinetics in dogs. If shortcomings are found in Aim 1, we will do lead-optimization studies in Aim 2 (UH3 phase) on backup EP2 antagonist scaffolds to develop 3 novel compounds for efficacy and preclinical testing. In Aim 3, we confirm the efficacy of the lead EP2 antagonist in rat model of status epilepticus and identify formulation that allows us to conduct DRF-pharmacokinetic and DRF-toxicokinetic studies in rat and dog. The deliverable of the UH3 phase is a development candidate compound and its backup (s) for the clinical test of the hypothesis that EP2 receptor modulation after seizures can provide the first preventive treatment for one of the chief comorbidities of epilepsy.