Optimization of EP2 Antagonists for Post-Seizure Cognitive Deficits

针对癫痫发作后认知缺陷的 EP2 拮抗剂的优化

基本信息

批准号：
10467539
负责人：
RAYMOND J DINGLEDINE
金额：
$ 67.75万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10467539
关键词：
Acute Disease Address Alzheimer&apos s Disease Animal Model Anti-Inflammatory Agents Biological Assay Biological Availability Blood - brain barrier anatomy Brain CYP3A4 gene Canis familiaris Cell Line Cell model Chronic Disease Cognition Cognitive Cognitive deficits Development Dinoprostone Disease Progression Dose Drug Kinetics EP4 receptor Epilepsy Extravasation Fluorescence Resonance Energy Transfer Formulation Goals Histopathology Hour Human Inflammation Inflammation Mediators Inflammatory Lead Liquid substance Mediating Memory Metabolism Methods Methylcellulose Microglia Migraine Modeling Mus Neurologic Neuronal Injury No-Observed-Adverse-Effect Level Oral Organ PTGS2 gene Pathology Penetration Persons Pharmaceutical Chemistry Pharmaceutical Preparations Phase Phase I Clinical Trials Phenotype Plasma Preclinical Testing Preventive therapy Preventive treatment Property Prostaglandin Receptor Quality of life Rattus Reaction Research Rodent Seizures Signal Transduction Solubility Status Epilepticus Sterility Stomach Structure-Activity Relationship Suspensions Testing Therapeutic Agents Therapeutic Index Toxic effect Toxicokinetics Water analog antagonist aqueous base clinical candidate comorbidity cyclooxygenase 2 efficacy evaluation efficacy testing immunoregulation in vivo interest lead optimization monocyte nervous system disorder neuroinflammation neuron loss nonhuman primate novel object recognition post stroke pre-clinical prevent receptor research clinical testing scaffold scale up tool

项目摘要

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.

外行总结癫痫是继中风、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，伴有认知缺陷的认知合并症大大降低了患者的生活质量。尽管有许多抗癫痫药物可用，但没有批准的药物可以减轻认知功能。炎症是所有慢性疾病的一个组成部分，包括癫痫、它是包括环氧合酶-2 (COX-2) 在内的多种广泛信号级联反应的结果。研究表明，前列腺素 E2 的 EP2 受体的激活是导致血脑屏障渗漏的原因癫痫发作引起的 COX-2 后的大部分炎症反应、神经元损伤和认知缺陷我们之前已经合成并测试了超过 500 种化合物作为竞争性拮抗剂。人类 EP2 受体，并在三只动物中证明了两种研究先导化合物的体内功效在最近的 UG3 项目中，我们研究了先导 EP2 的候选开发活动。然而，BPN30343 (TG11-77.HCl) 在 ADMET 检测中显示出两个弱点。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 EP2 拮抗剂在具体目标 1 (UG3) 中，我们将测试最近合成的 13 项新颖研究。用于关键 ADMET 测试的 EP2 拮抗剂，可选择最多 3 种在狗中具有必需药代动力学的化合物。如果在目标 1 中发现缺陷，我们将在备用 EP2 上进行目标 2（UH3 阶段）的先导优化研究拮抗剂支架开发 3 种新化合物用于功效和临床前测试在目标 3 中，我们确认了。主要 EP2 拮抗剂在大鼠癫痫持续状态模型中的功效，并确定使我们能够在大鼠和狗中进行 DRF 药代动力学和 DRF 毒代动力学研究 UH3 阶段的可交付成果。是一种正在开发的候选化合物及其备份，用于 EP2 受体假设的临床测试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个预防性治疗。