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

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

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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.

摘要摘要癫痫病是中风后第四最普遍的神经系统疾病，阿尔茨海默氏症和偏头痛通常是伴随着认知缺陷。认知合并症大大降低了患有癫痫。尽管有许多抗塞氏菌药物可用，但尚无批准的药物减轻认知疾病的问题或进展。炎症是所有慢性疾病的组成部分，包括癫痫，这是几个广泛的信号级联反应的结果，包括环氧酶-2（COX-2）。我们有表明前列腺素E2的EP2受体的激活负责血脑屏障泄漏和发作发作的COX-2之后的许多炎症反应，神经元损伤和认知防御大脑诱导。我们较早地合成并测试> 500种化合物作为竞争性拮抗剂人类EP2受体，并在三种动物中使用两种研究铅化合物证明体内效率癫痫的模型。在最近的UG3项目中，我们调查了有关铅EP2的候选发展活动拮抗剂BPN30343（TG11-77.HCL）。但是，它显示了ADMET分析中的两个弱点。因此，我们现在建议进行其他发现阶段铅优化研究以识别EP2拮抗剂候选人促进辅助研究。在特定的目标1（ug3）中，我们将测试最近合成13个新颖 EP2拮抗剂用于关键ADMET测试，可在狗中选择多达3种具有必要药代动力学的化合物。如果在AIM 1中发现缺点，我们将在AIM 2（UH3阶段）的备份EP2中进行铅优化研究拮抗剂支架开发3种新型化合物，以进行效率和临床前测试。在AIM 3中，我们确认铅EP2拮抗剂在状态癫痫次癫痫群的大鼠模型中的功效，并确定使我们得以实现的公式在大鼠和狗中进行DRF-PHARMACINETIC和DRF TOXICICINETIC研究。 UH3阶段的交付是一种开发候选化合物及其备份，用于EP2受体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首次预防治疗。