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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.

把总结