EP2 Antagonists for Ischemic Stroke

EP2 拮抗剂治疗缺血性中风

基本信息

批准号：
10723017
负责人：
Jianxiong Jiang
金额：
$ 38.5万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10723017
关键词：
Ablation Adult Affinity Alteplase Anabolism Animals Anti-Inflammatory Agents Antiinflammatory Effect Anxiety Arteries Behavioral Binding Biological Availability Brain Brain Injuries Brain Ischemia Cardiovascular system Cause of Death Cell Death Induction Cell Line Cerebral Ischemia Cerebrovascular system Chemicals Cognition Corpus striatum structure Coupled Coxibs Cytokine Suppression Cytoprotection Darkness Development Dinoprostone Dose Eligibility Determination Emergency Situation Encephalitis Enzymes Formulation Future GTP-Binding Protein alpha Subunits, Gs Glucose Goals Half-Life Human Impairment In Vitro Infarction Inflammatory Intravenous Ischemia Ischemic Brain Injury Ischemic Stroke Isoenzymes Lead Leucocytic infiltrate Light Liver Microsomes Measures Mechanics Mediating Metabolic Microglia Middle Cerebral Artery Occlusion Modeling Motor Mus Neuroglia Neurologic Neurons Pathogenicity Pathway interactions Patients Penetration Permeability Pharmaceutical Preparations Phase Plasma Pre-Clinical Model Prostaglandin Receptor Prostaglandin-Endoperoxide Synthase Prostaglandins Protein Isoforms Recommendation Reperfusion Therapy Research Risk Role Safety Signal Transduction Solubility Survivors Testing Therapeutic Effect Thrombectomy Thrombolytic Therapy Vascular System acute stroke alternative treatment analog antagonist aqueous behavioral outcome cell type cerebroprotection cyclooxygenase 2 cytokine cytotoxicity deprivation disability drug clearance drug development drug distribution effective therapy enzyme biosynthesis excitotoxicity improved in vivo innovation ischemic injury lead optimization meter mouse model neuroinflammation neuropathology neuroprotection neurotoxicity new therapeutic target novel novel strategies novel therapeutics object recognition oxygen compounds patient subsets pharmacologic postnatal pre-clinical prevent radioligand rational design receptor scaffold small molecule stroke model therapeutic target thrombolysis water solubility

项目摘要

PROJECT SUMMARY Brain ischemia accounts for ~87% acute stroke cases and constitutes a leading cause of deaths in adults and permanent disabilities among survivors. The current intravenous thrombolysis is the only available medication for ischemic stroke; mechanical thrombectomy is an emerging alternative treatment for occlusion of large arteries and has shown promise in selected subsets of patients. However, the overall narrow treatment windows and potential risks largely limit the patient eligibility. It is thus urgently needed to identify novel drug targets to develop new, safer, and more effective treatment for ischemic stroke. As the rate-limiting enzyme in biosyntheses of prostanoids, cyclooxygenase (COX), particularly the inducible isozyme COX-2, has long been implicated in mechanisms of acute stroke-induced brain injury and inflammation. However, therapeutically targeting COX-2 has been greatly dampened due to unacceptable complications of cardiovascular and cerebrovascular systems caused by long-term use of COX-2 inhibitors. As a major COX product in the brain, prostaglandin E2 (PGE2) is elevated by excitotoxic insults and in turn aggravates the neurotoxicity largely via the Gαs-coupled receptor EP2, inspiring us to target this key pro-inflammatory pathway and to develop bioavailable brain-permeable antagonists for the EP2 receptor. Recent studies redefined neuropathogenic roles of PGE2/EP2 signaling in ischemic brain and validated the feasibility of pharmacologically targeting the EP2 receptor for ischemic stroke in mouse model of middle cerebral artery occlusion (MCAO) using our first-in-class EP2 antagonists. Our overarching goal is to develop new EP2 antagonists that can be given after cerebral ischemia onset to prevent inflammatory neuropathology and improve behavioral outcomes. Specifically, utilizing rational design and targeted synthesis, we will identify novel EP2 antagonists with improved PD, PK, metabolic, and safety profiles (R61 phase). We will then evaluate therapeutic effects of new EP2 antagonists in multiple animal stroke models (R33 phase). Successful completion of this project will lead to a proof of concept that EP2 antagonism might represent a novel strategy to mitigate ischemic injury. Anticipated results will also justify future studies on ADME-Tox, formulation, off-target activities, efficacy, and more extensive lead-optimization if needed to devise a delayed adjunctive treatment – along with reperfusion therapy – for brain ischemia.

项目摘要脑缺血占急性中风病例约87％，构成成人死亡的主要原因生存之间的永久残疾。当前的静脉溶栓是唯一可用的药物缺血性中风；机械血栓切除术是一种新兴的替代治疗，用于阻塞大动脉并显示了选定的患者子集的希望。但是，整体狭窄的治疗窗口和潜在风险在很大程度上限制了患者的可用性。因此，迫切需要确定新的药物靶新，更安全，更有效的缺血性中风治疗。作为生物合成率限制酶前列腺素，环氧合酶（COX），尤其是诱导同工酶COX-2，长期以来一直与急性中风引起的脑损伤和炎症的机制。但是，热靶向COX-2 由于心血管和脑血管系统的不可接受的并发症，由于不可接受由长期使用COX-2抑制剂引起的。作为大脑中主要的Cox产品，前列腺素E2（PGE2）为通过兴奋性毒性侮辱升高，进而通过GαS偶联受体EP2加剧了神经毒性激发我们针对这一关键的促炎途径，并发展生物利用的脑渗透对手对于EP2受体。最近的研究重新定义了PGE2/EP2信号在缺血性脑中的神经病作用并验证了在小鼠模型中靶向EP2受体的药理靶向EP2受体的可行性使用我们的第一类EP2拮抗剂的大脑中动脉闭塞（MCAO）。我们的总体目标是开发新的EP2拮抗剂，可以在脑缺血发作后给出以防止炎症神经病理学并改善行为结果。具体而言，利用有理设计和目标合成，我们将确定具有改进的PD，PK，代谢和安全性剖面（R61期）的新型EP2拮抗剂。我们将然后评估新EP2拮抗剂在多种动物中风模型（R33期）中的治疗作用。该项目的成功完成将导致概念证明EP2拮抗可能代表一种新颖减轻缺血损伤的策略。预期的结果还将证明未来关于ADME-TOX，公式，脱离目标的活动，有效性和更广泛的铅优化，如果需要设计延迟的辅助手段治疗 - 以及再灌注疗法 - 用于脑缺血。