EP2 Antagonists for Ischemic Stroke

项目摘要 脑缺血约占急性中风病例的87%，是成人死亡的主要原因， 幸存者的永久性残疾。目前静脉溶栓是唯一可用的药物 对于缺血性卒中;机械血栓切除术是大动脉闭塞的新兴替代治疗方法 并在选定的患者子集中显示出希望。然而，整体狭窄的治疗窗口和 潜在的风险在很大程度上限制了患者的资格。因此，迫切需要确定新的药物靶点来开发 新的，更安全，更有效的治疗缺血性中风。作为生物合成的限速酶， 前列腺素类、环氧合酶（考克斯），特别是诱导型同工酶考克斯-2，长期以来被认为与前列腺增生有关。 急性中风引起的脑损伤和炎症的机制。然而，治疗靶向考克斯-2 由于心血管和脑血管系统不可接受的并发症， 长期使用考克斯-2抑制剂引起的。前列腺素E2（PGE 2）是脑内的主要考克斯产物， 通过兴奋性毒性损伤升高，进而主要通过Gα s偶联受体EP 2减轻神经毒性， 启发我们瞄准这一关键的促炎通路，并开发生物可利用的脑渗透性拮抗剂， EP 2受体。最近的研究重新定义了PGE 2/EP 2信号通路在缺血性脑损伤中的作用 在小鼠缺血性脑卒中模型中验证了以EP 2受体为靶点的血管紧张素转换酶抑制剂的可行性 大脑中动脉闭塞（MCAO）使用我们的一流的EP 2拮抗剂。我们的首要目标是 开发新的EP 2拮抗剂，可在脑缺血发作后给予，以防止炎症 神经病理学和改善行为结果。具体而言，通过合理设计和靶向合成， 我们将鉴定具有改善的PD、PK、代谢和安全性特征的新型EP 2拮抗剂（R61期）。我们将 然后在多种动物中风模型（R33期）中评价新的EP 2拮抗剂的治疗效果。 该项目的成功完成将导致概念验证，即EP 2拮抗作用可能代表一种新的 减轻缺血性损伤的策略。预期结果也将证明未来对ADME-Tox制剂的研究是合理的， 脱靶活动、有效性和更广泛的电极导线优化（如果需要），以设计延迟治疗 治疗-沿着再灌注治疗-用于脑缺血。

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.