EP2 Antagonists for Ischemic Stroke

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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.