EP2 Allosteric Potentiators for Subarachnoid Hemorrhage

描述（由申请人提供）：脑部疾病或损伤是导致死亡和发病的主要原因，并经常造成长期残疾，伴随的社会和医疗费用异常高。EP2受体激活在几种急性脑缺血动物模型中已被证明具有神经保护作用。我们最近创造了第一个EP2受体的变构增强剂，并在体外证明它们具有神经保护作用。发生蛛网膜下腔出血的患者在动脉瘤卷取或夹闭手术后4-14天有发生类似中风的缺血性事件的风险。在重症监护监测下，神经保护剂可在缺血性事件发生前给予该人群。这里提出的工作旨在确定EP2受体的环境依赖性变构增强剂，适合在临床环境中预防性使用，用于治疗SAM患者。我们的原型化合物具有良好的血浆半衰期和脑穿透性，但溶解度和/或效力必须提高，才能在体内系统给药。本研究的目标是开发一种人EP2受体的小分子变构增强剂，通过临床前安全性测试到IND申请，然后进行治疗蛛网膜下腔出血后脑损伤的I期临床试验。我们已经开发了一套基于细胞的EP2受体检测方法，具有必要的通量和疾病相关性，并且已经确定了几个有希望的先导分子，这些先导分子将与神经科学蓝图研究团队合作进一步完善，以提高效力。我们将与Blueprint团队合作，建立用于SAH患者的必要临床前安全包和给药间隔，以支持IND。IND将在项目期间提交，并在之后不久启动I期临床试验。

DESCRIPTION (provided by applicant): Disease or injury of the brain is a major cause of death and morbidity, and often produces long-term disability with unusually high accompanying social and medical costs. EP2 receptor activation has been shown to be neuroprotective in several animal models of acute cerebral ischemia. We have recently created the first allosteric potentiators of the EP2 receptor for PGE2 and have shown they are neuroprotective in vitro. Patients experiencing a subarachnoid hemorrhage are at substantial risk of experiencing a stroke-like ischemic event 4-14 days after their surgery to coil or clip their aneurysm. Neuroprotective agents can be administered to this population prior to the ischemic event under intensive care monitoring. The work proposed here is aimed at identifying a context-dependent allosteric potentiator of the EP2 receptor that is suitable for prophylactic use in the clinical setting for the treatment of SAM patients. Our prototype compound has good plasma half-life and brain penetration, but solubility and/or potency must be improved to be practical for systemic administration in vivo. The goal of the proposed research is to develop a small molecule allosteric potentiator of human EP2 receptors, progress it through preclinical safety testing to IND submission, and then to carry out a phase I clinical trial for treatment of cerebral injury following subarachnoid hemorrhage. We have developed a suite of cell-based EP2 receptor assays that have the requisite throughput and disease relevance, and have identified several promising lead molecules that will be further refined in collaboration with the Blueprint for Neuroscience Research team to improve potency, ADMET and pharmaceutical properties to deliver a compound suitable for filing an IND. We will work with the Blueprint team to establish the requisite preclinical safety package and dosing interval for use in SAH patients to support an IND. An IND will be filed within the project period and a phase I clinical trial initiated shortly thereafter. PUBLIC HEALTH RELEVANCE: Disease or injury of the brain is a major cause of death and morbidity, and often produces long-term disability with unusually high accompanying social and medical costs. We intend to create novel drugs that target inflammation pathways to minimize the cognitive deficits that often accompany brain injury. We specifically focus on injury that is associated with subarachnoid hemorrhage.