EP2 Allosteric Potentiators for Subarachnoid Hemorrhage

描述(申请人提供)：脑部疾病或损伤是死亡和发病的主要原因，通常会导致长期残疾，伴随着异常高昂的社会和医疗成本。EP2受体的激活在几种急性脑缺血动物模型中被证明具有神经保护作用。我们最近为PGE2创造了第一个EP2受体的变构增强剂，并证明它们在体外具有神经保护作用。经历蛛网膜下腔出血的患者在手术后4-14天有很大风险经历类似中风的缺血事件，以圈闭或夹闭他们的动脉瘤。在重症监护下，可以在缺血事件发生前对这一人群使用神经保护剂。这项工作的目的是确定一种上下文依赖的EP2受体变构增强剂，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能力，但必须提高溶解度和/或效力，才能在体内实现全身给药。这项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进行IND提交，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受体分析，具有必要的吞吐量和疾病相关性，并确定了几个有希望的先导分子，将与神经科学研究团队合作进一步提炼，以改善效力、ADMET和药学性质，以提供适合提交IND的化合物。我们将与Blueprint团队合作，为SAH患者建立必要的临床前安全方案和剂量间隔，以支持IND。IND将在项目期内提交，随后不久将启动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.