EP2 Allosteric Potentiators for Subarachnoid Hemorrhage

描述（由申请人提供）：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，伴随着异常高的社会和医疗成本。在几种急性脑缺血的动物模型中，EP 2受体激活已显示出神经保护作用。我们最近创造了第一个PGE 2的EP 2受体的变构增效剂，并在体外显示它们具有神经保护作用。经历蛛网膜下腔出血的患者在其手术以弹簧圈或夹闭其动脉瘤后4-14天处于经历中风样缺血事件的实质性风险。神经保护剂可在缺血事件发生前在重症监护下给予该人群。本文提出的工作旨在鉴定EP 2受体的上下文依赖性变构增效剂，其适合于在临床环境中用于治疗SAM患者的预防性使用。我们的原型化合物具有良好的血浆半衰期和脑渗透性，但溶解度和/或效力必须得到改善才能用于体内全身给药。该研究的目标是开发一种人EP 2受体的小分子变构增效剂，通过临床前安全性测试以提交IND申请，然后进行I期临床试验，用于治疗蛛网膜下腔出血后的脑损伤。我们已经开发了一套基于细胞的EP 2受体测定，具有必要的通量和疾病相关性，并确定了几种有前途的先导分子，将与神经科学研究团队的蓝图合作进一步完善，以提高效力，ADMET和药物特性，以提供适合提交IND的化合物。我们将与Blueprint团队合作，建立必要的临床前安全性包装和给药间隔用于SAH患者，以支持IND。IND将在项目期间提交，并在此后不久启动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.