GPR39 as a Therapeutic Target in Subarachnoid Hemorrhage (SAH)

标题：GPR 39作为蛛网膜下腔出血（SAH）的治疗靶点 摘要 动脉瘤性蛛网膜下腔出血（SAH）是一种破坏性的中风形式，影响20- 30，000例患者 在美国每年有三分之一到一半的受害者死于这种疾病。在全球范围内，SAH负责更多 每年有超过40万人死亡除了最初的手术治疗外，目前还没有有效的治疗SAH的方法 或者血管内介入来止血然而，大多数死亡发生在首次出血后，由于 早期脑损伤（EBI）或迟发性脑缺血（DCI）。我们建议开发一流的小型 一种靶向新型GPCR（GPR 39）的分子药物， EBI 和DCI。为支持 为了证实该通路与SAH的相关性，我们最近完成了一项SAH的1b期随机临床试验 患者使用一种化合物，增加这种受体的天然配体的内源性水平（称为 14，15-环氧二十碳三烯酸酯，14，15-EET）。在临床试验中，增加14，15-EET（通过抑制其 将住院时间从29天减少到17天，并在90天时改善功能结局 SAH后从重度到中度残疾和从中度到轻度残疾。我们最近 发现GPR 39作为14，15-EET的受体，这增加了刺激受体的机会 直接，而不是通过增加其配体间接。为此，我们已经完成了高通量 筛选（HTS）含有超过250，000个分子的小分子文库， 具有高选择性、效力和药物样性质的有前途的化合物。第一阶段STTR的目标是 使用GPR 39敲除小鼠和药物可获得的GPR 39激动剂来确认GPR 39在SAH中的作用， 称为C3，由其他人开发用于其他适应症。研究将使用3个月和12个月大的雄性和雌性 小鼠研究还将确定C3的C3血浆PK，以及其是否穿透血脑屏障 （BBB）。未来的第二阶段STTR将支持一项旨在确定 具有高体外效力、体内功效和有利PK/PD性质（包括血液- 脑屏障穿透

TITLE: GPR39 as a Therapeutic Target in Subarachnoid Hemorrhage (SAH) Summary Abstract Aneurysmal subarachnoid hemorrhage (SAH) is a devastating form of stroke that affects 20-30,000 patients in the US every year, killing between a third and a half of its victims. Worldwide, SAH is responsible for more than 400,000 deaths each year. There is currently no effective treatment for SAH beyond the initial surgical or endovascular intervention to stop the bleed. However, most deaths occur after the initial bleed, due to early brain injury (EBI) or delayed cerebral ischemia (DCI). We propose to develop a first-in-class small molecule drug that targets a novel GPCR (GPR39) that is relevant to both EBI and DCI. In support of the relevance of this pathway to SAH, we have recently completed a Phase 1b randomized clinical trial in SAH patients using a compound that increases the endogenous level of the natural ligand for this receptor (called 14,15-epoxyeicosatrienoate, 14,15-EET). In the clinical trial, increasing 14,15-EET (by inhibiting its breakdown) reduced hospital stay from 29 days to 17 days, and improved functional outcome at 90 days after SAH from severe to moderate disability and from moderate to slight disability. We have recently discovered GPR39 as the receptor for 14,15-EET, which raises the opportunity to stimulate the receptor directly, rather than indirectly by increasing its ligand. To that end, we have completed high-throughput screening (HTS) of a small-molecule library containing more than 250,000 molecules that identified several promising compounds with high selectivity, potency and drug-like properties. The goal of this Phase I STTR is to confirm the role of GPR39 in SAH using GPR39 knockout mice and a publically available GPR39 agonist, called C3, developed by others for other indications. Studies will use 3- and 12-month old male and female mice. Studies will also determine C3 plasma PK for C3, and whether it penetrates the blood-brain barrier (BBB). Future Phase II STTR will support a hit-to-lead medicinal-chemistry campaign aimed at identifying a lead compound with high in-vitro potency, in-vivo efficacy, and favorable PK/PD properties, including blood- brain barrier penetration.