GPR39 as a Therapeutic Target in Subarachnoid Hemorrhage (SAH)

GPR39 作为蛛网膜下腔出血 (SAH) 的治疗靶点

基本信息

批准号：
10478533
负责人：
Nabil J Alkayed
金额：
$ 25.19万
依托单位：
NEUVARX, LLC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10478533
关键词：
Acute Adverse effects Affect Agonist Aneurysmal Subarachnoid Hemorrhages Blood - brain barrier anatomy Blood Vessels Blood flow Brain Brain Injuries Brain hemorrhage Cerebral Ischemia Cerebral hemisphere hemorrhage Cerebrovascular Circulation Cessation of life Clinical Trials Complication Dose Drug Targeting Equilibrium Female Future G-Protein-Coupled Receptors GPR39 gene GTP-Binding Protein alpha Subunits, Gs Glial Fibrillary Acidic Protein Goals Hemorrhage Hydrocephalus ITGAM gene Image Immunohistochemistry In Vitro Intervention Intracranial Hypertension Ischemic Stroke Knock-out Knockout Mice Laser Speckle Imaging Lead Length of Stay Ligands Magnetic Resonance Imaging Measures Microvascular Dysfunction Modeling Mus Operative Surgical Procedures Outcome PTPRC gene Pathway interactions Patients Perforation Persons Pharmaceutical Chemistry Pharmaceutical Preparations Phase Plasma Play Prognostic Factor Property Publications Randomized Clinical Trials Role Ruptured Aneurysm Small Business Technology Transfer Research Stroke Structure-Activity Relationship Subarachnoid Hemorrhage Survivors Testing Vascular Cell Adhesion Molecule-1 Vasospasm Woman age effect blood-brain barrier penetration disability effective therapy functional outcomes high throughput screening human old age (65+)improved improved outcome in vivo intraventricular hemorrhage male men mortality neurobehavior neurobehavioral test neuroinflammation neuron loss new therapeutic target novel novel lead compound pharmacokinetics and pharmacodynamics receptor small molecule small molecule libraries therapeutic target young adult

项目摘要

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.

标题：GPR39 作为蛛网膜下腔出血 (SAH) 的治疗靶点摘要摘要动脉瘤性蛛网膜下腔出血 (SAH) 是一种破坏性的中风，影响 20-30,000 名患者每年在美国都会造成三分之一到二分之一的受害者死亡。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，目前尚无有效的 SAH 治疗方法或血管内介入止血。然而，大多数死亡发生在初次失血后，原因是早期脑损伤（EBI）或迟发性脑缺血（DCI）。我们建议开发一个一流的小型靶向与两者相关的新型 GPCR (GPR39) 的分子药物息税前利润和 DCI。为了支持由于该途径与 SAH 的相关性，我们最近完成了 SAH 的 1b 期随机临床试验患者使用可增加该受体天然配体的内源水平的化合物（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（通过抑制其细分）将住院时间从 29 天减少到 17 天，并在 90 天时改善功能结果 SAH 后从重度到中度残疾以及从中度到轻微残疾。我们最近有发现GPR39作为14,15-EET的受体，这增加了刺激受体的机会直接地，而不是通过增加其配体间接地。为此，我们完成了高通量对包含超过 250,000 个分子的小分子文库进行筛选 (HTS)，该文库鉴定了多种分子具有高选择性、效力和类药物特性的有前途的化合物。第一阶段 STTR 的目标是使用 GPR39 敲除小鼠和公开的 GPR39 激动剂来确认 GPR39 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 个月大的男性和女性老鼠。研究还将确定 C3 的血浆 PK，以及它是否能穿透血脑屏障（BBB）。未来的 II 期 STTR 将支持一项先导药物化学活动，旨在确定一个先导化合物具有高体外效力、体内功效和良好的 PK/PD 特性，包括血液- 脑屏障穿透。