TITLE: GPR39 as a Therapeutic Target in Subarachnoid Hemorrhage (SAH) Aneurysmal subarachnoid hemorrhage (SAH) is a devastating form of stroke that affects 20-30,000 patientsin the US every year, killing between a third and a half of its victims. Worldwide, SAH is responsible for morethan 400,000 deaths each year. There is currently no effective treatment for SAH beyond the initial surgicalor endovascular intervention to stop the bleed. However, most deaths occur after the initial bleed, due toearly brain injury (EBI) or delayed cerebral ischemia (DCI). We propose to develop a first-in-class smallmolecule drug that targets a novel GPCR (GPR39) that is relevant to bothEBIand DCI. In support of therelevance of this pathway to SAH, we have recently completed a Phase 1b randomized clinical trial in SAHpatients using a compound that increases the endogenous level of the natural ligand for this receptor (called14,15-epoxyeicosatrienoate, 14,15-EET). In the clinical trial, increasing 14,15-EET (by inhibiting itsbreakdown) reduced hospital stay from 29 days to 17 days, and improved functional outcome at 90 daysafter SAH from severe to moderate disability and from moderate to slight disability. We have recentlydiscovered GPR39 as the receptor for 14,15-EET, which raises the opportunity to stimulate the receptordirectly, rather than indirectly by increasing its ligand. To that end, we have completed high-throughputscreening (HTS) of a small-molecule library containing more than 250,000 molecules that identified severalpromising compounds with high selectivity, potency and drug-like properties. The goal of this Phase I STTRis 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 femalemice. 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 alead compound with high in-vitro potency, in-vivo efficacy, and favorable PK/PD properties, including blood-brain barrier penetration.
Public Health Relevance Statement: The proposal will investigate the role of a novel therapeutic target, called GPR39, in hemorrhagic
stroke resulting from aneurysm rupture. This is a devastating form of stroke with no effective
therapy. The long-term goal of the project is to develop a small molecule drug for this type of
stroke.
Project Terms: <α-Gs><65+ years old> 