GPR39 as a Therapeutic Target in Subarachnoid Hemorrhage (SAH)

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.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.