Refinement of lead compounds to modulate water permeability through AQP4

DESCRIPTION (provided by applicant): Cerebral edema (and its counterpart in the spinal cord) is a major contributor to the damage caused by stroke, traumatic brain injury, traumatic spinal-cord injury, and bacterial meningitis. Stroke alone is the third leading cause of death in the USA and the leading cause of disability. Unfortunately, few treatment options are available for cerebral and spinal-cord edema, and these are of limited efficacy. Central in the development of cerebral and spinal-cord edema is the H2O channel aquaporin-4 (AQP4) in the astrocytic end feet that envelope CNS blood vessel at the blood-brain barrier (BBB). AQP4 is upregulated by ischemia, traumatic brain injury, and a diverse array of other CNS pathologies associated with inflammation. But, paradoxically, AQP4- null mice do substantially better than their wild-type counterparts in experimental models of ischemic stroke, retinal ischemia, and bacterial meningitis, making AQP4 an attractive drug target. A unique aspect of the present proposal is the recognition that the AQPs are bifunctional proteins that are permeable not only to water, but also to dissolve gases (CO2, O2, NO). Indeed, the upregulation of AQP4 in the aforementioned pathologies may have the beneficial effect of maximizing O2 permeability across the BBB, with the side effect of increasing osmotic water permeability and predisposing to cerebral edema. The long-term goal of Aeromics is to develop a drug that treats cerebral edema by blocking the water permeability of AQP4, leaving gas permeability intact. In its Phase I SBIR, Aeromics already accomplished its major goals of (a) developing a very successful high-throughput screen (HTS), (b) developing appropriate counterscreens, and (c) identifying 6 hits from four different structural classes. The goals of this Phase II SBIR application are to: (1) optimize discovery-stage safety and efficacy screens, (2) use available compounds and some synthesis for medicinal chemistry to refine leads, generating several compounds appropriate for in-vivo testing, (3) perform in-vivo pharmacologic proof of principle, and (4) determine mechanism of action. The proposed work will prepare Aeromics for a Phase II renewal that will include additional medicinal chemistry, as well as the preclinical work necessary for filing an IND application for treating stroke-induced cerebral edema. PUBLIC HEALTH RELEVANCE: Swelling of the brain (cerebral edema) and spinal cord is a major contributor to the damage caused by stroke, traumatic brain/spinal-cord injury, and bacterial meningitis. Unfortunately, only a few treatment options are available for such edema, and these are of limited efficacy. In its Phase I SBIR, Aeromics developed technology to identify new drugs for treating cerebral edema while maintaining the oxygen delivery to the brain, and in fact discovered 6 new drugs in 4 drug families. In this Phase II SBIR, Aeromics plans to use this information to create new drugs that it will test in animal models of cerebral edema and stroke. The next step will be to refine the drugs further and prepare them for human testing.