Current therapy for ischemic stroke is limited and new treatment is needed since the mortality and morbidity of subjects with this condition remain high. Effort aimed at blocking immune cell- mediated inflammation represents a novel approach. The specific background for the proposed project is that we have identified the myeloid P2X4 receptor (P2X4R), which induces inflammation, as a new therapeutic target for ischemic stroke. Through our collaboration with Dr. Kenneth A. Jacobson, we have synthesized new small molecule antagonists at the P2X4R based on their prototypes and their efficacy in reducing stroke infarct size and improving functional behavioral outcomes. This structure-activity relationship study provided guidance on the type of compounds that may have anti-stroke efficacy. The goal here is to screen the new compounds for their affinity and selectivity at human P2X4R vs. other major human P2X receptors, and then perform preclinical proof of concept studies for efficacy in an established murine ischemic stroke model as well as in blocking P2X4R in myeloid cells of stroke patients. Cornovus is a company, in collaboration with its academic partner University of Connecticut School of Medicine?s research laboratories, and Laboratory of Bioorganic Chemistry of the National Institute of Diabetes, Digestive and Kidney Diseases of NIH, is well-positioned to perform the proposed feasibility studies. The objective of the grant is to screen and identify two lead compounds and then test them in the in vivo murine ischemic stroke model and the ex vivo human myeloid cell model obtained from ischemic stroke patients. The proposed studies should add to scientific knowledge on the chemistry and pharmacology of P2X4 antagonists and may also yield new insights into the science of such an anti-inflammatory approach. Pending successful outcomes, the proposal should position the company to pursue IND-enabling studies in the future.
Patients with ischemic stroke are in need of new medical therapy. The goal here is to determine the feasibility of a new ant-inflammatory approach to treat ischemic stroke. We aim to identify a lead and a co-lead small molecule agents based on synthesis, screening, and testing in biological models of new compounds. Preclinical proof of concept studies performed will determine feasibility of this novel medical therapy. The proposed work would position us to move to IND-enabling safety studies and manufacturing to proceed to a successful IND application.