The long-term objective is to develop a new class of small molecule compounds that are neuroprotective and attractive for future drug development. The short term goal is the discovery of compounds that will confer protection from hypoxia-ischemia (HI) induced brain injury, and have the appropriate molecular properties to serve as lead compounds in future drug development. HI induced tissue injury is a major problem across multiple disease areas. HI induced brain injury, such as found in stroke, is of special concern because of the compromised function of individuals who survive as well as the significant number of deaths each year. Currently, there is an unmet need for safe and effective therapies in this major disease area. The clinical presentation of patients is such that the therapeutic window starts four to six hours after trauma, placing a robust demand on candidate new drugs. The spreading of neuronal death away from the site of initial injury in patients and the pathological changes that occur in animal models have focused attention on programmed cell death, but targeting of late stages in the mechanism have proven disappointing. Therefore, targeting early steps in the pathway prior to cell commitment to death is key. Death inducing protein kinases are early in the mechanism, have been identified as potential therapeutic targets, and feasibility studies with kinase inhibitors that cross the blood brain barrier have provided a proof of concept for kinase inhibition preventing HI induced brain injury. We propose to (1) use the co-crystal structures of the target kinase domain containing bound but inactive compounds as the starting point for (2) structure assisted synthetic design, synthesis and testing of focused libraries of potential lead compounds, and (3) validation of final products in an in vivo animal model. We hypothesize that the structure based molecular fragment approach, used in the context of biological considerations of cellular mechanism and clinical needs, will yield the required lead compounds for this high-risk area of research and development. The successful completion will help validate the emerging use of this structure based approach to medicinal chemistry, provide insight into molecular properties key for blood brain barrier penetrance and efficacy in an area of unmet need in CNS discovery chemistry, and generate broadly useful reagents for in vivo signal transduction research.
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