Inhibitors of TrkB Signaling

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Abstract Temporal lobe epilepsy (TLE) is a common and often devastating form of human epilepsy that currently lacks preventive or disease modifying therapy. Evidence from clinical and preclinical studies supports the idea that an episode of prolonged seizures (status epilepticus or SE) contributes to development of TLE. Defining the molecular mechanisms by which SE transforms a normal brain into an epileptic brain can identify molecular targets for preventive therapies. We conducted an extensive series of target validation experiments and identified a druggable molecular target that can prevent TLE in mice, namely the brain-derived neurotrophic factor receptor tyrosine kinase, TrkB. We conducted a high-throughput screen seeking small molecule inhibitors and have identified two broad chemotypes, each of which contains multiple chemical series. Here we seek to enter the Discovery stage of the Blueprint Network during which we will prosecute a medicinal chemistry effort to improve the potency and drug-like properties of promising bioactive compounds. We propose the following Aims. Aim 1: To complete preparation for entering UH3 phase. Aim 2 (UH3 phase): To prosecute an SAR lead optimization effort to identify a clinical candidate molecule. Aim 3 (UH3 Phase): To conduct IND enabling studies. The lack of effective preventive and disease modifying therapies for common disorders of the human nervous system is a glaring unmet medical need critical to the mission of NINDS. The work proposed here represents a novel and innovative approach to develop drugs for prevention and disease modification of TLE, a common disorder of the CNS.