Inhibitors of TrkB Signaling

摘要 颞叶癫痫（TLE）是一种常见的并且通常是破坏性的人类癫痫形式， 缺乏预防性或改善疾病的治疗。来自临床和临床前研究的证据支持这一观点 长时间癫痫发作（癫痫持续状态或SE）有助于TLE的发展。限定 SE将正常大脑转化为癫痫大脑的分子机制可以识别分子 预防性治疗的目标。我们进行了一系列广泛的目标验证实验， 确定了一种可以预防小鼠TLE的药物分子靶点，即脑源性神经营养因子。 因子受体酪氨酸激酶，TrkB。我们进行了高通量筛选，寻找小分子 抑制剂，并确定了两个广泛的化学型，其中每一个包含多个化学系列。这里 我们寻求进入蓝图网络的发现阶段，在此期间，我们将起诉一种药物， 化学努力提高有前途的生物活性化合物的效力和药物样性质。我们 提出以下目标。目标1：完成进入UH3阶段的准备工作。目标2（UH3阶段）： 进行SAR先导优化工作以鉴定临床候选分子。目标3（UH3阶段）： 开展IND赋能研究。缺乏有效的预防和疾病修饰疗法， 人类神经系统疾病是一个明显的未满足的医疗需求，对NINDS的使命至关重要。的 这里提出的工作代表了一种新的和创新的方法来开发药物，用于预防和疾病 TLE是一种常见的中枢神经系统疾病。

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.