Inhibitors of TrkB Signaling

TrkB 信号传导抑制剂

基本信息

批准号：
9752114
负责人：
James O. McNamara
金额：
$ 62.27万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9752114
关键词：
Adult Animals Anticonvulsants Autoimmune Process Biological Assay Brain Central Nervous System Diseases Cessation of life Chemicals Clinic Clinical Research Clinical Trials Comorbidity Development Disadvantaged Disease Disease Pathway Disease remission Drug Design Drug Kinetics Epilepsy Fluorescence Resonance Energy Transfer Formulation Glare Human In Vitro Lead Mediating Medical Mission Modeling Modification Molecular Molecular Target Mus National Institute of Neurological Disorders and Stroke Nervous system structure Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 PLC gamma1 Pathway interactions Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Phase Phosphotransferases Preparation Prevention Preventive Preventive therapy Property Protein Tyrosine Kinase Recurrence Seizures Series Signal Pathway Signal Transduction Status Epilepticus Structure Temporal Lobe Epilepsy Time Validation Work anxiety-like behavior base brief intervention chemical genetics clinical candidate design experimental study genetic approach high throughput screening improved in vitro Assay in vivo inhibitor/antagonist injured innovation lead optimization lead series mouse model novel preclinical safety preclinical study prevent safety study screening small molecule small molecule inhibitor success symptom treatment

项目摘要

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.

抽象的颞叶癫痫 (TLE) 是人类癫痫的一种常见且往往具有破坏性的形式，目前缺乏预防或疾病改变疗法。临床和临床前研究的证据支持这个想法长期癫痫发作（癫痫持续状态或 SE）会导致 TLE 的发生。定义 SE 将正常大脑转变为癫痫大脑的分子机制可以识别分子机制预防性治疗的目标。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 的可药物分子靶点，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已鉴定出两种广泛的化学型，每种化学型都包含多个化学系列。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项药物化学努力提高有前途的生物活性化合物的效力和类药物特性。我们提出以下目标。目标1：完成进入UH3阶段的准备。目标 2（UH3 阶段）：进行 SAR 先导优化工作以确定临床候选分子。目标 3（UH3 阶段）：开展 IND 赋能研究。常见疾病缺乏有效的预防和疾病缓解疗法人类神经系统疾病是一个明显未得到满足的医疗需求，这对 NINDS 的使命至关重要。这这里提出的工作代表了一种开发预防和疾病药物的新颖和创新方法 TLE（一种常见的中枢神经系统疾病）的修饰。