Development of Nav1.7 Selective Inhibitors for the Treatment of Chronic Cough

开发用于治疗慢性咳嗽的 Nav1.7 选择性抑制剂

基本信息

批准号：
10258238
负责人：
John Cureton Hunter
金额：
$ 67.76万
依托单位：
SITEONE THERAPEUTICS, INC.
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 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10258238
关键词：
Action Potentials Acute Adult Afferent Neurons Allergic Antitussive Agents Asthma Blood specimen Bronchiectasis C Fiber Capsaicin Cations Cavia Chemical Stimulation Chemicals Chronic Chronic Obstructive Airway Disease Citric Acid Clinical Conscious Coronavirus Coughing Development Disease Dose Drug Exposure Drug Kinetics Economics Etiology Exhibits Fiber Formulation Gastroesophageal reflux disease Guidelines Heterogeneity Human Hypersensitivity Individual Influenza Inhalation Inhalation Drug Administration Irritants Lead Lung Lung diseases Measures Mechanical Stimulation Mechanics Medical Modeling Modification Motor Motor Neurons Mus Nature Nebulizer Nerve Neuraxis Neurologic Nodose Ganglion Nucleus solitarius Obstruction P2X-receptor Pathologic Patients Pharmaceutical Preparations Phase Population Prevalence Protein Isoforms Publishing Quality of life Rattus Reflex action Refractory Reporting Rhinovirus Risk Rodent Safety Sensory Sensory Physiology Sensory Receptors Series Skeletal Muscle Small Business Innovation Research Grant Sodium Channel Stigmatization Stimulus Subcutaneous Injections Telemetry Therapeutic Therapeutic Index Time Tissues Trachea Unconscious State United States Viral Respiratory Tract Infection Virus Diseases afferent nerve base cardiovascular effects drug development guanidinium human tissue idiopathic pulmonary fibrosis inhibitor/antagonist neuronal circuitry nonhuman primate patient subsets porcine model pre-clinical programs psychologic receptor response side effect small molecule small molecule inhibitor social social anxiety therapeutically effective voltage

项目摘要

PROJECT SUMMARY Chronic cough, or cough that persists for more than eight weeks, is a condition that is often associated with diseases such as chronic obstructive pulmonary disorder (COPD), asthma, idiopathic pulmonary fibrosis, bronchiectasis or gastroesophageal reflux disease (GERD). In other cases, the etiology is unknown, although it has been noted that the cough often first arises following a severe viral respiratory infection. Chronic cough has significant physical, psychological, social and economic consequences that negatively impact quality of life. Prevalence in the United States is as high as 11%, and in a majority of cases the condition is refractory. Compelling evidence supports the hypothesis that chronic cough arises from alterations in sensory physiology that cause hypersensitivity to previously innocuous stimuli. The voltage-gated sodium ion channel NaV1.7 is highly expressed in unmyelinated vagal nerve afferents that trigger cough through a sensorimotor reflex circuit. Results from a published pre-clinical report show that reducing expression of NaV1.7 nearly abolishes cough evoked by inhaled irritants, indicating that it is a promising target for reducing cough. SiteOne Therapeutics has discovered potent and selective small molecule inhibitors of NaV1.7 that block vagal C fiber activity in a dose-dependent manner. During a Phase 1 program, our team demonstrated that systemic administration of an isoform-selective NaV1.7 inhibitor abolishes the cough response to inhaled irritants in conscious guinea pigs. The objective of our Phase 2 program is evaluate safety, pharmacokinetic and efficacy endpoints, and to advance an inhaled NaV1.7 inhibitor into IND-enabling development as a therapeutic for chronic cough.

项目概要慢性咳嗽，或持续超过八周的咳嗽，是一种经常与以下疾病相关的疾病：患有慢性阻塞性肺疾病（COPD）、哮喘、特发性肺纤维化等疾病，支气管扩张或胃食管反流病（GERD）。在其他情况下，病因尚不清楚，但值得注意的是，咳嗽通常是在严重的病毒性呼吸道感染后首先出现的。慢性咳嗽有严重的身体、心理、社会和经济后果，对生活质量产生负面影响。在美国，患病率高达 11%，而且大多数情况下病情是难治性的。令人信服的证据支持这样的假设：慢性咳嗽是由感觉改变引起的导致对以前无害的刺激过敏的生理学。电压门控钠离子通道 NaV1.7 在无髓迷走神经传入神经中高度表达，通过感觉运动触发咳嗽反射电路。已发表的临床前报告结果表明，减少 NaV1.7 的表达几乎消除吸入刺激物引起的咳嗽，表明它是减少咳嗽的有希望的目标。站点一 Therapeutics 发现了 NaV1.7 的强效选择性小分子抑制剂，可阻断迷走神经 C 纤维活性呈剂量依赖性。在第一阶段计划中，我们的团队证明了系统性给予异构体选择性 NaV1.7 抑制剂可消除吸入刺激物引起的咳嗽反应有意识的豚鼠。我们第二阶段计划的目标是评估安全性、药代动力学和功效终点，并将吸入式 NaV1.7 抑制剂推进 IND 开发，作为慢性病的治疗方法咳嗽。