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

• 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
• 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

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.

项目摘要 慢性咳嗽，或持续超过八周的咳嗽，是一种通常与 慢性阻塞性肺病（COPD）、哮喘、特发性肺纤维化 支气管扩张或胃食管反流病（GERD）。在其他情况下，病因不明，虽然它 已经注意到，咳嗽通常首先在严重的病毒性呼吸道感染之后出现。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。 在美国的患病率高达11%，在大多数情况下，这种情况是难治性的。 令人信服的证据支持这一假设，即慢性咳嗽是由感觉器官的改变引起的。 对以前无害的刺激产生超敏反应的生理学。电压口控钢离子通道 NaV1.7在通过感觉运动触发咳嗽的无髓鞘迷走神经传入中高度表达 反射电路来自已发表的临床前报告的结果显示，NaV1.7表达的降低几乎 消除由吸入刺激物引起的咳嗽，表明它是减少咳嗽的有希望的靶点。SiteOne Therapeutics已经发现了阻断迷走神经C纤维的NaV1.7的有效和选择性小分子抑制剂 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 同种型选择性NaV1.7抑制剂的给药消除了哮喘患者对吸入刺激物的咳嗽反应， 清醒的豚鼠我们的2期项目的目的是评估安全性、药代动力学和疗效 终点，并将吸入性NaV1.7抑制剂推进IND使能开发，作为慢性 咳嗽.