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

项目总结 慢性咳嗽，或持续八周以上的咳嗽，是一种经常与 患有慢性阻塞性肺疾病(COPD)、哮喘、特发性肺纤维化、 支气管扩张或胃食道反流病(GERD)。在其他情况下，病因尚不清楚，尽管 已经注意到，咳嗽通常首先出现在严重的病毒呼吸道感染之后。慢性咳嗽有 严重的生理、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慢性咳嗽是由感官改变引起的假设 对先前无害的刺激引起过敏的生理学。电压门控钠离子通道 NAV1.7在无髓迷走神经传入中高表达，可通过感觉运动引发咳嗽 反射回路。一份已发表的临床前报告的结果显示，减少Nav1.7的表达几乎 消除吸入刺激物引起的咳嗽，表明它是一个有希望的目标，以减少咳嗽。Site One Treateutics公司发现了有效和选择性的Nav1.7小分子抑制剂，可以阻断迷走神经C纤维 活性呈剂量依赖关系。在第一阶段的项目中，我们的团队展示了系统性 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 清醒的豚鼠。我们第二阶段计划的目标是评估安全性、药代动力学和疗效 终点，并将吸入的Nav1.7抑制剂推进到能够促进IND的开发，作为治疗慢性 咳嗽。

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.