Pharmacological characterization of a novel ROCK inhibitor for COPD

描述（由申请人提供）：慢性阻塞性肺疾病（COPD）是全球发病率和死亡率的主要原因之一。目前可用的治疗在很大程度上是姑息性的，并且对COPD中的炎症过程的影响最小，该炎症过程不可避免地导致肺功能下降。与哮喘不同，吸入皮质类固醇是一种非常有效的治疗方法，COPD似乎是一种主要的类固醇耐药疾病。因此，迫切需要开发也针对疾病的其他成分的药物，主要是气道炎症和重塑。通过减少气道阻力和炎症方面，Rho激酶抑制剂代表了一种新的方法，以提供症状改善和减缓疾病的进展。我们的总体目标是开发一种吸入性、安全有效的ROCK抑制剂，作为COPD（包括慢性支气管炎和肺气肿）患者气流阻塞的维持治疗。Theron已经鉴定出一种人类ROCK-1和ROCK-2同工酶的高效抑制剂。该提案的目的是进一步表征与气道阻力、炎症和重塑相关的模型中的先导抑制剂TRN-101。该I期提案的具体目的是：1）证明吸入ROCK抑制剂TRN-101对麻醉大鼠中乙酰甲胆碱诱导的支气管痉挛的支气管保护作用;和2）使用COPD恶化的体内小鼠模型评估TRN-101对气道炎症的作用。后一项研究将集中于吸入ROCK抑制剂对用脂多糖（LPS）激发的小鼠气道中的中性粒细胞运输的影响。通过实现上述具体目标，我们相信Theron Pharmaceuticals可以推进COPD的新型药物治疗。由于潜在的抗炎活性和对组织重塑的影响，ROCK抑制剂可以为治疗这种疾病提供前所未有的益处。 公共卫生相关性：慢性阻塞性肺疾病（COPD）是全球发病率和死亡率的主要原因之一。目前可用的治疗在很大程度上是姑息性的，并且对导致肺功能不可阻挡地下降的COPD中的炎症过程的影响最小。通过减少气道阻力和炎症方面，Rho激酶抑制剂代表了一种新的方法，以提供症状改善和减缓疾病的进展。我们的总体目标是开发一种吸入性、安全有效的ROCK抑制剂，作为COPD（包括慢性支气管炎和肺气肿）患者气流阻塞的维持治疗。

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality worldwide. The currently available treatments are largely palliative and have minimal impact on the inflammatory process in COPD that inexorably leads to a decline in lung function. Unlike asthma, for which inhaled corticosteroids are a highly effective treatment, COPD appears to be a largely steroid- resistant disease. Therefore, there is a pressing need to develop drugs that also target other components of the disease, mainly airway inflammation and remodeling. By reducing airway resistance and aspects of inflammation, Rho kinase inhibitors represent a novel approach to provide symptomatic improvement and slow the progression of the disease. Our overall objective is to develop an inhaled, safe and efficacious ROCK inhibitor as maintenance therapy for airflow obstruction in patients with COPD, including chronic bronchitis and emphysema. Theron has identified a highly potent inhibitor of the human ROCK-1 and ROCK-2 isoenzymes. The purpose of this proposal is to further characterize the lead inhibitor TRN-101 in models that are relevant to airway resistance, inflammation and remodeling. The specific aims of this phase I proposal are: 1) to demonstrate the bronchoprotective effect of an inhaled ROCK inhibitor, TRN-101, against methacholine-induced bronchospasm in anaesthetized rats; and 2)to evaluate the effects of TRN-101 on airway inflammation using an in vivo mouse model of COPD exacerbation. The latter study will focus on the effects of an inhaled ROCK inhibitor on neutrophil trafficking in the airways of mice challenged with lipopolysaccharide (LPS). By achieving the specific aims outlined above, we believe Theron Pharmaceuticals can advance a novel pharmacological treatment for COPD. Because of the potential anti-inflammatory activity and impact on tissue remodeling, ROCK inhibitors could offer unprecedented benefits for the treatment of this disease. PUBLIC HEALTH RELEVANCE: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality worldwide. The current available treatments are largely palliative and have minimal impact on the inflammatory process in COPD that leads to an inexorable decline in lung function. By reducing airway resistance and aspects of inflammation, Rho kinase inhibitors represent a novel approach to provide symptomatic improvement and to slow the progression of the disease. Our overall objective is to develop an inhaled, safe and efficacious ROCK inhibitor as maintenance therapy for airflow obstruction in patients with COPD, including chronic bronchitis and emphysema.