Pharmacological characterization of a novel ROCK inhibitor for COPD

描述(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。目前可用的治疗方法主要是姑息性的，对COPD的炎症过程影响很小，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，而COPD似乎是一种在很大程度上对类固醇具有抵抗力的疾病。因此，迫切需要开发针对疾病其他组成部分的药物，主要是呼吸道炎症和重塑。通过减少呼吸道阻力和炎症方面，Rho激酶抑制剂代表了一种新的方法，可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型、安全有效的ROCK抑制剂，作为COPD患者气流阻塞的维持疗法，包括慢性支气管炎和肺气肿。塞隆已经确定了一种高度有效的人类ROCK-1和ROCK-2同工酶的抑制剂。这项建议的目的是在与气道阻力、炎症和重塑相关的模型中进一步鉴定先导抑制剂TRN-101的特征。这一第一阶段提案的具体目的是：1)证明吸入岩石抑制剂TRN-101对麻醉大鼠乙酰甲胆碱诱导的支气管痉挛的保护作用；以及2)使用COPD加重的活体小鼠模型评估TRN-101对呼吸道炎症的影响。后一项研究将集中在吸入ROCK抑制剂对脂多糖(LPS)攻击小鼠呼吸道中性粒细胞运输的影响。通过实现上述具体目标，我们相信塞隆制药公司可以推进COPD的一种新的药物治疗。由于潜在的抗炎活性和对组织重塑的影响，岩石抑制剂可以为这种疾病的治疗提供前所未有的好处。 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。目前可用的治疗方法主要是姑息性的，对COPD的炎症过程影响很小，炎症过程导致肺功能不可避免的下降。通过减少呼吸道阻力和炎症方面，Rho激酶抑制剂代表了一种新的方法来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型、安全有效的ROCK抑制剂，作为COPD患者气流阻塞的维持疗法，包括慢性支气管炎和肺气肿。

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.