Pharmacological characterization of a novel ROCK inhibitor for COPD

新型 ROCK 抑制剂治疗 COPD 的药理学特征

• 批准号: 7999779
• 负责人: Xiaoming Zhang
• 金额: $ 16.38万
• 依托单位: THERON PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7999779
• 关键词: Acetylcholine; Actins; Address; Adrenal Cortex Hormones; Agonist; Airway Resistance; Anti-Inflammatory Agents; Anti-inflammatory; Asthma; Breathing; Bronchial Spasm; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Bronchoconstrictor Agents; Bronchodilator Agents; Caliber; Cavia; Cells; Characteristics; Chemotaxis; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Combined Modality Therapy; Development; Disease; Disease Progression; Disease Resistance; Environmental air flow; Goals; Human; Infiltration; Inflammation; Inflammatory; Inhibitory Concentration 50; Isoenzymes; Lead; Leukocyte Elastase; Lipopolysaccharides; Lung; Maintenance Therapy; Measures; Modeling; Molecular; Mono-S; Morbidity - disease rate; Mus; Muscle relaxation phase; Neutrophil Infiltration; Obstruction; Pathogenesis; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacological Treatment; Phase; Play; Process; Prostaglandins; Protein-Serine-Threonine Kinases; Pulmonary Emphysema; ROCK1 gene; Rattus; Regulatory Pathway; Research Design; Respiratory physiology; Rho-associated kinase; Role; Side; Signal Transduction; Smooth Muscle; Source; Steroid Resistance; Stimulus; Symptoms; Therapeutic Effect; Time; Tissues; airway inflammation; chemokine; cytokine; effective therapy; eosinophil; experience; in vivo; inhibitor/antagonist; kinase inhibitor; lead series; lipid mediator; methacholine; methylxanthine; migration; mortality; mouse model; neutrophil; novel; novel strategies; palliative; pressure; prototype; public health relevance; residence; respiratory smooth muscle; response; rho; rho GTP-Binding Proteins; symptomatic improvement; trafficking

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.

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。目前可用的治疗方法在很大程度上是姑息性的，对慢性阻塞性肺病的炎症过程影响最小，而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，慢性阻塞性肺病似乎是一种很大程度上的类固醇抵抗性疾病。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提供症状改善和减缓疾病进展的新方法。我们的总体目标是开发一种安全有效的吸入性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发现了一种高效的人类ROCK-1和ROCK-2同工酶抑制剂。本提案的目的是进一步表征导联抑制剂TRN-101在与气道抵抗、炎症和重塑相关的模型中的特征。该I期研究的具体目的是：1)证明吸入ROCK抑制剂TRN-101对麻醉大鼠甲基苯丙胺引起的支气管痉挛的支气管保护作用；2)通过COPD急性加重小鼠体内模型评价TRN-101对气道炎症的影响。后一项研究将重点关注吸入ROCK抑制剂对脂多糖（LPS）刺激小鼠气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。