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Novel ROCK inhibitors for COPD

COPD 的新型 ROCK 抑制剂

基本信息

批准号：
8979611
负责人：
Jurg Pfister
金额：
$ 71.52万
依托单位：
THERATROPHIX, LLC
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-15 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8979611
关键词：
Adrenal Cortex Hormones Affect Aftercare Agonist Animal Model Anti-Inflammatory Agents Anti-inflammatory Biological Breathing Bronchodilation Bronchodilator Agents Cardiotoxicity Cause of Death Characteristics Chronic Obstructive Airway Disease Clinic Clinical Clinical Trials Contracts Data Decision Making Deposition Development Disease Disease Progression Dose Drug Interactions Drug Kinetics Drug Targeting Ensure Evaluation Excretory function Fibroblasts Goals Health Care Costs Human In Vitro Individual Inflammatory Intravenous Investigation Isoenzymes Lead Link Lung Lung Inflammation Lung diseases Maintenance Maintenance Therapy Medical Medicine Metabolic Metabolism Modeling Molecular Morbidity - disease rate Oral Administration Patients Pennsylvania Pharmaceutical Preparations Pharmacodynamics Phase Phosphotransferases Plasma Proteins Platelet-Derived Growth Factor Play Prevalence Process Property Prophylactic treatment Protein Binding Protein Isoforms ROCK1 gene Research Proposals Resistance Respiratory physiology Rho-associated kinase Risk Rodent Role Route Safety Series Slice Small Business Innovation Research Grant Smooth Muscle Myocytes Symptoms System Testing Therapeutic Tissues United States absorption airway hyperresponsiveness analog base cigarette smoke-induced cytokine drug metabolism environmental tobacco smoke exposure fasudil human disease improved in vitro Assay in vivo in vivo Model inhibitor/antagonist migration mortality mouse model novel novel strategies novel therapeutics ozone exposure palliative pharmacokinetic characteristic pre-clinical preclinical study prototype public health relevance pulmonary function research study respiratory smooth muscle translational medicine

项目摘要

DESCRIPTION (provided by applicant): Our overall objective is to develop an inhaled, safe and efficacious Rho kinase (ROCK) inhibitor as novel maintenance therapy for patients with chronic obstructive pulmonary disease (COPD), with the unique potential to slow disease progression. COPD is one of the leading causes of morbidity and mortality worldwide due to high disease prevalence and ineffective therapies. COPD is the 3rd leading cause of death in the United States and is responsible for billions of dollars in annual healthcare costs. Current treatments are largely palliative and have minimal impact on the key inflammatory processes in COPD that inexorably lead to disease progression and associated decline in lung function. Therefore, there is an urgent need to develop drugs that target components of COPD not affected by present medicines. There is increasing evidence that the ROCK isoforms, ROCK1 and ROCK2, play an important role in the maintenance of airways tone and in lung inflammation and remodeling, suggesting that ROCK inhibitors may represent a novel approach for COPD. Theratrophix (TRX) has identified potent inhibitors of the human ROCK1 and ROCK2 isoenzymes, including the lead TRX-101, that are more potent than the prototype ROCK inhibitors, fasudil and Y-27632. The results of the previous Phase 1 SBIR (1R43HL104902-01) demonstrated that TRX-101 had bronchoprotective, anti-inflammatory and anti-fibrotic effects in rodent systems in vitro and in vivo. In this proposal we outline a series of decision-making preclinical studies to evaluate and progress an inhaled ROCK inhibitor, TRX-101 or analog, to the preclinical development phase as a potential novel therapeutic for COPD; the profiling is underpinned by investigation in several disease-relevant systems. The specific aims of this Phase 2 proposal are: Aim 1: Developability profile of TRX-101 and analogs, including pharmacokinetic (PK) characteristics - to determine which compound has the desired characteristics for a long-acting, inhaled compound, including sustained lung retention and pharmacodynamic activity, and the physicochemical characteristics for inhaled delivery; Aim 2: Assessment of bronchodilator and anti-inflammatory effects of selected TRX-compound in human lung systems - A series of key translational medicine studies will be conducted using human precision-cut lung slices and human airway smooth muscle cells, and human lung fibroblasts; Aim 3: Evaluation of inhaled TRX- compound in mouse models of cigarette smoke-induced COPD, to determine the in vivo effects in a disease-relevant animal model that is resistant to corticosteroids. By achieving the specific aims outlined it is anticipated that Theratrophix will have identified a quality inhaled ROCK inhibitor which will be ready to enter IND-enabling studies as a critical step towards initiation of clinical trials in COPD. Based upon the ability to produce potent bronchodilation, anti-inflammatory activity and an impact on tissue remodeling in a single molecular entity, an inhaled ROCK inhibitor has the potential to have a unique profile which could offer unprecedented therapeutic benefits in COPD, in particular slowing disease progression.