Development of Small Molecule Antagonists of PAR-2 for treatment of asthma

开发用于治疗哮喘的 PAR-2 小分子拮抗剂

基本信息

批准号：
10326155
负责人：
Scott Boitano
金额：
$ 28.34万
依托单位：
PARMEDICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2022-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10326155
关键词：
Adrenal Cortex Hormones Adrenergic beta-Agonists Adult Aerosols Affect Affinity Agonist Allergens Alternaria Animals Antibody Therapy Arizona Asthma Biological Biological Sciences Biosensor Blocking Antibodies Bronchodilation Canis familiaris Cessation of life Collaborations Complex Custom Development Dictyoptera Dinoprostone Disease Drug Delivery Systems Drug Kinetics Elastases Epithelial Epithelial Cells Extrinsic asthma Filtration Formulation G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Genetically Modified Animals German population Goals Headache Health Care Costs Health Expenditures Human Hyperplasia In Vitro Individual Infiltration Inflammation Inflammatory Inhalation Interleukin 4 Receptor Interleukin-13 Interleukin-5 Lead Leukocyte Elastase Leukocytes Leukotrienes Ligands Liquid substance Lung MAPK3 gene Mediating Membrane Microsomes Modification Molecular Montana Morbidity - disease rate Mucous body substance Mus Muscle relaxation phase Nasopharyngitis Outcome PAR-2 Receptor Pathway interactions Patients Peptide Hydrolases Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Phase Physiological Plasma Play Pre-Clinical Model Principal Investigator Production Productivity Property Protease Inhibitor Pyroglyphidae Rattus Relaxation Respiratory System Respiratory Tract Infections Role Serine Protease Severities Side Signal Transduction Small Business Technology Transfer Research Smooth Muscle Solubility Symptoms TMPRSS2 gene Testing Therapeutic Time Trypsin Tryptase United States Universities Xolair adverse outcome airway hyperresponsiveness airway inflammation anti-IgE arrestin 2 asthma exacerbation asthma model asthmatic base beta-arrestin cell analyzer cytokine design eosinophil fungus improved in vivo inflammatory lung disease inhibitor/antagonist injured airway interleukin-19 methylcholine mortality mouse model neutrophil novel novel therapeutics omalizumab pathogen patient subsets pre-clinical preservation programs protective effect pulmonary function decline pyroglyphid receptor release of sequestered calcium ion into cytoplasm response small molecule standard of care

项目摘要

ABSTRACT: Current treatments for asthma largely are aimed at reducing exacerbations by directly treating airway inflammation. While successful in a subset of patients, asthma exacerbations remain a significant cause of morbidity and mortality and can result in airway injury, lung function decline and death. Exacerbations in more severe asthmatics are of particular concern, as health care costs and lost productivity account for $21 billion/year in US annual health care expenditures. Thus, there is a critical need to develop new therapies to be used in the treatment of asthma. Protease-activated receptor-2 (PAR-2) is a G-protein-coupled receptor activated by serine proteases released from asthma-inducing allergens (e.g. German cockroach, dust mites and the fungus Alternaria alternata), as well as by mast cell tryptase, human airway trypsin, membrane bound TMPRSS2 and neutrophil elastase. Activated of PAR-2 via allergens or agonists results in complex cellular signaling (b-arrestin and Gaq-Ca2+) that contribute to the physiological response. Using genetically modified animals, we have shown that PAR-2/b-arrestin signaling can lead to detrimental outcomes (e.g., cytokine production, leukocyte infiltration, epithelial hyperplasia, mucus secretion and airway hyperresponsivenes) while PAR-2/ Gaq-Ca2+ pathways can be beneficial (e.g., broncho-relaxation). Our decade-long ligand-identification program has resulted in some of the most potent and selective PAR-2 agonists and the first full PAR-2 antagonist, C391. Further, we have shown that C391 can reduce the detrimental A. alternata-induced asthma indicators in pre-clinical models. Recently, we have identified several novel small molecule PAR-2 antagonists, including the b-arrestin- selective antagonist C781 that is a promising candidate for targeting only the detrimental effects of PAR-2 in the airway. Our central hypothesis is that b-arrestin-selective antagonism of PAR-2 will reduce allergen-induced asthma indicators that lead to exacerbations. The first objective of this Phase I STTR proposal is to demonstrate the first small molecule biased antagonistic PAR- 2 ligand (C781) can effectively limit allergen-induced asthma indicators in a pre-clinical mouse model. The second objective is to modify C391 and C781 for pulmonary-specific targeting while retaining/improving on their PAR-2 antagonistic function. Our company, PARMedics, was founded on the principle that we can create custom modifications with improved pharmacokinetic properties and stability for the development of this new class of asthma therapeutics.

摘要：目前治疗哮喘的主要目的是通过以下方式减少哮喘发作：直接治疗气道炎症。虽然在部分患者身上取得了成功，但哮喘病情加重仍然是发病率和死亡率的一个重要原因，并可能导致气道阻塞损伤、肺功能下降和死亡。更严重的哮喘患者的病情加重是尤其值得关注的是，美国每年的医疗保健费用和生产力损失高达 210 亿美元每年的医疗保健支出。因此，迫切需要开发新疗法用于治疗哮喘。蛋白酶激活受体 2 (PAR-2) 是一种 G 蛋白偶联受体受体由诱发哮喘的过敏原（例如德国过敏原）释放的丝氨酸蛋白酶激活蟑螂、尘螨和真菌 Alternaria alternata)，以及肥大细胞类胰蛋白酶，人气道胰蛋白酶、膜结合 TMPRSS2 和中性粒细胞弹性蛋白酶。 PAR-2的激活通过过敏原或激动剂导致复杂的细胞信号传导（b-arrestin 和 Gaq-Ca2+）有助于生理反应。使用转基因动物，我们已经证明 PAR-2/b-arrestin 信号传导可能导致有害结果（例如细胞因子的产生、白细胞浸润、上皮增生、粘液分泌和气道高反应性）而 PAR-2/ Gaq-Ca2+ 途径可能是有益的（例如，支气管松弛）。我们的十年配体识别程序已经产生了一些最有效和选择性的 PAR-2 激动剂和第一个完整的 PAR-2 拮抗剂 C391。此外，我们还表明 C391 可以减少临床前模型中由链格孢菌诱发的有害哮喘指标。最近，我们已经鉴定出几种新型小分子 PAR-2 拮抗剂，包括 b-arrestin- 选择性拮抗剂 C781，是仅针对有害影响的有前途的候选药物气道中的 PAR-2。我们的中心假设是 PAR-2 的 b-arrestin 选择性拮抗作用将减少过敏原诱发的哮喘指标，从而导致病情加重。第一个目标是这一阶段的 STTR 提案是为了证明第一个小分子偏向拮抗 PAR- 2配体（C781）可以有效限制临床前小鼠过敏原诱发的哮喘指标模型。第二个目标是修改 C391 和 C781 以实现肺部特异性靶向，同时保留/改善其 PAR-2 拮抗功能。我们的公司 PARMedics 是建立的原则是我们可以通过改进来创建自定义修改开发此类新型哮喘的药代动力学特性和稳定性疗法。