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：当前对哮喘的治疗主要旨在减少通过直接治疗气道炎症。尽管在一部分患者中成功，但哮喘恶化仍然是发病率和死亡率的重要原因，并可能导致呼吸道受伤，肺功能下降和死亡。更严重的哮喘患者加剧是特别关心的是，美国医疗保健费用和损失的生产力帐户在美国/年为210亿美元年度医疗保健支出。因此，迫切需要开发新疗法用于治疗哮喘。蛋白酶激活的受体-2（PAR-2）是G蛋白偶联的受哮喘诱导过敏原释放的丝氨酸蛋白酶激活的受体（例如德国蟑螂，尘螨和真菌替代品）以及肥大细胞胰蛋白酶人气道胰蛋白酶，膜结合的TMPRSS2和中性粒细胞弹性酶。激活PAR-2 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，我们显示了 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，粘液分泌和气道高血弹蛋白）虽然PAR-2/ GAQ-CA2+途径可能是有益的（例如，支气管 - 释放）。我们的十年配体识别计划导致了一些最有效，最有选择性的PAR-2 激动剂和第一个完整的PAR-2拮抗剂C391。此外，我们已经表明C391可以在临床前模型中减少有害的A.替代抗诱导的哮喘指标。最近，我们已经确定了几个新型的小分子PAR-2拮抗剂，包括B- arrestin- 选择性拮抗剂C781是仅针对有害效应的有前途的候选人气道中的PAR-2。我们的中心假设是B- arrestin选择性拮抗PAR-2的拮抗作用将减少过敏原引起的哮喘指标，导致加重。第一个目标这一I阶段ISTTR提案是证明第一个小分子偏置拮抗par- 2配体（C781）可以有效地限制过敏原诱导的哮喘指标模型。第二个目标是修改C391和C781进行肺特异性靶向保留/改进其PAR-2拮抗功能。我们的公司Parmedics是基于以下原则，即我们可以通过改进来创建自定义修改这种新类哮喘的药代动力学特性和稳定性疗法。