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Development of PAR2 Antagonists for Control of Asthma

开发用于控制哮喘的 PAR2 拮抗剂

基本信息

批准号：
9592081
负责人：
Scott Boitano
金额：
$ 22.72万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9592081
关键词：
Acute Address Adult Adverse effects Affect Allergens Alternaria Animal Model Arrestins Asthma Benign Cells Child Chronic Collaborations Competitive Binding Data Development Dictyoptera Dinoprostone Disease Environmental Exposure Epithelial Epithelial Cells Exploratory/Developmental Grant Exposure to Extrinsic asthma G-Protein-Coupled Receptors GPR17 gene GTP-Binding Proteins Human Hyperplasia Immune response In Vitro Industrialization Inflammation Inflammatory Knock-out Knockout Mice Laboratories Libraries Lung diseases MAP Kinase Gene Measures Metabolism Modeling Mucous body substance Mus PAR-2 Receptor Pain Pathway interactions Patients Peptide Hydrolases Performance Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Pharmacotherapy Physiological Pollen Population Pre-Clinical Model Prevalence Prostaglandin Production Reporting Respiratory Signs and Symptoms Role Signal Transduction Symptoms Syndrome Testing Therapeutic Toxic effect absorption airway hyperresponsiveness arrestin 2 clinically relevant cytokine drug development drug discovery experimental study fungus improved in vivo in vivo Model inflammatory pain mouse model neutralizing antibody new therapeutic target novel novel strategies novel therapeutics peptidomimetics pre-clinical preclinical evaluation protective effect pyroglyphid recruit response screening small molecule

项目摘要

Project Abstract Allergic asthma is increasing in prevalence and triggered by specific environmental exposures. Over the past several decades asthma treatments have been largely unchanged and it is an unfortunate reality that asthma remains uncontrolled in more than half the patients receiving standard asthma medication. Unlike more benign allergens such as pollens, asthma-associated allergens (asthmagens; e.g., certain fungi, cockroaches, and dust mites) have protease activity. Asthmagen proteases provide multiple mechanisms for increased allergen activity including the direct activation of the G protein-coupled receptor (GPCR), Protease-activated receptor-2 (PAR2). In mouse models, knockout of PAR2 significantly reduces asthma allergen-induced asthma symptoms. Recent reports have shown that PAR2 neutralizing antibodies can also effectively reduce allergen- induced asthma symptoms. Taken together, PAR2 provides a novel target for drug discovery in the control of allergic asthma. We have recently developed a potent and specific PAR2 antagonist shown to block airway epithelial PAR2 signaling in vitro and block PAR2-associated pain response in vivo. Preliminary data from our laboratory suggests that C391 can effectively reduce allergen-induced asthma in conventional mouse models. In this application we propose to optimize C391 for pharmacological control of the development of allergic asthma in highly relevant in vivo models. Optimization includes reduced size, improved absorption, distribution, metabolism and toxicity performance as well as improved in vivo performance as measured by asthma symptom control in highly relevant pre-clinical models. The completion of these aims will provide a large pre- clinical step toward the development of a new class of asthma therapeutics.

项目摘要