Development of PAR2 Antagonists for Control of Asthma

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.