Lay Abstract: Asthma is a widely prevalent condition that affects 1 in 12 adults in the United States and an estimated 300 million individuals worldwide. Mild asthma is well controlled by current standard of care (SOC), including long-acting b-adrenergic receptor agonists, anti- leukotrienes and/or inhaled corticosteroids. As patients progress to severe disease add-on treatment options can include newer biologics/antibody treatments. While these treatments are useful for certain conditions, their application and known side effects limit their applicability resulting in 50% of asthmatics remaining untreated. There is a clear need for developing novel asthma drugs to treat this population. Protease-activated receptor-2 (PAR2) is a G-protein- coupled receptor activated by serine proteases released from asthma-inducing pathogens as well as by endogenous proteases associated with asthma inflammation. We have shown that PAR2 is a viable target for asthma drug development by identifyin two small molecule PAR2 antagonists, C391 and C781, that limit allergen-induced asthma indicators following direct nasal application in pre-clinical animal models. In this application we propose to characterize two novel PAR2 antagonists (C937 and C938) with improved pharmacodynamics and pharmacokinetics that could allow for novel PAR2-directed antagonism treatment following oral drug administration. Successful completion of the proposed feasibility studies (Phase I) will establish a novel drug lead for asthma and allow for development of a small business Phase 2 application that will include drug optimization and formulation, in vivo efficacy of lead compounds in allergen challenges of chronic exposure mouse models as well as larger animal asthma models (rats and dogs) and advanced in vivo PK studies. Our overall goal is to move these drug leads forward so that they can be tested (Clinical Phase I studies) and used in humans to control asthma.