. Mucus dysfunction underlies the pathophysiology of a number of common respiratory diseases including asthma, cystic fibrosis, and chronic obstructive pulmonary disease (COPD). Asthma alone impacts 9% of the US population, resulting in considerable cost, morbidity, and occasional mortality caused by mucus hypersecretion. Recently, it was discovered that Synaptotagmin-2 (Syt2) regulates fast exocytosis of mucin granules in the lungs, and that Syt2 is limiting with respect to stimulated mucus secretion. These findings suggest that small-molecule inhibitors of Syt2 may comprise a new class of therapeutic agents allowing the clinical modulation of stimulated mucus secretion. We have developed a number of early lead inhibitors of Syt2, capable of inhibiting mucus secretion in airways of mice with IL-13-induced mucous metaplasia. These include Exo1, our early lead compound. Phase I studies will focus on the derivatization of the Exo1 compound, and success would advance a new drug class likely to improve quality-of-life for patients with a number of life threatening, chronic respiratory conditions including asthma, cystic fibrosis, and COPD. Phase II work would include formulation and delivery studies followed by pre-IND studies including GLP toxicology and animal efficacy studies in accordance with the most recent CDER guidance.
. In this Phase I project, inhibitors against Syt2 are pursued as potential clinical therapeutic agents targeting mucus hypersecretion. Mucus dysfunction is at the heart of major respiratory diseases including asthma, cystic fibrosis, and chronic obstructive pulmonary disease. Following up on recent findings that Syt2 plays a limiting role in mucus hypersecretion in the lungs, this project proposes optimization of lead compound Exo1.