Parmedics, Inc

Development of Small Molecule Antagonists of PAR-2 for Treatment of Asthma - 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.