Airway smooth muscle (ASM) represents an attractive therapeutic target in severe asthma. Current bronchodilator medications are remarkably ineffective in severe asthma, probably because they activate a long and complex relaxant signaling pathway, whose multiple steps are vulnerable to antagonism by inflammation- activated pathways that confound relaxant signaling. Instead, a more robust strategy to disrupt ASM contraction is to target the contractile apparatus directly. To this end, we identified small molecules that inhibit smooth muscle myosin polymerization, relax human airway myocytes, and blunt bronchoconstriction in mouse lung slices and from these selected a lead compound. We now propose a comprehensive program in which the lead compound is chemically optimized for efficacy, potency, selectivity, safety, and desirable pharmacological and pharmaceutical properties when administered by inhalation. This program will culminate in the development of a new candidate medicine whose preclinical properties demonstrate its suitability for testing in human asthmatics. An IND application will be submitted to enable such testing. If successful, this project will result in the complete preclinical development of a new class of asthma medication (smooth muscle myosin polymerization inhibitor) with an entirely novel mechanism of action (literally dissolving the contractile apparatus) directed at a novel molecular target (smooth muscle myosin filaments). Because they dissolve myosin filaments, we call the new class of medication myosolvins.
During an acute asthma attack, muscle bands that encircle the bronchial airways contract, thereby constricting the airway and blocking airflow, but currently available bronchodilator medications often fail to relax that mus- cle. To satisfy the unmet need for more effective bronchodilator medications in asthma, we propose to develop a new class of drugs that literally dissolve a key element of the contractile apparatus within airway muscle. The research proposed here should result in the creation of a new bronchodilator medication ready for testing in people.