Chronic obstructive pulmonary disease (COPD) and especially asthma affect millions of Americans. As of 1995, an estimated 14.9 million persons suffer chronic symptoms. Despite several different therapeutic approaches, disease severity also is on the rise as reflected by increasing mortality rates. The treatment of COPD and asthma relies on long-term reduction of the chronic inflammatory response and acute symptomatic control by the use of bronchodilators. In the latter class, inhaled Beta adrenergic agents are most commonly used but suffer from reduced efficacy with prolonged use secondary to receptor desensitization. We propose to begin development of a new class of bronchodilators that act directly on the target responsible for force generation, the motor protein smooth muscle myosin. We plan to introduce this target into Cytokinetic's robust high throughput screening technology to discover compounds that will act via this unique mechanism. Using biochemical and physiological means, these compounds will be screened for secondary undesirable properties and then tested in semi-intact systems. We expect to identify chemical compounds that have the potential to demonstrate proof of principle in relevant models of bronchoconstriction. These compounds may then eventually lead to a novel pharmacologic class of smooth muscle relaxants with applicability in other therapeutic areas. PROPOSED COMMERCIAL APPLICATIONS: Given the number of individuals that use bronchodilators in various lung diseases, the potential market is enormous. The estimated 2002 market size for the most widely used inhaled beta-adrenergic agents (albuterol and salmeterol) is $1.3 billion dollars (Med Ad News, 2000, Vol. 19, p. 59). Agents that directly target the contractile machinery could be used either as adjunctive therapy or potentially as a primary agent. In addition, a potent smooth muscle relaxant may have applications in the other large therapeutic areas such as hypertension, pre-term labor, and bladder spasmaticity leading to incontinence.
