Identifying Molecular Targets for New Drug Development for Chronic Obstructive Pulmonary Disease: What Does the Future Hold?

There is an urgent need to develop more effective therapies for chronic obstructive pulmonary disease (COPD) that target the underlying inflammatory disease process. Current therapies with long-acting bronchodilators and inhaled corticosteroids fail to prevent either disease progression or mortality, as they do not suppress the underlying inflammation. With better understanding of the inflammatory and destructive process in the pathophysiology of COPD, several new therapeutic targets have been identified. Several mediator antagonists or inhibitors tested in COPD have so far been disappointing. Broad-spectrum anti-inflammatory drugs may be more effective, and include inhibitors of the proinflammatory enzymes phosphodiesterase-4, p38 mitogen-activated protein kinase, Janus-activated kinases, NF-κB kinase, and PI3kinase-γ and -δ, but side effects after oral administration are a major limitation; therefore, in future inhaled delivery may be necessary. A new promising approach is reversal of corticosteroid resistance through increasing histone deacetylase-2 activity. This might be achieved by existing treatments such as theophylline, nortriptyline, and macrolides, or more selectively by PI3kinase-δ inhibitors. Other treatments in development target oxidative stress, the failure to resolve inflammation, aberrant repair mechanisms, and accelerated lung aging.