Development of New Drugs for COPD

Peter      J. Barnes

Abstract

Chronic obstructive pulmonary disease (COPD) is an increasing global health problem and cause of death. COPD is a chronic inflammatory disease predominantly affecting small airways and lung parenchyma that leads to progressive airway obstruction. However, current therapies fail to prevent either disease progression or mortality. The mainstay of current drug therapy is long-acting bronchodilators. Several once daily inhaled β2-agonists and muscarinic antagonists (and combinations) are now in development. No treatments effectively suppress chronic inflammation in COPD lungs. 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, but CXCR2 antagonists that block pulmonary neutrophil and monocyte recruitment are more promising. Broad spectrum anti-inflammatory drugs may be more effective, and include inhibitors of the proinflammatory enzymes phosphodiesterase-4, p38 mitogen-activated protein kinase, Janus kinases, NF-κB kinase and PI3 kinase-γ and -δ, but side effects after oral administration are a major limitation so that in future inhaled delivery may be necessary. A new promising approach is reversal of corticosteroid resistance through increasing histone deacetylase-2 (HDAC2) activity. This might be achieved by existing treatments such as theophylline, nortriptyline and macrolides, or more selectively by PI3 kinase-δ inhibitors. Thus although there have been major advances in the development of long-acting bronchodilators for COPD, it has proved difficult to find anti-inflammatory treatments that are safe and effective.

Keywords: Anti-inflammatory, bronchodilator, chemokine, cytokine, histone deacetylase, Janus kinase, nuclear factor-κB, p38 mitogen-activated protein kinase, phosphodiesterase-4, phosphoinositide-3-kinase