Phosphodiesterase-4 inhibitor therapy for lung diseases

Abstract

Phosphodiesterases (PDEs) are a superfamily of enzymes that catalyze the breakdown of cAMP and/or cyclic guanosine monophosphate (GMP) to their inactive form. PDE4 is the main selective cAMP-metabolizing enzyme in inflammatory and immune cells. Because PDE4 is highly expressed in leukocytes and other inflammatory cells involved in the pathogenesis of inflammatory lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD), inhibition of PDE4 has been predicted to have an antiinflammatory effect and thus therapeutic efficacy. The limited and inconsistent efficacy and side effects of the early compounds made their further development less desirable in asthma, given the excellent efficacy/tolerability ratio of inhaled steroids. The lack of effective antiinflammatory drug treatment for COPD has thus shifted the interest in development toward COPD. Roflumilast, the only PDE4 inhibitor that has reached the market because of the good efficacy/tolerability ratio, is recommended for patients with COPD with severe airflow limitation, symptoms of chronic bronchitis, and a history of exacerbations, whose disease is not adequately controlled by long-acting bronchodilators. Albeit safe, it maintains significant side effects (diarrhea, nausea, weight loss) that make it intolerable in some patients. Future developments of PDE4 inhibitors include extended indications of roflumilast (1) in patients with COPD, and (2) in other respiratory (e.g., asthma) and nonrespiratory chronic inflammatory/metabolic conditions (e.g., diabetes), as well as (3) the development of new molecules with PDE4 inhibitory properties with an improved efficacy/tolerability profile.