Table 5.
Developmental status of cAMP and cGMP phosphodiesterase inhibitors
| Mediator | Role in COPD | Drug | Clinical development | References |
|---|---|---|---|---|
| PDE4 (phosphodiesterase subtype 4) | Hydrolyzes cAMP, an inhibitor of inflammatory pathways; expressed in a wide variety of cells. | Roflumilast, a selective PDE4 inhibitor; GSK-256066; CHF6001; MK0359; MK-0873; tofimilast; UK-500,001; tetomilast (OPC-6535, PDE4 inhibitor with modest PDE3 inhibitory activity); oglemilast; QAK423A; TPI 1100. | Roflumilast is only US FDA approved PDE4 inhibitor; it reduced exacerbation frequency and also produced clinically significant improvements in dyspnea. GSK-256066 (4-week inhaled treatment) in DBPCRT (NCT00549679) improved residual volume and showed a nonsignificant trend toward augmenting postbronchodilator FEV1. Preclinical testing of CHF6001 (inhaled) shows efficacy and low toxicity in several rat models of pulmonary inflammation. It is in clinical testing (28-day treatment) (NCT01730404) but no results have been reported. Numerous other PDE inhibitors are in clinical testing, including MK-0359 (NCT00482235); MK-0873 (NCT00132730); tofimilast (NCT00219622); UK-500,001 (NCT00263874); tetomilast (OPC-6535) (NCT00874497), terminated, NCT00917150); oglemilast (NCT00671073); QAK423A (NCT01197287); and TPI 1100 (NCT00914433). |
10, 42, 80, 99, 127–129 |
| PDE3/PDE4 | PDE3 degrades both cAMP and cGMP. It is expressed on airway smooth muscle cells and acts as a bronchoconstrictor. Combined PDE3/PDE4 inhibition is often additive or synergistic. | RPL554 | RPL554 (up to 94-day treatment) is being investigated as an adjunct to salbutamol and ipratropium in COPD patients in DBPCRT (NCT02542254). | 10 |
| PDE5 | PDE5 promotes pulmonary arterial vasoconstriction and vessel wall hypertrophy. | Tadalafil (inhibits PDE5) | Tadalafil, which is approved for pulmonary arterial hypertension, in DBPCRT (12-week treatment) (NCT01197469) did not improve exercise capability or quality of life. Another study (NCT01862536) is in progress. | 130 |
Abbreviations: FEV1, forced expiratory volume in 1 second; DBPCRT, double-blind, placebo-controlled, randomized trial; FDA, Food and Drug Administration.