Phosphodiesterase 4 Inhibitors for the Treatment of Asthma and COPD

Abstract

Type 4 cyclic nucleotide phosphodiesterases (PDE4s) are metallo-hydrolases which specifically hydrolyze cAMP to AMP in various cells types. The catalytic core is a bimetallic ion center composed of a tightly bound Zn(2+) and a loosely bound Mg(2+), which plays a dictating role in eliciting cAMP binding and catalysis activation. An invariant glutamine positioned opposite to the ion center serves as the substrate recognition determinant and synergizes the transient Mg-oxo-phosphate interaction in the substrate complex. The Mg(2+) binding is activated by a PKA-mediated serine phosphorylation and modulated through protein-protein interactions, thus, providing efficient mechanisms in the temporal regulation of cAMP signaling. Several PDE4 inhibitors including roflumilast, cilomilast and rolipram also rely on the interaction with the glutamine and metallic ion center for binding, with their affinity enhanced dramatically by the presence of the Mg(2+) ion. Recent studies have provided new insights into the role of this enzyme in inflammatory settings, CFTR regulation, long term potentiation, and its importance in immune surveillance. The major inflammatory cytokines which are modulated with PDE4 inhibitors include TNFalpha, IL-2, IFNgamma, IL-12, GM-CSF and LTB(4). The role of PDE4 inhibitors in modulating cytokines, lipid mediators and in mucociliary clearance, along with clinical efficacy in asthma and/or COPD demonstrated with roflumilast and cilomilast, suggest a broad anti-inflammatory spectrum for these compounds. Presently, the major impediment to approval of these novel therapies has been the mechanism based gastrointestinal adverse events which has limited the dosing and the ultimate efficacy with these novel therapeutic agents.

Phosphodiesterase-4 inhibition attenuates pulmonary inflammation in neonatal lung injury

“…Phosphodiesterase-4 inhibitors are under clinical investigation as a novel therapeutic strategy for adult inflammatory lung diseases, such as asthma and chronic obstructive pulmonary disease. The selective phosphodiesterase-4 inhibitors cilomilast and roflumilast have been evaluated in clinical trials (phase III) for chronic obstructive pulmonary disease, but these drugs have not yet been approved [13,14,24,54]. Phosphodiesterase-4 inhibitors have not yet been evaluated as a therapeutic strategy for neonatal inflammatory lung diseases such as bronchopulmonary dysplasia.…”

“…PDE4 isoforms are expressed selectively in the brain, leukocytes (including neutrophilic and eosinophilic granulocytes, macrophages and T-lymphocytes), mast cells, dendritic cells and in the vascular endothelium [15]. Inhibition of PDE4 has anti-inflammatory properties in inflammatory pulmonary diseases in adult laboratory animals [16][17][18][19] and has therapeutic potential in patients suffering from chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome and asthma [13,14,[20][21][22][23][24]. BPD and COPD are serious chronic lung diseases at the extreme stages of life and PDE4 inhibitors may also provide a therapeutic option for very premature infants with BPD.…”

Pivotal effects of phosphodiesterase inhibitors on myocyte contractility and viability in normal and ischemic hearts

“…Recently, new PDE4 inhibitors with fewer side effects have been developed. Clinically relevant examples include cilomilast (Ariflo®) and roflumilast (Daxas®), which are both under investigation for the treatment of inflammatory airway disease [148] . In the heart, PDE4 inhibitors seem to affect contrac tility only when the myocardium is already stimulated.…”

“…The two selec tive PDE4 inhibitors, cilomilast and roflimilast, have been shown to be effective in the treatment of asthma or COPD without the emetic side effect of rolipram [148] . There is limited information available regarding the cardiovascular effects of PDE4 inhibitors in the clinical setting.…”

Improvement of Neuronal Differentiation by PDE4 Inhibition in Human Bone Marrow-mesenchymal Stem Cells

“…Rolipram [11]은 PDE4 억제 화합물로 알츠하이머 병 [5], 인 지장애 [14], 헌팅턴무도 병(Huntington disease) [12], 외상적 뇌손상 [1], 척수 손상 [6], 호흡기 질환 [7] 등 여러 질병모델에서 폭넓게 연구되었다. 천연 폴리페놀계 화합물인 resveratrol (RSV; 3, 4, 5'-tri-hydroxy-trans-stillbene, C14H12O) 역시 PDE4 를 억제 물질로 cAMP를 증가시킨다고 보고되었다 [15].…”