PDE4 inhibitors as new anti-inflammatory drugs: effects on cell trafficking and cell adhesion molecules expression.
Phosphodiesterase 4 (PDE4) is a major cyclic AMP-hydrolyzing enzyme in inflammatory and immunomodulatory cells. The wide range of inflammatory mechanisms under control by PDE4 points to this isoenzyme as an attractive target for new anti-inflammatory drugs. Selective inhibitors of PDE4 have demonstrated a broad spectrum of anti-inflammatory activities including the inhibition of cellular trafficking and microvascular leakage, cytokine and chemokine release from inflammatory cells, reactive oxygen species production, and cell adhesion molecule expression in a variety of in vitro and in vivo experimental models. The initially detected side effects, mainly nausea and emesis, appear at least partially overcome by the 'second generation' PDE4 inhibitors, some of which like roflumilast and cilomilast are in the later stages of clinical development for treatment of chronic obstructive pulmonary disease. These new drugs may also offer opportunities for treatment of other inflammatory diseases.
Sanz
María Jesús
MJ
Department of Pharmacology, Faculty of Medicine, University of Valencia, Avenida Blasco Ibáñez 15, E-46010 Valencia, Spain.
Cortijo
Julio
J
Morcillo
Esteban J
EJ
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000631:Aminopyridines / Q000494:pharmacology / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D002264:Carboxylic Acids / Q000494:pharmacology / Q000627:therapeutic use; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002465:Cell Movement / Q000187:drug effects; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003509:Cyclohexanecarboxylic Acids; D003521:Cyclopropanes / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D009570:Nitriles / Q000494:pharmacology / Q000627:therapeutic use; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy
D000631:Aminopyridines; D000893:Anti-Inflammatory Agents; D001549:Benzamides; D002264:Carboxylic Acids; D015815:Cell Adhesion Molecules; D003509:Cyclohexanecarboxylic Acids; D003521:Cyclopropanes; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors; C424423:Roflumilast; C433247:Cilomilast; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4