The potential of PDE4 inhibitors in asthma or COPD.
At least 11 families of distinct phosphodiesterase (PDE) isoenzymes are known to regulate the function of many cells secondary to altering the intracellular levels of second messengers including cyclic 3'5-monophosphate (cyclic AMP) and cyclic 3'5 guanosine monophosphate (cyclic GMP). While there is a wide distribution of these enzymes throughout the body, it is of interest that inflammatory cells thought to participate in the pathogenesis of inflammatory diseases including asthma and chronic obstructive pulmonary disease (COPD), preferentially express PDE4. This finding has stimulated the search for highly selective inhibitors of these enzymes. Unfortunately, PDE4 inhibitors tend to be associated with a number of unwanted side effects including headache and emesis. However, attempts have been made through rational drug design to synthesize compounds that demonstrate improved side effect profile. Such drugs offer an exciting opportunity to selectively downregulate inflammatory cell function as a novel therapeutic approach in the treatment of airway disease.
Spina
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Sackler Institute of Pulmonary Pharmacology, Department of Respiratory Medicine and Allergy, GKT School of Medicine, King's College London, Bessemer Rd, London, SE5 9PJ UK. domenico.spina@kcl.ac.uk
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006801:Humans; D008173:Lung Diseases, Obstructive / Q000188:drug therapy*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*
D018927:Anti-Asthmatic Agents; D010726:Phosphodiesterase Inhibitors; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4