New phosphodiesterase inhibitors as therapeutics for the treatment of chronic lung disease.
Phosphodiesterase 4 (PDE4) is a member of the growing family cyclic AMP and cyclic GMP. Earliest described inhibitors of PDE4, such as rolipram, demonstrate marked anti-inflammatory and bronchodilatory effects in vitro and in vivo. The clinical utility of these earlier compounds was limited by their propensity to elicit gastrointestinal side effects. This has led to an extensive effort to identify novel PDE4 inhibitors that maintain the anti-inflammatory activity and bronchodilatory activity of rolipram but with a reduced potential to produce side effects. This article summarizes the evidence supporting the utility of selective PDE4 inhibitors in the treatment of asthma and chronic obstructive pulmonary disease, discusses the recent results obtained in clinical trials with second-generation inhibitors, and presents two approaches designed to identify additional novel selective PDE4 inhibitors.
Barnette
M S
MS
Department of Pulmonary Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939, USA.
Underwood
D C
DC
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000402:Airway Obstruction / Q000201:enzymology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D008173:Lung Diseases, Obstructive / Q000188:drug therapy* / Q000503:physiopathology; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*
D010726:Phosphodiesterase Inhibitors; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4