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Phosphodiesterase-4

Selective and Dual-Specificity Inhibitors for the Therapy of Chronic Obstructive Pulmonary Disease

Department of Pharmacology and Therapeutics, Institute of Immunity, Infection, and Inflammation, University of Calgary, Calgary, Alberta, Canada

Correspondence and requests for reprints should be addressed to Mark A. Giembycz, Ph.D., Department of Pharmacology and Therapeutics, Respiratory Research Group, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1 Canada. E-mail: giembycz{at}ucalgary.ca

Phosphodiesterase-4 isoenzymes have absolute specificity for cyclic adenosine-3',5'-monophosphate and are considered potential therapeutic targets for the treatment of chronic inflammatory disorders, such as chronic obstructive pulmonary disease, with small-molecule inhibitors. Several selective phosphodiesterase-4 inhibitors are in clinical trials of chronic obstructive pulmonary disease, including cilomilast and roflumilast. Despite some encouraging data from phase III clinical trials, the current generation of phosphodiesterase-4 inhibitors is hampered by a low therapeutic ratio. Indeed, a major obstacle is their propensity to evoke non–steroid-like side effects, of which nausea, diarrhea, abdominal pain, vomiting, and dyspepsia are the most common. In addition, a particularly worrying potential toxicity of phosphodiesterase-4 inhibitors, also shared by phosphodiesterase-3 inhibitors and other vasodilators, is arteritis/periarteritis. One potential means of improving the therapeutic ratio and safety of phosphodiesterase-4 inhibitors may lie in the development of compounds that have broader phosphodiesterase specificity. Of the 11 phosphodiesterase families that have been unequivocally identified, dual-specificity compounds that inhibit phosphodiesterase-4 and phosphodiesterase-1, phosphodiesterase-3, or phosphodiesterase-7 may offer the best opportunities to enhance clinical efficacy.

Key Words: cyclic adenosine monophosphate • dual-specificity phosphodiesterase inhibitors • phosphodiesterase-1 • phosphodiesterase-3 • phosphodiesterase-7

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