Phosphodiesterase 7A: a new therapeutic target for alleviating chronic inflammation?
Over the last fifteen years there has been much excitement in the idea that targeting phosphodiesterase (PDE) 4 with small molecule inhibitors could lead to the discovery of novel, steroid-sparing compounds with utility in treating a multitude of diseases associated with chronic inflammation. However, dose-limiting side effects, of which nausea and vomiting are the most common are worrisome, have hampered their clinical development. Indeed, a fundamental obstacle that still is to be overcome by the pharmaceutical industry is to make compounds that dissociate beneficial from the adverse events. Unfortunately, both of these activities of PDE4 inhibitors represents an extension of their pharmacology and improving the therapeutic ratio has proved to be a major challenge. Several strategies have been considered, with some degree of success, but compounds with an optimal pharmacophore still have not been reported. An alternative approach to targeting PDE4 is to inhibit other cAMP PDE families that are also expressed in immune and pro-inflammatory cells in the hope that the beneficial activity can be retained at the expense of side effects. One such candidate is PDE7A. In this article we review the literature on PDE7A and explore the possibility that selective small molecule inhibitors of this enzyme family could provide a novel approach to alleviate the inflammation that is associated with many inflammatory diseases including asthma, chronic obstructive pulmonary disease, atopic dermatitis, psoriasis, lupus, rheumatoid arthritis and multiple sclerosis.
Giembycz
M A
MA
Department of Pharmacology and Therapeutics, Respiratory Research Group, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada. giembycz@ucalgary.ca
Smith
S J
SJ
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D018836:Inflammation Mediators / Q000494:pharmacology / Q000627:therapeutic use*; D008969:Molecular Sequence Data; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*
D000893:Anti-Inflammatory Agents; D018836:Inflammation Mediators; D010726:Phosphodiesterase Inhibitors; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7; C517458:PDE7A protein, human