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The Molecular Biology of Phosphodiesterase 4 Enzymes as Pharmacological Targets: An Interplay of Isoforms, Conformational States, and Inhibitors.
Pharmacol Rev
July 2021
Department of Psychiatry & Neuropsychology, School for Mental Health and Neuroscience, EURON, Maastricht University, Maastricht, The Netherlands (D.P, M.S., B.R., D.v.d.H., T.V., J.P.); Department of Neuroscience, Neuro-Immune Connect and Repair laboratory, Biomedical Research Institute, Hasselt University, Hasselt, Belgium (D.P., M.S., B.R., T.V.); and Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany (D.v.d.H.)
The phosphodiesterase 4 (PDE4) enzyme family plays a pivotal role in regulating levels of the second messenger cAMP. Consequently, PDE4 inhibitors have been investigated as a therapeutic strategy to enhance cAMP signaling in a broad range of diseases, including several types of cancers, as well as in various neurologic, dermatological, and inflammatory diseases. Despite their widespread therapeutic potential, the progression of PDE4 inhibitors into the clinic has been hampered because of their related relatively small therapeutic window, which increases the chance of producing adverse side effects.
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