Research on phosphodiesterases both in academic labs and in the pharmaceutical industry has remained steady over the past 35 years. Although there have been some clinical successes, they have been clustered around just a couple of PDE isoforms, and disproportionate to the huge investment put forth against what seem like very druggable targets. This review attempts to uncover the reasons for the lack of productivity in PDE drug discovery, and summarizes the current hot areas of research. In addition, new insights gathered about structure-function relationships are highlighted, in particular those relating to enzyme regulation. Lastly, novel strategies for targeting the activation or inactivation of selected PDEs are proposed that may allow for a more targeted approach for PDE modulation.
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