RESUMEN
Cyclic nucleotides (cAMP, cGMP) play a major role in normal and pathologic signaling. Beyond receptors, cyclic nucleotide phosphodiesterases; (PDEs) rapidly convert the cyclic nucleotide in its respective 5'-nucleotide to control intracellular cAMP and/or cGMP levels to maintain a normal physiological state. However, in many pathologies, dysregulations of various PDEs (PDE1-PDE11) contribute mainly to organs and tissue failures related to uncontrolled phosphorylation cascade. Among these, PDE4 represents the greatest family, since it is constituted by 4 genes with multiple variants differently distributed at tissue, cellular and subcellular levels, allowing different fine-tuned regulations. Since the 1980s, pharmaceutical companies have developed PDE4 inhibitors (PDE4-I) to overcome cardiovascular diseases. Since, they have encountered many undesired problems, (emesis), they focused their research on other PDEs. Today, increases in the knowledge of complex PDE4 regulations in various tissues and pathologies, and the evolution in drug design, resulted in a renewal of PDE4-I development. The present review describes the recent PDE4-I development targeting cardiovascular diseases, obesity, diabetes, ulcerative colitis, and Crohn's disease, malignancies, fatty liver disease, osteoporosis, depression, as well as COVID-19. Today, the direct therapeutic approach of PDE4 is extended by developing allosteric inhibitors and protein/protein interactions allowing to act on the PDE interactome.