cAMP-specific phosphodiesterase inhibitors: promising drugs for inflammatory and neurological diseases

PDEs are key enzymes in the adenosine and guanosine cyclic nucleotides (cAMP and cGMP) signaling cascade. Their inhibition increases cyclic nucleotide levels inside the cell. Thus, pharmacological modulation of PDE activity can have profound effects on the function of cells and organ systems throughout the body.Among the large PDE families, only PDE4, PDE7 and PDE8 are cAMP-specific hydrolyzing enzymes. cAMP is an important second messenger not only by its involvement in a vast number of physiological processes but also by activation of protein kinase A, exchange protein activated by cAMP (Epac) and cAMP response element-binding (CREB) or cyclic nucleotide-gated channels. Clearly, such enzymes represent ideal drug targets for the pharmacological treatment of many pathologies. The discovery and development of small molecules targeting cAMP-specific PDEs reported in the last 5 years is the focus of the present review.The first PDE4 inhibitors recently reached the market, having avoided, by different strategies, their dose-limiting side effects (after more than two decades of drug development). Meanwhile, new cAMP-specific PDE7 and PDE8 inhibitors emerged as effective and safe drugs for severe unmet diseases. The therapeutic potential of these inhibitors will be tested in the near future, as many of these drug candidates are ready to start clinical trials.