Selective targeting phosphodiesterase-5 (PDE5): clinical progress, design strategies, and emerging prospects.

PDE5 is a subfamily member of the phosphodiesterase (PDE) superfamily. It is encoded by a single PDE5A gene, and its primary function is to specifically hydrolyse cyclic guanosine monophosphate. To date, a few inhibitors targeting PDE5, exemplified by sildenafil, tadalafil, and vardenafil, have been approved for the treatment of several diseases including pulmonary arterial hypertension and erectile dysfunction. However, due to their low subtype selectivity, the currently marketed PDE5 inhibitors cause some severe adverse effects in clinical applications, including headaches and visual disturbances. Therefore, discovering new PDE5 inhibitors featuring novel scaffolds and high subtype selectivity for disease treatment and target research remains to attract significant interest from both academics and industry. This review emphasises the rational design, advantages, and potential limitations of PDE5 inhibitors with diverse scaffolds, aiming to generate insights into the discovery and development of novel subtype-selective PDE5 inhibitors.