Advances in the development of phosphodiesterase 5 inhibitors

Phosphodiesterase 5 (PDE5) can hydrolyze cyclic guanosine monophosphate (cGMP), which is critical for maintaining various physiological processes in organisms. Currently, clinically approved indications for PDE5 inhibitors encompass therapeutic agents for erectile dysfunction (ED), symptoms associated with lower urinary tract symptoms (LUTS), and pulmonary artery hypertension (PAH). Despite the fact that the development of selective PDE5 inhibitors has been a significant focus in drug development for some time following the proven success of sildenafil as a PDE5 inhibitor for ED treatment, fewer than ten drugs in this therapeutic class have been marketed in the past 25 years, often accompanied by adverse effects. Therefore, the development of novel, isozyme-selective PDE5 inhibitors is highly warranted. In this review, we systematically summarize the research progress of PDE5 inhibitors over the past 20 years, focusing on the meticulously combing and categorizing the structures of PDE5 inhibitors and natural products exhibiting PDE5 inhibitory activities, along with their therapeutic potentials. We hope that this summary will aid in better understanding of PDE5 inhibitors and provide insights for developing novel therapies targeting PDE5.