An overview of phosphodiesterase 9 inhibitors: Insights from skeletal structure, pharmacophores, and therapeutic potential

Cyclic nucleotide phosphodiesterase 9 (PDE9), a specifically hydrolytic enzyme with the highest affinity for cyclic guanosine monophosphate (cGMP) among the phosphodiesterases family, plays a critical role in many biological processes. Consequently, the development of PDE9 inhibitors has received increasing attention in recent years, with several compounds undergoing clinical trials for the treatment of central nervous system (CNS) diseases such as Alzheimer's disease, schizophrenia, and psychotic disorders, as well as heart failure and sickle cell disease. This review analyzes the recent primary literatures and patents published from 2004 to 2023, focusing on the structure, pharmacophores, selectivity, and therapeutic potential of PDE9 inhibitors. It hoped to provide a comprehensive overview of the field's current state to inform the development of novel PDE9 inhibitors.