Advances in targeting Phosphodiesterase 1: From mechanisms to potential therapeutics

Phosphodiesterase 1 (PDE1) is an enzyme entrusted with the hydrolysis of the second messengers cAMP and cGMP, thereby governing a plethora of metabolic processes, encompassing ion channel modulation and cellular apoptosis. Recent advancements in the realm of small molecule structural variations have greatly facilitated the exploration of innovative applications for PDE1. Remarkably, a recent series of PDE1 inhibitors (PDE1i) have been meticulously formulated and devised, showcasing enhanced selectivity and potency. Among them, ITI-214 has entered Phase II clinical trials, holding promise for the treatment of Parkinson's disease and heart failure. Nevertheless, the majority of current PDE1 inhibitors have encountered substantial side effects in clinical trials attributable to their limited selectivity, this predicament presents a formidable obstacle in the development of specific small molecule inhibitors targeting PDE1. This Perspective endeavors to illuminate the potential design approaches, structure-activity relationships, and biological activities of current PDE1i, aiming to offer support and insights for clinical practice and the development of novel PDE1i.