Discovery of novel azetidine-based imidazopyridines as selective and orally bioavailable inhibitors of phosphodiesterase 10A for the treatment of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a chronic, progressive disorder of the pulmonary vasculature characterized by associated pulmonary and cardiac remodeling. Phosphodiesterase 10A (PDE10A) plays a crucial role in regulating cAMP concentration, thereby influencing pulmonary inflammation and pulmonary vascular remodeling. However, there is a lack of ideal PDE10A selective inhibitors available for PAH treatment. Herein, we employed structure-based drug design to develop a series of azetidine-based imidazopyridines, among which A30 demonstrated an IC₅₀ value of 3.5 nmol/L against PDE10A with high selectivity over other PDEs, low blood-brain barrier permeability, and improved drug-like properties. Oral administration of A30 exhibited significant anti-PAH effects not only in monocrotaline-induced rats, but also in Sugen/hypoxia(Su/Hx)-induced PH mice. Our findings indicate that A30 inhibits PDE10A to suppress pulmonary vascular remodeling through the activation of cAMP-associated signaling pathways.