Design, synthesis, and evaluation of quinolin-2(1H)-ones as PDE1 inhibitors for the treatment of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease that affects the entire gastrointestinal tract. The complex etiology of IBD made it difficult to cure. Phosphodiesterases (PDEs) have garnered significant attention due to their involvement in immune and inflammatory responses in IBD. Most recently, we have reported a novel PDE1 inhibitor 1 with quinolin-2(1H)-one scaffold, demonstrating anti-IBD effects. However, its short half-life (t) in the rat liver microsomes (RLMs) is relatively short. In this study, structural optimization of compound 1 was performed to improve metabolic stability. Combined with molecular docking and dynamics simulations, a series of quinolin-2(1H)-one derivatives were synthesized. Among them, compound 7a showed an excellent IC value of 11 nM, high selectivity to PDE1 compared to other PDEs, and good metabolic stability with RLM t of 67.3 min. The binding pattern between 7a and PDE1 revealed an additional hydrogen bond with Cys410, which could enhance the inhibitory activity. Furthermore, compound 7a demonstrated anti-inflammatory properties by reducing cytokine production and antioxidant activity in LPS-induced Raw264.7 cells, which contributed to its effectiveness against IBD. We believe that compound 7a could serve as an ideal tool for further pharmacological research on IBD.