Liver fibrosis is a common pathological feature of most chronic liver diseases with no effective drugs available. Phosphodiesterase 1 (PDE1), a subfamily of the PDE super enzyme, might work as a potent target for liver fibrosis by regulating the concentration of cAMP and cGMP. However, there are few PDE1 selective inhibitors, and none has been investigated for liver fibrosis treatment yet. Herein, compound AG-205/1186117 with the dihydropyrimidine scaffold was selected as the hit by virtual screening. A hit-to-lead structural modification led to a series of dihydropyrimidine derivatives. Lead 13h exhibited the IC50 of 10 nM against PDE1, high selectivity over other PDEs, as well as good safety properties. Administration of 13h exerted significant anti-liver fibrotic effects in bile duct ligation-induced fibrosis rats, which also prevented TGF-β-induced myofibroblast differentiation in vitro, confirming that PDE1 could work as a potential target for liver fibrosis.
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(1 H )-one scaffold, demonstrating anti-IBD effects. However, its short half-life (t 1/2 ) 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(1 H )-one derivatives were synthesized. Among them, compound 7a showed an excellent IC 50 value of 11 nM, high selectivity to PDE1 compared to other PDEs, and good metabolic stability with RLM t 1/2 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.
危险品化学品经营许可证（带存储）