Identification of Novel Quinolin-2(1H)-ones as Phosphodiesterase 1 Inhibitors for the Treatment of Inflammatory Bowel Disease

Phosphodiesterase 1 (PDE1) is a subfamily of PDE superenzyme familiesthat can hydrolyze cyclic adenosine monophosphate and cyclic guanosinemonophosphate simultaneously. Currently, the number of PDE1 inhibitorsis relatively few, significantly limiting their application. Herein,a novel series of quinolin-2(1H)-ones were designedrationally, leading to compound 10c with an IC50 of 15 nM against PDE1C, high selectivity across other PDEs, andremarkable safety properties. Furthermore, we used the lead compound 10c as a chemical tool to explore whether PDE1 could workas a novel potential target for the treatment of inflammatory boweldisease (IBD), a disease which is a chronic, relapsing disorder ofthe gastrointestinal tract inflammation lacking effective treatment.Our results showed that administration of 10c exertedsignificant anti-IBD effects in the dextran sodium sulfate-inducedmice model and alleviated the inflammatory response, indicating thatPDE1 could work as a potent target for IBD.