To further explore the structure–activity relationship around the chromeno­[2,3-c]­pyrrol-9­(2H)-one scaffold, 19 derivatives as inhibitors against PDE5 were discovered. The most potent inhibitor 3 has an IC₅₀ of 0.32 nM with remarkable selectivity and druglike profile. Oral administration of 3 (1.25 mg/kg) caused comparable therapeutic effects to sildenafil (10.0 mg/kg) against pulmonary arterial hypertension. Further, different binding patterns from sildenafil were revealed in cocrystal structures, which provide structural templates for discovery of highly potent PDE5 inhibitors.