Discovery of 3-(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-9(2H)-one as a phosphodiesterase-5 inhibitor and its complex crystal structure.

摘要: Phosphodiesterase-5 (PDE5) inhibitors have been approved for the treatment of erectile dysfunction and pulmonary hypertension, but enthusiasm on discovery PDE5 continues their potential new applications. Reported here is a series by structure-based design, molecular docking, chemical synthesis, enzymatic characterization. The best compound, 3-(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-9(2H)-one (57), has an IC₅₀ 17 nM against catalytic domain good selectivity over other PDE families. crystal structure in complex with 57 was determined at 2A resolution showed that occupies same pocket as inhibitors, different binding pattern detail. On basis 57, novel scaffold can be proposed candidate inhibitors.