Phosphodiesterase-5 (PDE5) inhibitors have been approved for the treatment of erectile dysfunction and pulmonary hypertension, but enthusiasm on discovery of PDE5 inhibitors continues for their potential new applications. Reported here is discovery of a series of new PDE5 inhibitors by structure-based design, molecular docking, chemical synthesis, and enzymatic characterization. The best compound, 3-(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-9(2H)-one (57), has an IC(5)(0) of 17 nM against the PDE5 catalytic domain and good selectivity over other PDE families. The crystal structure of the PDE5 catalytic domain in complex with 57 was determined at 2A resolution and showed that 57 occupies the same pocket as other PDE5 inhibitors, but has a different binding pattern in detail. On the basis of the binding pattern of 57, a novel scaffold can be proposed as a candidate of PDE inhibitors.

中文翻译：

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发现 3-(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-9(2H)-one 作为磷酸二酯酶 5 抑制剂及其复杂的晶体结构。

磷酸二酯酶 5 (PDE5) 抑制剂已被批准用于治疗勃起功能障碍和肺动脉高压，但对发现 PDE5 抑制剂的热情仍在继续，因为它们具有潜在的新应用。这里报道的是通过基于结构的设计、分子对接、化学合成和酶学表征发现了一系列新的 PDE5 抑制剂。最好的化合物 3-(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-9(2H)-one (57) 的 IC(5)(0)对 PDE5 催化结构域的 17 nM 和对其他 PDE 家族的良好选择性。在 2A 分辨率下测定了与 57 复合的 PDE5 催化结构域的晶体结构，显示 57 与其他 PDE5 抑制剂占据相同的口袋，但在细节上具有不同的结合模式。在57的绑定模式的基础上，