School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China.
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China; Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC 27599-7260, USA.
Biochem Pharmacol. 2014 May 1;89(1):86-98. doi: 10.1016/j.bcp.2014.02.013. Epub 2014 Feb 22.
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 IC₅₀ 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 2Å 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.
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，但由于其潜在的新应用，人们对 PDE5 抑制剂的发现仍充满热情。本文报道了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。最佳化合物 3-(4-羟基苄基)-1-(噻吩-2-基)色满并[2,3-c]吡啶-9(2H)-酮（57）对 PDE5 催化结构域的 IC₅₀为 17 nM，对其他 PDE 家族具有良好的选择性。与 57 复合物的 PDE5 催化结构域的晶体结构在 2Å 分辨率下确定，表明 57 占据与其他 PDE5 抑制剂相同的口袋，但在细节上具有不同的结合模式。基于 57 的结合模式，可以提出一种新的支架作为 PDE 抑制剂的候选物。
