School of Pharmaceutical Sciences , Sun Yat-Sen University , Guangzhou 510006 , P. R. China.
J Med Chem. 2018 Sep 27;61(18):8468-8473. doi: 10.1021/acs.jmedchem.8b01209. Epub 2018 Sep 7.
To further explore the structure-activity relationship around the chromeno[2,3- c]pyrrol-9(2 H)-one scaffold, 19 derivatives as inhibitors against PDE5 were discovered. The most potent inhibitor 3 has an IC 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.
为了进一步探索色烯并[2,3-c]吡咯-9(2H)-酮骨架周围的结构-活性关系，发现了 19 种作为 PDE5 抑制剂的衍生物。最有效的抑制剂 3 的 IC 为 0.32 nM，具有显著的选择性和类药性。3（1.25 mg/kg）的口服给药在治疗肺动脉高压方面与西地那非（10.0 mg/kg）相当。此外，在共晶结构中揭示了与西地那非不同的结合模式，为发现高效 PDE5 抑制剂提供了结构模板。
