Methyl(11aS)-1,2,3,5,11,11a-Hezahydro-3,3-dimethyl-1-ozo-6H-imidazo-3,4:1,2pyridin3,4-b-indol-2-Substituted Acetates: Synthesis and Three-Dimensional Quantitative Structure-Activity Relationship Investigation as a Class of Novel Vasodilator
To find selective inhibitor of phosphodicstcrasc type 5 (PDE5), the essential structure elements of clinically used drugs sildenafil, vardenafil, and tadalalil were combined and a tetracyelic parent was constructed to which in 2-positions substituted acetic acid methylesters were introduced to form 17 novel vasodilators, methyl (1 laS)-1,2,3,5,11,11a-hexahydro-3,3-dimethyl-1-oxo-6H-imidazo3,4: 1,2-pyridin3,4-blindol-2-substituted acetates. By molecular field analysis (MFA), an equation of three-dimensional quantitative structure-activity relationship (3D QSAR) was established, which not only revealed the dependence of the in vitro vasorelaxation activities on the structures but also pointed out the way to design new lead compounds properly. Docking these novel vasodilators into the hydrophobic pocket of phosphodiesterase type 5 (PDE5) revealed that their adaptabilities to this pocket did significantly affect on their vasorelaxation activity. Actually, the docking adaptabilities of these novel vasodilators to PDE5 were consistent with the conformational requirements of them to MFA and with the crystal conformation of two representatives.
Jiawang Liu Ming Zhao Guohui Cui Xiaoyi Zhang Jun Wang Shiqi Peng
College of Pharmaceutical Sciences.Capital Medical University, Beijing 100069.PR China
国际会议
广州
英文
275-283
2008-11-01（万方平台首次上网日期，不代表论文的发表时间）