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首页> 外文会议>第四届国际分子模拟与信息技术应用学术会议（The 4th International Conference of Molecular Simulations and Applied Informatics Technologies）论文集 >Methyl(11aS)-1,2,3,5,11,11a-Hexahydro-3,3-dimethyl-1-oxo-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
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Methyl(11aS)-1,2,3,5,11,11a-Hexahydro-3,3-dimethyl-1-oxo-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

机译：甲基（11aS）-1,2,3,5,11,11a-六氢-3,3-二甲基-1-氧代-6H-咪唑-3'，4'：1,2吡啶3,4- b-吲哚-2-取代的乙酸酯：一类新型血管扩张剂的合成与三维定量构效关系研究

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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-imidazo[3',4': 1,2]-pyridin[3,4-b]lindol-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.
机译：为了找到5型磷酸磷酸二氢吡啶酯（PDE5）的选择性抑制剂，将临床使用的药物西地那非，伐地那非和他达拉利的基本结构要素进行了组合，并构建了一个四环亲代体，在其2位上引入了取代的乙酸甲酯，以形成17种新颖的血管扩张药，甲基（1 laS）-1,2,3,5,11,11a-六氢-3,3-二甲基-1-氧代-6H-咪唑[3'，4'：1,2]-吡啶[3 ，4-b] lindol-2-取代的乙酸酯。通过分子场分析（MFA），建立了三维定量构效关系（3D QSAR）方程，该方程不仅揭示了体外血管舒张活性对结构的依赖性，还指出了设计新方法的途径。正确地铅化合物。将这些新型血管扩张剂对接在5型磷酸二酯酶（PDE5）的疏水口袋中，表明它们对该口袋的适应性确实对其血管舒张活性产生了显着影响。实际上，这些新型血管扩张剂对PDE5的对接适应性与它们对MFA的构象要求以及两个代表的晶体构象是一致的。

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