全新结构钾离子通道开放剂先导化合物的设计合成与QSAR的研究  

Design and Synthesis of Novel Potassium Channel Openers and QSAR Studies

作　　者：王炜[1] 崔智勇[1] 许凤荣[1] 李仁利[1] 杨明娜[2] 李长龄[2] 苏阳[3] 周家驹[3] 

机构地区：[1]北京大学药学院药物化学系,北京100083 [2]北京大学药学院生化药理系,北京100083 [3]中国科学院化工冶金所计算机化学开放实验室,北京100080

出　　处：《中国药物化学杂志》2001年第4期198-204,共7页Chinese Journal of Medicinal Chemistry

基　　金：国家自然科学基金资助课题 (3 9670 85 4 )

摘　　要：在进一步研究钾离子开放剂的药效团基础上设计并合成了 1 7个化合物 ,连同以前合成的4个化合物用SYBYL软件优化了它们的构象并计算了芳环中心与氢键接受原子间的距离 (Ar HA)、芳环中心与疏水性部分中心的距离 (Ar Hy)、氢键接受原子与疏水性部分中心的距离 (HA Hy)及芳环中心垂直线和此中心与氢键接受原子连线间的夹角 (α)、芳环中心垂直线和此中心与疏水性结构的中心连线间的夹角 (β)。同时以CLOGP软件计算了这些化合物的ClogP值。以上述数值为参数研究了这些化合物的定量构效关系 ,发现HA Hy及β对动脉条舒张活性有较显著的影响。The pharmacophore of potassium channel openers has b een further studied.On the basis of the pharmacophore,17 compounds with five str uctures were designed and synthesized.In combination with 4 previously synthesiz ed compounds,their conformations were minimized by using SYBYL software package and the distances between the center of the aromatic ring and the hydrogen accep tor atom(Ar-H A),the center of the aromatic ring and the center of the hydroph obic moiety(Ar-Hy),and the center of the hydrophobic moiety and the hydrogen ac ceptor atom(H A-Hy)were measured.In the mean time,the angles between the norma l of the center of the aromatic plane and the linking line from the center to th e hydrogen acceptor atom(α)and the normal of the center of the aromatic plane a nd the linking line from the center to the center of hydrophobic moiety(β)were also measured.By the use of clogP program the clogP values of these compounds we re calculated.QSAR of these compounds was studied utilizing Ar-H A,Ar-Hy,H A -Hy,α,β and clogP as the parameters and the following equation was derived. log1/C=0335(±019)H A-Hy+0019(±0012)β+2031(±1016)(2) n=19,r=0814,S=0497 F 2,16=13755

关 键 词：钾离子开放剂 药效团 定量构效关系 设计合成 

分 类 号：TQ463[化学工程—制药化工]