Design,synthesis and bioevaluation of isoflavone derivative as a novel CLR/RAMP1 antagonist  

异黄酮类CLR/RAMP1拮抗剂的设计、合成及生物活性评价（英文）

作　　者：王俊杰[1] 王超[1] 吕鹏[1] 牛彦[1] 李宏月 黄文慧[1] 李灿[1] 徐凤荣[1] 梁磊[1] 徐萍[1] 

机构地区：[1]北京大学医学部药学院药物化学系,北京100191

出　　处：《Journal of Chinese Pharmaceutical Sciences》2017年第7期504-511,共8页中国药学（英文版）

基　　金：National Basic Research Program of China(Grant No.2012CB518000);Specialized Research Fund for the Doctoral Program of Higher Education of China(Grant No.20120001110010)

摘　　要：CGRP receptor（CLR） is a B class GPCR that functions only when combined with RAMPs. CLR/RAMP1 has been regarded as a promising target for migraine treatment, as its antagonists have been proved to be effective recently. In the present study we designed and synthesized small molecular antagonists against CLR/RAMP1, resulting in a novel type of structure with acceptable high potency. The molecules were designed via virtual screening. Afterwards, a series of modification were conducted on the hit compounds, resulting in compound 8 as the best scored compound in docking, which was further validated in vitro by cell-based functional assay.本文通过分析已有CLR/RAMP1胞外区与其拮抗剂分子共结晶结构以及已有小分子拮抗剂Telcagepant的构效关系,借助计算机辅助药物设计方法,以Telcagepant为模板进行形状筛选以得到结构新颖化合物,结合对接优化设计得到具有异黄酮结构母核的全新结构的化合物作为CLR/RAMP1拮抗剂。完成了化合物合成及细胞水平活性评价,为之后继续进行结构优化改造奠定基础。

关 键 词：ISOFLAVONE CLR/RAMP1 antagonist Research 

分 类 号：R914[医药卫生—药物化学] R96[医药卫生—药学]