新型Rho激酶抑制剂的设计、合成及生物活性评价
收稿日期: 2017-11-03
修回日期: 2017-11-24
网络出版日期: 2017-12-05
基金资助
中国医学科学院医学与健康科技创新工程资助项目（No.2016-I2M-3-009）、中国医学科学院、北京协和医学院“中央级公益性科研院所基本科研业务费”（No.2016ZX350024）资助项目.
Design, Synthesis and Biological Activity Evaluation of Novel Rho Kinase Inhibitors
Received date: 2017-11-03
Revised date: 2017-11-24
Online published: 2017-12-05
Supported by
Project supported by the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (No. CIFMS 2016-I2M-3-009) and the Fun-damental Research Funds for Chinese Academy of Medical Sciences (CAMS)/Peking Union Medical College (PUMC) (No. 2016ZX350024).
以前期结构优化得到的Rho激酶I（ROCK I）抑制剂N-（1H-吲唑-5-基）-1-（4-甲基苄基）吡咯-3-酰胺（I）为先导结构，采用拼接原理，设计合成16个新型含取代的四氢嘧啶-2-酮结构的吲唑类衍生物，并经1H NMR，13C NMR和HRMS确证目标产物的结构.生物活性结果显示，1-（1H-吲唑-5-基）-3-（4-硝基苯基）四氢嘧啶-2（1H）酮（8a）和4-（3-（1H-吲唑-5-基）-2氧四氢嘧啶-1（2H）-基）苯甲腈（8b）具有较好的ROCK I抑制活性，IC50值分别为6.01和9.46 μmol·L-1；离体实验显示化合物8a和8b具有较好的舒张脑基底膜动脉的活性，EC50值分别为15.92和20.61 μmol·L-1.
关键词： Rho相关激酶; 心脑血管疾病; 四氢嘧啶-2-酮类衍生物; 抑制剂
姚阳阳 , 刘晓宇 , 杨飞龙 , 杨颖 , 袁天翊 , 方莲花 , 杜冠华 , 焦晓臻 , 谢平 . 新型Rho激酶抑制剂的设计、合成及生物活性评价[J]. 有机化学, 2018 , 38(4) : 871 -882 . DOI: 10.6023/cjoc201711007
Based on the structure of N-(1H-indazol-5-yl)-1-(4-methylbenzyl) pyrrolidine-3-carboxamide (I), which was previously obtained via a structure-based optimization of ROCK 1 inhibitor, sixteen novel 1-substituted-(1H-indazol-5-yl)tetrahydro pyrimidin-2(1H)-one derivatives were designed and synthesized via an active substructure combination strategy. The structures of the target compounds were confirmed by 1H NMR, 13C NMR and HRMS. The bioassay data indicated that 1-(1H-indazol-5-yl)-3-(4-nitrophenyl) tetrahydropyrimidin-2(1H)-one (8a) and 4-(3-(1H-indazol-5-yl)-2-oxo tetrahydropyrimidin-1(2H)-yl)benzonitrile (8b) had good activities against ROCK I. The IC50 values for 8a and 8b were 6.01 and 9.46 μmol·L-1, respectively. Moreover, ex vivo studies demonstrated that 8a and 8b exhibited vasorelaxant activity in rat basilar artery ring. The EC50 values for 8a and 8b were 15.92 and 20.61 μmol·L-1, respectively.
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