摘要/Abstract

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
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.
Key words: Rho-associated kinase, cardio-cerebrovascular disease, tetrahydro pyrimidin-2(1H)-one derivative, inhibitor


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