| 1,3,5-三取代吡唑类ALK5抑制剂的合成与生物评价研究 |
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| 引用本文： | 李行舟,王莉莉,龙 隆,肖军海,李 松. 1,3,5-三取代吡唑类ALK5抑制剂的合成与生物评价研究[J]. 中国药物化学杂志, 2010, 20(4): 241-251 |
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| 作者姓名： | 李行舟 王莉莉 龙 隆 肖军海 李 松 |
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| 作者单位： | （军事医学科学院 毒物药物研究所，北京 100850） |
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| 基金项目： | 国家自然科学基金项目(0873135); 国家高技术研究发展计划项目(2006AA10A201) |
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| 摘 要： | 目的 设计合成1,3,5-三取代吡唑类化合物，并研究其对ALK5所介导的TGFβ信号通路的抑制活性，以期发现新型ALK5抑制剂。方法 先以取代的苯甲醛和4-乙酰苯甲腈为原料，合成取代的查儿酮，再与芳基肼或芳基肼盐酸盐反应生成1,3,5-三取代吡唑啉，然后氧化脱氢得到相应的1,3,5-三取代吡唑类化合物，最后对官能团做适当的变换，得到目标化合物。应用基于细胞的TGF-Smad2 检测评价了化合物的ALK5抑制活性。结果与结论 合成目标化合物29个，其结构均经过了核磁与质谱的确证，其中化合物6c显示有较好的ALK5抑制活性。
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| 关 键 词： | 化学合成；激酶抑制剂；ALK5； 1 3 5-三取代吡唑 |
| 收稿时间： | 2010-01-04 |
| 修稿时间： | 2010-05-20 |
Synthesis and biological evaluation of 1,3,5-trisubstituted pyrazoles as inhibitors of ALK5 |
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| LI Xing-zhou,WANG Li-li,LONG Long,XIAO Jun-hai,LI Song. Synthesis and biological evaluation of 1,3,5-trisubstituted pyrazoles as inhibitors of ALK5[J]. Chinese Journal of Medicinal Chemistry, 2010, 20(4): 241-251 |
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| Authors: | LI Xing-zhou WANG Li-li LONG Long XIAO Jun-hai LI Song |
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| Affiliation: | (Beijing Institute of Pharmacology & Toxicology, Beijing 100850, China) |
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| Abstract: | Aim To design and synthesize a series of novel 1,3,5-trisubstituted pyrazole derivatives with ALK5 inhibition activities. Methods Firstly, substituted chalcones were prepared through the condensation between substituted benzaldehyde and 4-acetylbenzonitril. Then, substituted chalcones were reacted with arylhydrazine or hydrochloric arylhydrazine to give the 1,3,5-trisubstituted pyrazolins, which were oxidized to corresponding 1,3,5-tri-substitutedpyrazoles subsequently. After further functional groups transformation, the target compounds were obtained. The synthesized compounds were evaluated for their ALK5 inhibitory activity in TGF-Smad2 assay. Results and conclusion Twenty-nine novel compounds were synthesized and characterized using 1H-NMR and MS. Compound 6c showed relatively potent ALK5 inhibitory activity. |
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| Keywords: | chemical synthesis kinase inhibitor ALK5 1 3 5-trisubstituted pyrazole |
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