Design and Synthesis of 5-Aminopyrazole and 5-Aminotriazole Derivatives as Fibroblast Growth Factor Receptor Inhibitors

doi:10.6023/cjoc201503045

Chin. J. Org. Chem. ›› 2015, Vol. 35 ›› Issue (9): 1939-1947.DOI: 10.6023/cjoc201503045 Previous Articles Next Articles

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5-氨基吡唑及5-氨基三唑类成纤维细胞生长因子受体激酶抑制剂的设计合成

董潜^a, 彭霞^b, 王雯^a, 戴阳^b, 赵伟利^a, 艾菁^b, 董肖椿^a

a 复旦大学药学院上海 201203;
b 中国科学院上海药物研究所肿瘤药理室上海 201203

收稿日期:2015-03-27 修回日期:2015-04-30 发布日期:2015-05-15
通讯作者: 艾菁, 董肖椿 E-mail:jai@simm.ac.cn;xcdong@fudan.edu.cn
基金资助:
教育部博士点基金(No. 20130071110071)和上海市科技支撑计划(No. 13431900102)资助项目.

Design and Synthesis of 5-Aminopyrazole and 5-Aminotriazole Derivatives as Fibroblast Growth Factor Receptor Inhibitors

Dong Qian^a, Peng Xia^b, Wang Wen^a, Dai Yang^b, Zhao Weili^a, Ai Jing^b, Dong Xiaochun^a

a School of Pharmacy, Fudan University, Shanghai 201203;
b Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai 201203

Received:2015-03-27 Revised:2015-04-30 Published:2015-05-15
Supported by:
Project supported by the Specialized Research Fund for the Doctoral Program of Higher Education of China (No. 20130071110071) and the Shanghai Municipal Science & Technology Pillar Program for Bio-pharmaceuticals (No. 13431900102).

1. Design and Synthesis of 5-Aminopyrazole and 5-Aminotriazole Derivatives as Fibroblast Growth Factor Receptor Inhibitors.PDF(1987KB)

Abstract

Fibroblast growth factor receptor (FGFR) is a promising therapeutic target for cancer treatment. A series of 5-aminopyrazole and 5-amino-1,2,3-triazole derivatives were designed as FGFR inhibitors based on the docking mode of Debio1347 within the FGFR kinase domain. The inhibitory effects on FGFR2 kinase and the antitumor activities against human gastric cancer SNU16 cell lines were evaluated. Furthermore, the preliminary structure-activity relationships (SAR) was discussed. The results demonstrated that several compounds present good potency against FGFR2 kinase. 1-(5-Amino-1-(2-methyl-1H-benzo[d]imidazol-6-yl)-1H-pyrazol-4-yl)-1-(1H-thieno[3,2-b]pyrrol-2-yl)methanone (8) and 1-(5-amino-1-(2-methyl-1H-benzo[d]imidazol-6-yl)-1H-1,2,3-triazol-4-yl)-1-(1H-indol-2-yl)methanone (18) were the most potent with IC₅₀ values of 3.3 and 2.3 nmol·L^－¹, respectively, which are similar to that of Debio1347. Compounds 8 and 18 exhibited slightly weaker antitumor activity against SNU16 cell lines than Debio1347 with IC₅₀ value of 77.3, 155.2 nmol·L^－¹, respectively.

Key words: 5-aminopyrazole, 5-amino-1,2,3-triazole, FGFR inhibitors, anti-tumor agent

Cite this article

Dong Qian, Peng Xia, Wang Wen, Dai Yang, Zhao Weili, Ai Jing, Dong Xiaochun. Design and Synthesis of 5-Aminopyrazole and 5-Aminotriazole Derivatives as Fibroblast Growth Factor Receptor Inhibitors[J]. Chin. J. Org. Chem., 2015, 35(9): 1939-1947.

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5-氨基吡唑及5-氨基三唑类成纤维细胞生长因子受体激酶抑制剂的设计合成

Design and Synthesis of 5-Aminopyrazole and 5-Aminotriazole Derivatives as Fibroblast Growth Factor Receptor Inhibitors

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