Design, Synthesis, and Biological Evaluation of Novel Imidazo[1,2-a]pyridine Derivatives as Potent c-Met Inhibitors
文献类型：期刊论文
| 作者 | Li, Chunpu2; Ai, Jing3 ; Zhang, Dengyou2; Peng, Xia3; Chen, Xi2; Gao, Zhiwei1; Su, Yi3; Zhu, Wei2; Ji, Yinchun3; Chen, Xiaoyan1
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| 刊名 | ACS MEDICINAL CHEMISTRY LETTERS
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| 出版日期 | 2015-05 |
| 卷号 | 6期号:5页码:507-512 |
| 关键词 | Receptor tyrosine kinase c-Met inhibitor imidazo[1,2-a]pyridine metabolic stability |
| ISSN号 | 1948-5875 |
| DOI | 10.1021/ml5004876 |
| 文献子类 | Article |
| 英文摘要 | A series of imidazo[1,2-a]pyridine derivatives against c-Met was designed by means of bioisosteric replacement. In this study, a selective, potent c-Met inhibitor, 22e was identified, with IC50 values of 3.9 nM against c-Met kinase and 45.0 nM against c-Met-addicted EBC-1 cell proliferation, respectively. Compound 22e inhibited c-Met phosphorylation and downstream signaling across different oncogenic forms in c-Met overactivated cancer cells and model cells. Compound 22e significantly inhibited tumor growth (TGI = 75%) with good oral bioavailability (F = 29%) and no significant hERG inhibition. On the basis of systematic metabolic study, the pathway of all possible metabolites of 22e in liver microsomes of different species has been proposed, and a major NADPH-dependent metabolite 33 was generated by liver microsomes. To block the metabolic site, 42 was designed and synthesized for further evaluation. Taken together, the imidazo[1,2-a]pyridine scaffold showed promising pharmacological inhibition of c-Met and warrants further investigation. |
| WOS关键词 | GROWTH-FACTOR RECEPTOR ; SCATTER-FACTOR ; KINASE INHIBITORS ; CANCER ; IDENTIFICATION ; MODULATOR |
| 资助项目 | National Natural Science Foundation of China[91229204] ; National Natural Science Foundation of China[81220108025] ; Major Project of Chinese National Programs for Fundamental Research and Development[2015CB910304] ; National High Technology Research and Development Program of China[2012AA020302] ; National Basic Research Program of China[2012CB518005] ; National ST Major Projects[2012ZX09103101-072] ; National ST Major Projects[2014ZX09507002-001] ; National ST Major Projects[2013ZX09507-001] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000354912900006 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276543]  |
| 专题 | 药理学第一研究室 药物化学研究室 |
| 通讯作者 | Geng, Meiyu |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Li, Chunpu,Ai, Jing,Zhang, Dengyou,et al. Design, Synthesis, and Biological Evaluation of Novel Imidazo[1,2-a]pyridine Derivatives as Potent c-Met Inhibitors[J]. ACS MEDICINAL CHEMISTRY LETTERS,2015,6(5):507-512. |
| APA | Li, Chunpu.,Ai, Jing.,Zhang, Dengyou.,Peng, Xia.,Chen, Xi.,...&Liu, Hong.(2015).Design, Synthesis, and Biological Evaluation of Novel Imidazo[1,2-a]pyridine Derivatives as Potent c-Met Inhibitors.ACS MEDICINAL CHEMISTRY LETTERS,6(5),507-512. |
| MLA | Li, Chunpu,et al."Design, Synthesis, and Biological Evaluation of Novel Imidazo[1,2-a]pyridine Derivatives as Potent c-Met Inhibitors".ACS MEDICINAL CHEMISTRY LETTERS 6.5(2015):507-512. |
入库方式： OAI收割
来源：上海药物研究所
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