2-chloro-5-(8-fluoro-3-(quinolin-6-ylmethyl)imidazo[1,2-a]pyridin-6-yl)-N-methylbenzamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 2-chloro-5-(8-fluoro-3-(quinolin-6-ylmethyl)imidazo[1,2-a]pyridin-6-yl)-N-methylbenzamide
• 英文别名: 2-chloro-5-[8-fluoro-3-(quinolin-6-ylmethyl)imidazo[1,2-a]pyridin-6-yl]-N-methylbenzamide
• 化学式: C₂₅H₁₈ClFN₄O
• 分子量: 444.896
• InChiKey: AOVTWYQGWKGKDO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  32
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  59.3
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2-氨基-3-氟吡啶 在 N-溴代丁二酰亚胺(NBS) 、 lithium hydroxide monohydrate 、 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex 、 sodium carbonate 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 65.0h， 生成 2-chloro-5-(8-fluoro-3-(quinolin-6-ylmethyl)imidazo[1,2-a]pyridin-6-yl)-N-methylbenzamide
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of Novel Imidazo[1,2-a]pyridine Derivatives as Potent c-Met Inhibitors

  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.

  DOI：

  10.1021/ml5004876

文献信息

• Design, Synthesis, and Biological Evaluation of Novel Imidazo[1,2-<i>a</i>]pyridine Derivatives as Potent c-Met Inhibitors
  作者：Chunpu Li、Jing Ai、Dengyou Zhang、Xia Peng、Xi Chen、Zhiwei Gao、Yi Su、Wei Zhu、Yinchun Ji、Xiaoyan Chen、Meiyu Geng、Hong Liu

  DOI：10.1021/ml5004876

  日期：2015.5.14

  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.