2. Academic Validation
  3. Discovery and optimization of a series of imidazo[4,5-b]pyrazine derivatives as highly potent and exquisitely selective inhibitors of the mesenchymal-epithelial transition factor (c-Met) protein kinase

Discovery and optimization of a series of imidazo[4,5-b]pyrazine derivatives as highly potent and exquisitely selective inhibitors of the mesenchymal-epithelial transition factor (c-Met) protein kinase

  • Bioorg Med Chem. 2016 Sep 15;24(18):4281-4290. doi: 10.1016/j.bmc.2016.07.019.
Fei Zhao 1,  Jing Zhang 1,  Leduo Zhang 1,  Yu Hao 1,  Chen Shi 1,  Guangxin Xia 1,  Jianxin Yu 2,  Yanjun Liu 3
Affiliations

Affiliations

  • 1 Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd, Building 5, No. 898 Halei Road, Shanghai 201203, PR China.
  • 2 Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd, Building 5, No. 898 Halei Road, Shanghai 201203, PR China. Electronic address: yujx@sphchina.com.
  • 3 Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd, Building 5, No. 898 Halei Road, Shanghai 201203, PR China. Electronic address: liuyj@sphchina.com.
PMID: 27448775 DOI: 10.1016/j.bmc.2016.07.019
Abstract

Aberrant c-Met activation has been implicated in multiple tumor oncogenic processes and drug resistance. In this study, a series of imidazo[4,5-b]pyrazine derivatives was designed and synthesized, and their inhibitory activities were evaluated in vitro. Structure-activity relationship (SAR) was investigated systematically and docking analysis was performed to elucidate the binding mode, leading to the identification of the most promising compound 1D-2 which exhibited significant inhibitory effect on both enzymatic (IC50=1.45nM) and cellular (IC50=24.7nM in H1993 cell line) assays, as well as exquisite selectivity and satisfactory metabolic stability in human and rat liver microsomes.

Keywords

Docking study; Imidazo[4,5-b]pyrazines; Structure–activity relationship; c-Met inhibitors.

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