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

Bioorganic & Medicinal Chemistry
2016.0

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.

DOI： 10.1016/j.bmc.2016.07.019

Knowledge Graph

Similar Paper

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
Bioorganic & Medicinal Chemistry 2016.0
Discovery of potent 1H-imidazo[4,5-b]pyridine-based c-Met kinase inhibitors via mechanism-directed structural optimization
Bioorganic & Medicinal Chemistry Letters 2015.0
Synthesis and evaluation of a series of pyridine and pyrimidine derivatives as type II c-Met inhibitors
Bioorganic & Medicinal Chemistry 2017.0
Synthesis and biological evaluation of new [1,2,4]triazolo[4,3-a]pyridine derivatives as potential c-Met inhibitors
Bioorganic & Medicinal Chemistry 2016.0
Discovery of N-(benzyloxy)-1,3-diphenyl-1H-pyrazole-4-carboxamide derivatives as potential antiproliferative agents by inhibiting MEK
Bioorganic & Medicinal Chemistry 2016.0
Imidazo[1,5-a]pyrazines: Orally efficacious inhibitors of mTORC1 and mTORC2
Bioorganic & Medicinal Chemistry Letters 2011.0
Design, synthesis and biological evaluation of novel 4-(pyrrolo[2,3-d]pyrimidine-4-yloxy)benzamide derivatives as potential antitumor agents
Bioorganic & Medicinal Chemistry Letters 2021.0
Structure activity relationship studies of imidazo[1,2-a]pyrazine derivatives against cancer cell lines
European Journal of Medicinal Chemistry 2010.0
Discovery and SAR exploration of a novel series of imidazo[4,5-b]pyrazin-2-ones as potent and selective mTOR kinase inhibitors
Bioorganic & Medicinal Chemistry Letters 2011.0
Molecular modeling studies and synthesis of novel quinoxaline derivatives with potential anticancer activity as inhibitors of c-Met kinase
Bioorganic & Medicinal Chemistry 2015.0