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Discovery of potent and selective 8-fluorotriazolopyridine c-Met inhibitors. 2015
Emily A Peterson, and
Yohannes Teffera, and
Brian K Albrecht, and
David Bauer, and
Steven F Bellon, and
Alessandro Boezio, and
Christiane Boezio, and
Martin A Broome, and
Deborah Choquette, and
Katrina W Copeland, and
Isabelle Dussault, and
Richard Lewis, and
Min-Hwa Jasmine Lin, and
Julia Lohman, and
Jingzhou Liu, and
Michele Potashman, and
Karen Rex, and
Roman Shimanovich, and
Douglas A Whittington, and
Karina R Vaida, and
Jean-Christophe Harmange
Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
The overexpression of c-Met and/or hepatocyte growth factor (HGF), the amplification of the MET gene, and mutations in the c-Met kinase domain can activate signaling pathways that contribute to cancer progression by enabling tumor cell proliferation, survival, invasion, and metastasis. Herein, we report the discovery of 8-fluorotriazolopyridines as inhibitors of c-Met activity. Optimization of the 8-fluorotriazolopyridine scaffold through the combination of structure-based drug design, SAR studies, and metabolite identification provided potent (cellular IC50 < 10 nM), selective inhibitors of c-Met with desirable pharmacokinetic properties that demonstrate potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver pharmacodynamic model.
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