Discovery of potent and selective 8-fluorotriazolopyridine c-Met inhibitors.
Basic Information
ID: ALA3414463
Journal: J Med Chem
Title: Discovery of potent and selective 8-fluorotriazolopyridine c-Met inhibitors.
Authors: Peterson EA, Teffera Y, Albrecht BK, Bauer D, Bellon SF, Boezio A, Boezio C, Broome MA, Choquette D, Copeland KW, Dussault I, Lewis R, Lin MH, Lohman J, Liu J, Potashman M, Rex K, Shimanovich R, Whittington DA, Vaida KR, Harmange JC.
Abstract: 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.
CiteXplore: 25699405
DOI: 10.1021/jm501913a
Patent ID: ┄