Discovery of (R)-6-(1-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one (AMG 337), a Potent and Selective Inhibitor of MET with High Unbound Target Coverage and Robust In Vivo A

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• 作者：Alessandro A. Boezio ; Katrina W. Copeland ; Karen Rex ; Brian K. Albrecht ; David Bauer ; Steven F. Bellon ; Christiane Boezio ; Martin A. Broome ; Deborah Choquette ; Angela Coxon ; Isabelle Dussault ; Satoko Hirai ; Richard Lewis ; Min-Hwa Jasmine Lin ; Julia Lohman ; Jingzhou Liu ; Emily A. Peterson ; Michele Potashman ; Roman Shimanovich ; Yohannes Teffera ; Douglas A. Whittington ; Karina R. Vaida ; Jean-Christophe Harmange
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：March 24, 2016
• 年：2016
• 卷：59
• 期：6
• 页码：2328-2342
• 全文大小：815K
• ISSN：1520-4804

文摘

Deregulation of the receptor tyrosine kinase mesenchymal epithelial transition factor (MET) has been implicated in several human cancers and is an attractive target for small molecule drug discovery. Herein, we report the discovery of compound 23 (AMG 337), which demonstrates nanomolar inhibition of MET kinase activity, desirable preclinical pharmacokinetics, significant inhibition of MET phosphorylation in mice, and robust tumor growth inhibition in a MET-dependent mouse efficacy model.