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 Antitumor Activity

• Published in: Journal of medicinal chemistry Vol. 59; no. 6; pp. 2328 - 2342
• Main Authors: Boezio, Alessandro A, Copeland, Katrina W, Rex, Karen, K. Albrecht, Brian, Bauer, David, Bellon, Steven F, Boezio, Christiane, Broome, Martin A, Choquette, Deborah, Coxon, Angela, Dussault, Isabelle, Hirai, Satoko, Lewis, Richard, Lin, Min-Hwa Jasmine, Lohman, Julia, Liu, Jingzhou, Peterson, Emily A, Potashman, Michele, Shimanovich, Roman, Teffera, Yohannes, Whittington, Douglas A, Vaida, Karina R, Harmange, Jean-Christophe
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.03.2016; Amer Chemical Soc
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Chemistry, Medicinal; Crystallography, X-Ray; Drug Design; Drug Discovery; Humans; Life Sciences & Biomedicine; Mice; Models, Molecular; Pharmacology & Pharmacy; Proto-Oncogene Proteins c-met - antagonists & inhibitors; Pyridones - chemical synthesis; Pyridones - pharmacokinetics; Pyridones - pharmacology; Science & Technology; Structure-Activity Relationship; Triazoles - chemical synthesis; Triazoles - pharmacokinetics; Triazoles - pharmacology; Xenograft Model Antitumor Assays; OPTIMIZATIONS; MECHANISM; LIPOPHILIC EFFICIENCY; PROGRESS; KINASE INHIBITOR; IDENTIFICATION; STRUCTURE-BASED DESIGN
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b01716

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.