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

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

doi:10.1021/acs.jmedchem.5b01716

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

J Med Chem. 2016 Mar 24;59(6):2328-42. doi: 10.1021/acs.jmedchem.5b01716. Epub 2016 Feb 11.

Authors

Alessandro A Boezio¹, Katrina W Copeland¹, Karen Rex², Brian K Albrecht¹, David Bauer¹, Steven F Bellon¹, Christiane Boezio¹, Martin A Broome², Deborah Choquette¹, Angela Coxon², Isabelle Dussault², Satoko Hirai¹, Richard Lewis¹, Min-Hwa Jasmine Lin¹, Julia Lohman¹, Jingzhou Liu¹, Emily A Peterson¹, Michele Potashman¹, Roman Shimanovich¹, Yohannes Teffera¹, Douglas A Whittington¹, Karina R Vaida¹, Jean-Christophe Harmange¹

Affiliations

¹ Amgen Incorporated , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
² Amgen Incorporated , One Amgen Center Drive, Thousand Oaks, California 91320, United States.

PMID: 26812066
DOI: 10.1021/acs.jmedchem.5b01716

Abstract

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.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology*
Crystallography, X-Ray
Drug Design
Drug Discovery
Humans
Mice
Models, Molecular
Proto-Oncogene Proteins c-met / antagonists & inhibitors*
Pyridones / chemical synthesis*
Pyridones / pharmacokinetics
Pyridones / pharmacology*
Structure-Activity Relationship
Triazoles / chemical synthesis*
Triazoles / pharmacokinetics
Triazoles / pharmacology*
Xenograft Model Antitumor Assays

Substances

AMG 337
Antineoplastic Agents
Pyridones
Triazoles
MET protein, human
Proto-Oncogene Proteins c-met