Discovery of a 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (MK-2461) inhibitor of c-Met kinase for the treatment of cancer

J Med Chem. 2011 Jun 23;54(12):4092-108. doi: 10.1021/jm200112k.

Jason D Katz ¹, James P Jewell, David J Guerin, Jongwon Lim, Christopher J Dinsmore, Sujal V Deshmukh, Bo-Sheng Pan, C Gary Marshall, Wei Lu, Michael D Altman, William K Dahlberg, Lenora Davis, Danielle Falcone, Ana E Gabarda, Gaozhen Hang, Harold Hatch, Rachael Holmes, Kaiko Kunii, Kevin J Lumb, Bart Lutterbach, Robert Mathvink, Naim Nazef, Sangita B Patel, Xianlu Qu, John F Reilly, Keith W Rickert, Craig Rosenstein, Stephen M Soisson, Kerrie B Spencer, Alexander A Szewczak, Deborah Walker, Wenxian Wang, Jonathan Young, Qinwen Zeng

Affiliations

Affiliation

1 Department of Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, BMB-2-114, Boston, Massachusetts 02115, United States. jason_katz2@merck.com

PMID: 21608528 DOI: 10.1021/jm200112k

Abstract

c-Met is a transmembrane tyrosine kinase that mediates activation of several signaling pathways implicated in aggressive Cancer phenotypes. In recent years, research into this area has highlighted c-Met as an attractive Cancer drug target, triggering a number of approaches to disrupt aberrant c-Met signaling. Screening efforts identified a unique class of 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one kinase inhibitors, exemplified by 1. Subsequent SAR studies led to the development of 81 (MK-2461), a potent inhibitor of c-Met that was efficacious in preclinical animal models of tumor suppression. In addition, biochemical studies and X-ray analysis have revealed that this unique class of kinase inhibitors binds preferentially to the activated (phosphorylated) form of the kinase. This report details the development of 81 and provides a description of its unique biochemical properties.

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