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

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• 作者：Jason D. Katz ; 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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：June 23, 2011
• 年：2011
• 卷：54
• 期：12
• 页码：4092-4108
• 全文大小：1312K
• 年卷期：v.54,no.12(June 23, 2011)
• ISSN：1520-4804

文摘

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.