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
  • 1. Department of Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, BMB-2-114, Boston, Massachusetts 02115, United States. [email protected]
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.