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Design, synthesis, and biological evaluation of potent c-Met inhibitors. 2008
Noel D D'Angelo, and
Steven F Bellon, and
Shon K Booker, and
Yuan Cheng, and
Angela Coxon, and
Celia Dominguez, and
Ingrid Fellows, and
Douglas Hoffman, and
Randall Hungate, and
Paula Kaplan-Lefko, and
Matthew R Lee, and
Chun Li, and
Longbin Liu, and
Elizabeth Rainbeau, and
Paul J Reider, and
Karen Rex, and
Aaron Siegmund, and
Yaxiong Sun, and
Andrew S Tasker, and
Ning Xi, and
Shimin Xu, and
Yajing Yang, and
Yihong Zhang, and
Teresa L Burgess, and
Isabelle Dussault, and
Tae-Seong Kim
Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, USA. dangelo@amgen.com
c-Met is a receptor tyrosine kinase that plays a key role in several cellular processes but has also been found to be overexpressed and mutated in different human cancers. Consequently, targeting this enzyme has become an area of intense research in drug discovery. Our studies began with the design and synthesis of novel pyrimidone 7, which was found to be a potent c-Met inhibitor. Subsequent SAR studies identified 22 as a more potent analog, whereas an X-ray crystal structure of 7 bound to c-Met revealed an unexpected binding conformation. This latter finding led to the development of a new series that featured compounds that were more potent both in vitro and in vivo than 22 and also exhibited different binding conformations to c-Met. Novel c-Met inhibitors have been designed, developed, and found to be potent in vitro and in vivo.
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Randall Hungate, and
Paula Kaplan-Lefko, and
Matthew R Lee, and
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