- Discovery of a 5 H-benzo[4,5]cyclohepta[1,2-b ]pyridin-5-one (MK-2461) inhibitor of c-Met kinase for the treatment of cancer
-
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.
- Katz, Jason D.,Jewell, James P.,Guerin, David J.,Lim, Jongwon,Dinsmore, Christopher J.,Deshmukh, Sujal V.,Pan, Bo-Sheng,Marshall, C. Gary,Lu, Wei,Altman, Michael D.,Dahlberg, William K.,Davis, Lenora,Falcone, Danielle,Gabarda, Ana E.,Hang, Gaozhen,Hatch, Harold,Holmes, Rachael,Kunii, Kaiko,Lumb, Kevin J.,Lutterbach, Bart,Mathvink, Robert,Nazef, Naim,Patel, Sangita B.,Qu, Xianlu,Reilly, John F.,Rickert, Keith W.,Rosenstein, Craig,Soisson, Stephen M.,Spencer, Kerrie B.,Szewczak, Alexander A.,Walker, Deborah,Wang, Wenxian,Young, Jonathan,Zeng, Qinwen
-
supporting information; experimental part
p. 4092 - 4108
(2011/08/06)
-
- Process development and large-scale synthesis of a c-Met kinase inhibitor
-
A highly convergent synthesis of c-Met kinase inhibitor 1 has been demonstrated on a multikilogram scale using three key fragments: dihalotricyclic core 2, chiral sulfamide side chain 3, and pyrazole boronic ester 4. The chirality in sulfamide side chain 3 was installed using the cheap and readily available starting material (S)-epichlorohydrin. A total of 2.71 kg of 1 were isolated in seven steps (the longest linear sequence).
- Stewart, Gavin W.,Brands, Karel M. J.,Brewer, Sarah E.,Cowden, Cameron J.,Davies, Antony J.,Edwards, John S.,Gibson, Andrew W.,Hamilton, Simon E.,Katz, Jason D.,Keen, Stephen P.,Mullens, Peter R.,Scott, Jeremy P.,Wallace, Debra J.,Wise, Christopher S.
-
p. 849 - 858
(2011/03/20)
-
- Tyrosine kinase inhibitors
-
This invention relates to salt forms of the compound N-[(2R)-1,4-dioxan-2-ylmethyl]-N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide, an inhibitor of tyrosine kinases, in particular the receptor tyrosine
- -
-
Page/Page column 15
(2009/07/25)
-