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Bioorg Med Chem Lett. 2011 Jan 1;21(1):164-7. doi: 10.1016/j.bmcl.2010.11.045. Epub 2010 Nov 11.

Fused bicyclic derivatives of 2,4-diaminopyrimidine as c-Met inhibitors.

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  • 1Worldwide Discovery Research, Cephalon, Inc, 145 Brandywine Parkway, West Chester, PA 19380-4245, USA.


The HGF-c-Met signaling axis is an important paracrine mediator of epithelial-mesenchymal cell interactions involving the regulation of multiple cellular activities including cell motility, mitogenesis, morphogenesis, and angiogenesis. Dysregulation of c-Met signaling (e.g., overexpression or increased activation) is associated with the development of a wide range of tumor types; thus, inhibiting the HGF-c-Met pathway is predicted to lead to anti-tumor effects in many cancers. Elaboration of a 2-arylaminopyrimidine scaffold led to a series of potent c-Met inhibitors bearing a C4-2-amino-N-methylbenzamide group. Specifically, a series of C2-benzazepinone analogs demonstrated potent inhibition of c-Met in enzymatic and cellular assays. Kinase selectivity could be tuned by varying the nature of the alkyl group on the benzazepinone nitrogen.

Copyright © 2010 Elsevier Ltd. All rights reserved.

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