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

Weinberg, Linda R; Albom, Mark S; Angeles, Thelma S; Husten, Jean; Lisko, Joseph G; McHugh, Robert J; Milkiewicz, Karen L; Murthy, Seetha; Ott, Gregory R; Theroff, Jay P; Tripathy, Rabindranath; Underiner, Ted L; Zificsak, Craig A; Dorsey, Bruce D.
Bioorg Med Chem Lett; 21(1): 164-7, 2011 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-21123062
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.
Selo DaSilva