Your browser doesn't support javascript.

Biblioteca Virtual em Saúde


Home > Pesquisa > ()
Imprimir Exportar

Formato de exportação:


Adicionar mais destinatários
| |

Design, synthesis, and anaplastic lymphoma kinase (ALK) inhibitory activity for a novel series of 2,4,8,22-tetraazatetracyclo[³,7.19,¹³]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene macrocycles.

Breslin, Henry J; Lane, Brandon M; Ott, Gregory R; Ghose, Arup K; Angeles, Thelma S; Albom, Mark S; Cheng, Mangeng; Wan, Weihua; Haltiwanger, R Curtis; Wells-Knecht, Kevin J; Dorsey, Bruce D.
J Med Chem; 55(1): 449-64, 2012 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-22172029
A novel set of 2,4,8,22-tetraazatetracyclo[,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene macrocycles were prepared as potential anaplastic lymphoma kinase (ALK) inhibitors, designed to rigidly lock an energy-minimized bioactive conformation of the diaminopyrimidine (DAP) scaffold, a well-documented kinase platform. From 13 analogues prepared, macrocycle 2m showed the most promising in vitro ALK enzymatic (IC(50) = 0.5 nM) and cellular (IC(50) = 10 nM) activities. In addition, macrocycle 2m exhibited a favorable kinase selectivity preference for inhibition of ALK relative to the highly homologous insulin receptor (IR) kinase (IR/ALK ratio of 173). The inclusive in vitro biological results for this set of macrocycles validate this scaffold as a viable kinase template and further corroborate recent DAP/ALK solid state studies indicating that the inverted "U" shaped conformation of the acyclic DAPs is a preferred bioactive conformation.
Selo DaSilva