RESUMO
5-Alkenyl or 5-alkynyl-4-anilinopyrimidines were prepared and evaluated for in vitro inhibition of EGFR/Her-2 kinase activity and the growth of tumor cell lines (BT474 and N87). Several of these compounds inhibited the growth of BT474 and N87 at concentrations below 200nM. Structure-activity relationship studies revealed a critical role for the 5-alkynyl moieties. The representative compound 19 exhibited significant antitumor potency in a mouse xenograft model.
Assuntos
Receptores ErbB/antagonistas & inibidores , Receptor ErbB-2/antagonistas & inibidores , Administração Oral , Animais , Química Farmacêutica/métodos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Inibidores Enzimáticos/farmacologia , Receptores ErbB/química , Humanos , Concentração de Íons de Hidrogênio , Concentração Inibidora 50 , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Químicos , Transplante de Neoplasias , Pirimidinas/química , Ratos , Receptor ErbB-2/química , Relação Estrutura-AtividadeRESUMO
A structure-activity relationship study of 4-anilinopyrimidines for dual EGFR/Her-2 inhibitor has resulted in the identification of 4-anilino-5-alkenyl or 5-alkynyl-6-methylpyrimidine derivatives that have exhibited effective inhibitory activity against both enzymes. The presence of 5-alkenyl or 5-alkynyl moiety bearing terminal hydrophilic group played important role for inhibition of these enzymes. Selected compounds in the series demonstrated some activity against Her-2 dependent cell line (BT474).
