RESUMO
Phosphatidylinositol-3-kinase (PI3K) is an important target in cancer due to the deregulation of the PI3K/ Akt signaling pathway in a wide variety of tumors. A series of thieno[3,2-d]pyrimidine derivatives were prepared and evaluated as inhibitors of PI3 kinase p110alpha. The synthesis, biological activity, and further profiling of these compounds are described. This work resulted in the discovery of 17, GDC-0941, which is a potent, selective, orally bioavailable inhibitor of PI3K and is currently being evaluated in human clinical trials for the treatment of cancer.
Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Indazóis/farmacologia , Neoplasias/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase , Sulfonamidas/farmacologia , Administração Oral , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Disponibilidade Biológica , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Humanos , Indazóis/administração & dosagem , Indazóis/farmacocinética , Indazóis/uso terapêutico , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêuticoRESUMO
A series of 4'-substituted ribonucleoside derivatives has been prepared and evaluated for inhibition of hepatitis C virus (HCV) RNA replication in cell culture. The most potent and non-cytotoxic derivative was compound 28 (4'-azidocytidine, R1479) with an IC(50) of 1.28 microM in the HCV replicon system. The triphosphate of compound 28 was prepared and shown to be an inhibitor of RNA synthesis mediated by NS5B (IC(50)=320 nM), the RNA polymerase encoded by HCV. Data on related analogues have been used to generate some preliminary requirements for activity within this series of nucleosides.