RESUMEN
A series of novel, potent quinolinyl-derived imidazo[1,5-a]pyrazine IGF-IR (IGF-1R) inhibitors--most notably, cis-3-(3-azetidin-1-ylmethylcyclobutyl)-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-8-ylamine (AQIP)--is described. Synthetic details, structure-activity relationships, and in vitro biological activity are reported for the series. Key in vitro and in vivo biological results for AQIP are reported, including: inhibition of ligand-stimulated autophosphorylation of IGF-IR and downstream pathways in 3T3/huIGFIR cells; inhibition of proliferation and induction of DNA fragmentation in human tumor cell lines; a pharmacokinetic profile suitable for once-per-day oral dosing; antitumor activity in a 3T3/huIGFIR xenograft model; and effects on insulin and glucose levels.
Asunto(s)
Imidazoles/síntesis química , Imidazoles/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Pirazinas/síntesis química , Pirazinas/farmacología , Quinolinas/química , Receptor IGF Tipo 1/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Glucemia/metabolismo , Línea Celular , Perros , Femenino , Humanos , Imidazoles/química , Insulina/sangre , Ligandos , Ratones , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Pirazinas/química , Ratas , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A series of [2-imidazol-1-yl-2-(6-alkoxy-naphthalen-2-yl)-1-methyl-ethyl]-dimethyl-amines were designed and synthesized as CYP26 inhibitors, serving as retinoic acid metabolic blocking agents (RAMBA's).