RESUMO
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.
Assuntos
Imidazóis/síntese química , Imidazóis/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/síntese química , Pirazinas/farmacologia , Quinolinas/química , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Glicemia/metabolismo , Linhagem Celular , Cães , Feminino , Humanos , Imidazóis/química , Insulina/sangue , Ligantes , Camundongos , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Pirazinas/química , Ratos , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A highly effective one-pot Friedländer quinoline synthesis using inexpensive reagents has been developed. o-Nitroarylcarbaldehydes were reduced to o-aminoarylcarbaldehydes with iron in the presence of catalytic HCl (aq.) and subsequently condensed in situ with aldehydes or ketones to form mono- or di-substituted quinolines in high yields (66-100%).
