RESUMO
The synthesis of a number of indole GnRH antagonists is described. Oxidation of the pyridine ring nitrogen, combined with alkylation at the two position, led to a compound with an excellent in vitro activity profile as well as oral bioavailability in both rats and dogs.
Assuntos
Indóis/síntese química , Indóis/farmacocinética , Receptores LHRH/antagonistas & inibidores , Administração Oral , Alquilação , Animais , Disponibilidade Biológica , Cães , Meia-Vida , Indóis/farmacologia , Concentração Inibidora 50 , Oxirredução , Piridinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
A series of 2-arylindoles containing novel heteroaromatic substituents on the tryptamine tether, based on compound 1, was prepared and evaluated for their ability to act as gonadotropin releasing hormone (GnRH) antagonists. Successful modifications of 1 included chain length variation (reduction) and replacement of the pyridine with heteroaromatic groups. These alterations culminated in the discovery of compound 27kk which had excellent in vitro potency and oral efficacy in rodents.