RESUMO
Stereospecific introduction of a methyl group to the indole-3-side chain enhanced activity in our tryptamine-derived series of GnRH receptor antagonists. Further improvements were achieved by variation of the bicyclic amino moiety of the tertiary amide and by adjustment of the tether length to a pyridine or pyridone terminus. These modifications culminated in analogue 24, which had oral activity in a rat model and acceptable oral bioavailability and half-life in dogs and monkeys.
Assuntos
Indóis/farmacocinética , Receptores LHRH/antagonistas & inibidores , Triptaminas/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Cães , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Hormônio Luteinizante/metabolismo , Macaca mulatta , Modelos Animais , Ratos , Relação Estrutura-Atividade , Triptaminas/síntese química , Triptaminas/química , Triptaminas/farmacologiaRESUMO
The 2-aryltryptamine class of GnRH receptor antagonists has been modified to incorporate carboxamide and acetamide substituents at the indole 5-position. With either a phenol or methanesulfonamide terminus on the N-aralkyl side chain, potent binding affinity to the GnRH receptor was achieved. A functional assay for GnRH antagonism was even more sensitive to structural modification and revealed a strong preference for branched tertiary amides.
Assuntos
Amidas/química , Indóis/farmacologia , Receptores LHRH/antagonistas & inibidores , Indóis/química , Indóis/metabolismo , Ligação Proteica , Receptores LHRH/metabolismoRESUMO
A pyridine side-chain terminus has been incorporated into the indole-5-carboxamide and indole-5-acetamide series of GnRH antagonists. Potent activity was observed in binding and functional assays. Certain branched or cyclic tertiary amides were identified as preferred in each series. Alkylation of the side-chain secondary amine had generally unfavorable effects. Variations of the gem-dialkyl substituents in the indole-5-acetamide series were also investigated.
