RESUMO
A novel series of N1 substituted tetrazole amides were prepared and showed to be potent growth hormone (GH) secretagogues. Among them, hydroxyl containing analog 31 displayed excellent in vivo activity by increasing plasma GH 10-fold in an anesthetized IV rat model.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Hormônio do Crescimento/metabolismo , Tetrazóis/química , Amidas/química , Animais , Linhagem Celular , Glioma/metabolismo , Hormônio do Crescimento/sangue , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
1H-tetrazole-1-alkanenitrile SR-9g exhibits a >10-fold in vivo potency enhancement over the lead nitrile 1 and has acceptable oral bioavailability in rats and dogs. An enantiospecific synthesis of 1H-tetrazole-1-alkanenitrile nitriles 9 has been developed.
Assuntos
Hormônio do Crescimento/metabolismo , Nitrilas/farmacologia , Tetrazóis/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Sistema Enzimático do Citocromo P-450/metabolismo , Cães , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Nitrilas/síntese química , Nitrilas/farmacocinética , Hipófise , Ratos , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/farmacocinéticaRESUMO
A novel class of Growth Hormone Secretagogues (GHS), based on a tetrazole template, has been discovered. In vitro SAR and in vivo potency within this new class of GHS are described. The tetrazole 9q exhibits good oral bioavailability in rats and dogs as well as efficacy following an oral 10 mg/kg dose in dogs. Solution and solid phase protocols for the synthesis of tetrazole based GHS have been developed.
