RESUMEN
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.
Asunto(s)
Hormona del Crecimiento/metabolismo , Nitrilos/farmacología , Tetrazoles/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Sistema Enzimático del Citocromo P-450/metabolismo , Perros , Espectroscopía de Resonancia Magnética , Estructura Molecular , Nitrilos/síntesis química , Nitrilos/farmacocinética , Hipófisis , Ratas , Relación Estructura-Actividad , Tetrazoles/síntesis química , Tetrazoles/farmacocinéticaRESUMEN
The structure-activity relationship of the O-benzyl serine side chain was investigated based on the tetrazole-based growth hormone secretagogue BMS-317180 (2). The ortho position of the benzyl moiety was found to be favorable for introduction of substituents. A series of ortho-substituted compounds were synthesized with improved in-vitro and in-vivo activity. Among them, the biphenyl compound 2p shows twofold improvement in potency compared to its parent compound BMS-317180 (2).
Asunto(s)
Diseño de Fármacos , Hormona del Crecimiento/metabolismo , Serina/análogos & derivados , Tetrazoles/química , Tetrazoles/farmacología , Animales , Carbamatos/farmacología , Estructura Molecular , Ratas , Serina/química , Relación Estructura-Actividad , Tetrazoles/síntesis químicaRESUMEN
A tetrazole-based peptidomimetic 2 (BMS-317180) was discovered as a human growth hormone secretagogue (GHS). Compound 2 is a potent, novel, orally effective GHS that shows an excellent safety profile in preclinical studies. The compound was advanced into clinical development.
Asunto(s)
Carbamatos/síntesis química , Hormona del Crecimiento/metabolismo , Tetrazoles/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Carbamatos/farmacocinética , Carbamatos/farmacología , Perros , Ésteres , Hormona del Crecimiento/sangre , Hormona de Crecimiento Humana/metabolismo , Humanos , Macaca fascicularis , Ratas , Solubilidad , Relación Estructura-Actividad , Tetrazoles/farmacocinética , Tetrazoles/farmacología , AguaRESUMEN
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.
Asunto(s)
Hormona del Crecimiento/metabolismo , Tetrazoles/química , Tetrazoles/farmacología , Animales , Perros , Relación Estructura-Actividad , Tetrazoles/síntesis químicaRESUMEN
Several novel series of tetrahydroisoquinoline 1-carboxamides were prepared and shown to be potent growth hormone (GH) secretagogues. Among them, carbamate 12a-E2 displays excellent in vivo activity by increasing plasma GH 10-fold in an anesthetized IV rat model.