RESUMEN
Benzimidazole and indane are the two key fragments in our potent and selective MCH-1 receptor (MCHR1) antagonists. To identify novel linkers connecting the two fragments, we investigated diamino-cycloalkane-derived analogs and discovered highly potent antagonists with cis-1,4-diaminocyclohexane as a unique spacer in this chemical class. Structural overlay suggested that cis-1-substituted-4-aminocyclohexane functions as a bioisostere of 4-substituted-piperidine and that the active conformation adopts a U-shaped orientation.
Asunto(s)
Ciclohexanos/química , Indanos/química , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Animales , Bencimidazoles/química , Semivida , Indanos/metabolismo , Indanos/farmacocinética , Isomerismo , Ratones , Unión Proteica , Ratas , Receptores de la Hormona Hipofisaria/metabolismoRESUMEN
This paper describes the lead optimization of a new series of potent, selective, orally bioavailable, brain-penetrant MCH-1 receptor antagonists. A major focus of the work was to achieve a selectivity profile appropriate for in vivo efficacy studies and safety.
Asunto(s)
Indanos/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Amidas/química , Amidas/farmacocinética , Amidas/farmacología , Animales , Bencimidazoles/química , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Cristalografía por Rayos X , Humanos , Indanos/química , Indanos/farmacocinética , Cinética , Piperidinas/química , Piperidinas/farmacocinética , Piperidinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Somatostatina/química , Receptores de Somatostatina/metabolismo , Relación Estructura-ActividadRESUMEN
A novel series of orally active pyrimido[5,4-3][1,2,4]triazine-5,7-diamine-based hypoglycemic agents have been identified. These compounds show non-selective inhibitory properties against a panel of protein tyrosine phosphatases including PTP1B. Compounds 12 and 13 display oral glucose lowering effects in ob/ob mice.