RESUMEN
The development of potent gamma-secretase inhibitors having substituted heterocycles attached to a benzobicyclo[4.2.1]nonane core is described. This work led to the identification of [6S,9R,11R]-2',3',4',5,5',6,7,8,9,10-decahydro-2-(5-(4-fluorophenyl)-1-methylpyrazol-3-yl)-5'-(2,2,2-trifluoroethyl)spiro[6,9-methanobenzocyclooctene-11,3'-[1,2,5]thiadiazole] 1',1'-dioxide (16), which has excellent in vitro potency (0.06 nM) and which reduced amyloid-beta in APP-YAC mice with an ED(50) of 1 mg/kg (po). 16 had a good pharmacokinetic profile in three preclinical species.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Péptidos beta-Amiloides/antagonistas & inhibidores , Ciclooctanos/farmacología , Inhibidores de Proteasas/farmacología , Tiadiazoles/farmacología , Administración Oral , Animales , Ciclooctanos/administración & dosificación , Ciclooctanos/síntesis química , Ciclooctanos/farmacocinética , Concentración 50 Inhibidora , Ratones , Inhibidores de Proteasas/administración & dosificación , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacocinética , Tiadiazoles/administración & dosificación , Tiadiazoles/síntesis química , Tiadiazoles/farmacocinéticaRESUMEN
A series of 4,4-disubstituted cyclohexylamine NK(1) antagonists containing a lactam ring is described. The compounds are brain penetrant and activity is demonstrated in a ferret emesis model.
Asunto(s)
Antieméticos/síntesis química , Antieméticos/farmacología , Lactamas/química , Lactamas/farmacología , Taquicininas/antagonistas & inhibidores , Amidas/química , Animales , Antieméticos/química , Gerbillinae , Humanos , Concentración 50 Inhibidora , Lactamas/síntesis química , Metilación , Estructura Molecular , Receptores de Neuroquinina-1/metabolismo , Relación Estructura-Actividad , Taquicininas/metabolismoRESUMEN
A series of novel 4,4-disubstituted cyclohexylamine based NK(1) antagonists is described. The effect of changes to the C(1)-C(4) relative stereochemistry on the cyclohexane ring and replacements for the flexible linker are discussed, leading to the identification of compounds with high affinity and good in vivo duration of action.
Asunto(s)
Ciclohexilaminas/síntesis química , Ciclohexilaminas/farmacología , Antagonistas del Receptor de Neuroquinina-1 , Animales , Sitios de Unión , Células CHO , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/metabolismo , Cricetinae , Ciclohexilaminas/farmacocinética , Gerbillinae , Concentración 50 Inhibidora , Conformación Molecular , Ensayo de Unión Radioligante , Receptores de Neuroquinina-1/química , Relación Estructura-ActividadRESUMEN
A series of novel 4,4-disubstituted cyclohexylamines as NK(1) receptor antagonists is described: modifications to the amine moiety retain NK(1) receptor binding affinity whilst disrupting I(Kr) affinity.
