RESUMEN
The development of a series of GABA(A) alpha2/alpha3 subtype selective pyridazine based benzodiazepine site agonists as anxiolytic agents with reduced sedative/ataxic potential is described, including the discovery of 16, a remarkably alpha3-selective compound ideal for in vivo study. These ligands are antagonists at the alpha1 subtype, with good CNS penetration and receptor occupancy, and excellent oral bioavailability.
Asunto(s)
Ansiolíticos/farmacología , Ansiedad/tratamiento farmacológico , Agonistas del GABA/farmacología , Agonistas de Receptores de GABA-A , Piridazinas/farmacología , Animales , Ansiolíticos/administración & dosificación , Ansiolíticos/síntesis química , Sitios de Unión , Agonistas del GABA/administración & dosificación , Agonistas del GABA/síntesis química , Humanos , Ligandos , Estructura Molecular , Piridazinas/administración & dosificación , Piridazinas/síntesis química , Ratas , Proteínas Recombinantes/agonistas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The synthesis of a novel spiro[1-benzofuran-2,4'-piperidin]-3-one scaffold has been achieved in five steps with an overall yield of 47%. The versatility of the spiropiperidine scaffold in the context of library synthesis is exemplified by selective and sequential derivatisation of the amino and aryl bromide functional groups, including the development of multi-step telescope reaction matrices.