RESUMEN
A novel class of adamantane ethers 11beta-hydroxysteroid hydrogenase type I inhibitors has been discovered. These compounds have excellent HSD-1 potency and selectivity against HSD-2. The structure-activity relationships, selectivity, metabolism, PK, ex vivo pharmacodynamic data, and an X-ray crystal structure of one of these inhibitors bound to h-HSD-1 are discussed.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/análogos & derivados , Adamantano/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/genética , Adamantano/síntesis química , Alquilación , Animales , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Éteres/síntesis química , Éteres/farmacología , Semivida , Humanos , Indicadores y Reactivos , Ratones , Ratones Noqueados , Microsomas Hepáticos/enzimología , Microsomas Hepáticos/metabolismo , Modelos MolecularesRESUMEN
High throughput screening efforts have identified a novel class of dichloroaniline amide 11beta-HSD1 inhibitors. SAR studies initiated from dichloroaniline 4 focused on retaining the potency and selectivity profile of the lead.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Síndrome Metabólico/tratamiento farmacológico , Carbenoxolona/química , Carbenoxolona/farmacología , Inhibidores Enzimáticos/uso terapéutico , Humanos , Conformación Molecular , Piperazinas/química , Piperazinas/farmacología , Sulfonamidas/química , Sulfonamidas/farmacología , Tiazoles/química , Tiazoles/farmacologíaRESUMEN
Biaryl amides derived from a reported series of ureas 1 were evaluated and found to be potent human glucagon receptor antagonists. The benzofuran analogue 6i was administered in Sprague-Dawley rats and blocked the effects of an exogenous glucagon challenge.