RESUMEN
Starting from a rapidly metabolized adamantane 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitor 22a, a series of E-5-hydroxy-2-adamantamine inhibitors, exemplified by 22d and (+/-)-22f, was discovered. Many of these compounds are potent inhibitors of 11beta-HSD1 and are selective over 11beta-HSD2 for multiple species (human, mouse, and rat), unlike other reported species-selective series. These compounds have good cellular potency and improved microsomal stability. Pharmacokinetic profiling in rodents indicated moderate to large volumes of distribution, short half-lives, and a pharmacokinetic species difference with the greatest exposure measured in rat with 22d. One hour postdose liver, adipose, and brain tissue 11beta-HSD1 inhibition was confirmed with (+/-)-22f in a murine ex vivo assay. Although 5,7-disubstitued-2-adamantamines provided greater stability, a single, E-5-position, polar functional group afforded inhibitors with the best combination of stability, potency, and selectivity. These results indicate that adamantane metabolic stabilization sufficient to obtain short-acting, potent, and selective 11beta-HSD1 inhibitors has been discovered.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/análogos & derivados , Adamantano/síntesis química , Piperazinas/síntesis química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/genética , Adamantano/farmacocinética , Animales , Línea Celular , Humanos , Técnicas In Vitro , Ratones , Microsomas Hepáticos/metabolismo , Piperazinas/farmacocinética , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Distribución TisularRESUMEN
Potent and selective adamantane sulfone and sulfonamide inhibitors of 11-beta-HSD-1 have been discovered. Selected compounds from these series have robust pharmacokinetic profiles and strongly inhibit liver, fat, and brain HSD1 for extended periods after oral dosing.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/análogos & derivados , Adamantano/síntesis química , Adamantano/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/antagonistas & inhibidores , Tejido Adiposo/enzimología , Animales , Encéfalo/enzimología , Cristalografía por Rayos X , Diseño de Fármacos , Inhibidores Enzimáticos/farmacocinética , Humanos , Indicadores y Reactivos , Hígado/enzimología , Ratones , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
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
A series of potent and selective adamantane aminoamide 11-beta-HSD-1 inhibitors has been optimized. Chemically these studies were expedited by utilizing readily obtained amino acids as starting materials or an isocyanide multicomponent reaction. Structure-activity relationship studies resulted in the discovery of dual human and mouse 11-beta-HSD-1 potent and selective inhibitors like adamantane 11 and related compounds with high metabolic stability and robust pharmacokinetic profiles.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/síntesis química , Adamantano/farmacología , Cianuros/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/antagonistas & inhibidores , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/metabolismo , Adamantano/química , Adamantano/farmacocinética , Animales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Humanos , Ratones , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A series of structurally novel and metabolically stable bridged bicyclic carbocycle and heterocycle adamantane replacements have been synthesized and biologically evaluated. Several of these compounds exhibit excellent human and mouse 11beta-HSD1 potency and 11beta-HSD2 selectivity.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/síntesis química , Adamantano/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/antagonistas & inhibidores , Adamantano/química , Animales , Línea Celular , Evaluación Preclínica de Medicamentos , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Humanos , Técnicas In Vitro , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Conformación Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of metabolically stable adamantane amide 11beta-HSD1 inhibitors have been synthesized and biologically evaluated. These compounds exhibit excellent HSD1 potency and HSD2 selectivity and good pharmacokinetic and pharmacodynamic profiles.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/síntesis química , Adamantano/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/antagonistas & inhibidores , Adamantano/química , Animales , Línea Celular , Evaluación Preclínica de Medicamentos , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Humanos , Técnicas In Vitro , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Conformación Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of metabolically stable butyrolactam 11beta-HSD1 inhibitors have been synthesized and biologically evaluated. These compounds exhibit excellent HSD1 potency and HSD2 selectivity, pharmacokinetic, and pharmacodynamic profiles.