RESUMEN
KCNQ2/3 voltage-gated potassium channels conduct low-threshold, slowly activating and non-inactivating currents to repolarize the neuronal resting membrane potential. The channels negatively regulate neuronal excitability and KCNQ2/3 openers are efficacious in hyperexcited states such as epilepsy and pain. We developed and utilized thallium influx assays to profile novel KCNQ2/3 channel openers with respect to selectivity across KCNQ subtypes and on requirement for tryptophan 236 of KCNQ2, a critical residue for activity of the KCNQ opener retigabine. Using distinct chemical series of openers, a quinazolinone series showed relatively poor selectivity across multiple KCNQ channels and lacked activity at the KCNQ2(W236L) mutant channel. In contrast, several novel benzimidazole openers showed selectivity for KCNQ2/3 and KCNQ2 and retain activity at KCNQ2(W236L). Profiling of several hundred KCNQ2/3 openers across multiple diverse chemical series revealed that openers show differential degrees of selectivity across subtypes, with selectivity most difficult to achieve against KCNQ2. In addition, we report the significant finding that KCNQ openers can pharmacologically differentiate between homomeric and heteromeric channels containing subtypes in common. Moreover, most openers assayed were dependent on the W236 for activity, whereas only a small number appear to use a distinct mechanism. Collectively, we provide novel insights into the molecular pharmacology of KCNQ channels by demonstrating differential selectivity and site of action for KCNQ2/3 openers. The high-throughput thallium influx assays should prove useful for rapid characterization of KCNQ openers and in guiding efforts to identify selective compounds for advancement towards the clinic.
Asunto(s)
Activación del Canal Iónico/efectos de los fármacos , Canal de Potasio KCNQ2/metabolismo , Canal de Potasio KCNQ3/metabolismo , Talio/farmacocinética , Carbamatos/farmacología , Células HEK293 , Humanos , Activación del Canal Iónico/genética , Canales de Potasio KCNQ/genética , Canales de Potasio KCNQ/metabolismo , Canales de Potasio KCNQ/fisiología , Canal de Potasio KCNQ2/genética , Canal de Potasio KCNQ2/fisiología , Canal de Potasio KCNQ3/genética , Canal de Potasio KCNQ3/fisiología , Mutación , Fenilendiaminas/farmacologíaRESUMEN
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
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
The structure-activity relationship studies on a series of tetralin carboxamide growth hormone secretagogue receptor (GHS-R) antagonists are discussed. It was found that certain 2-alkoxycarbonylamino substituted tetralin carboxamides are potent, selective, and orally bioavailable GHS-R antagonists.
Asunto(s)
Amidas/síntesis química , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Tetrahidronaftalenos/farmacología , Administración Oral , Amidas/farmacología , Animales , Sitios de Unión , Disponibilidad Biológica , Diseño de Fármacos , Concentración 50 Inhibidora , Fenilendiaminas/química , Ratas , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Ghrelina , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Amidas/farmacología , Receptores de Glucagón/antagonistas & inhibidores , Amidas/química , Animales , Haplorrinos , Humanos , Ratones , Ratas , Ratas Sprague-DawleyRESUMEN
We report the discovery of a novel class of glucocorticoid receptor (GR) antagonists based on the chromene molecular scaffold. The compounds exhibit good functional potency and an improved receptor selectivity profile for GR over other steroid receptors when compared to the classical steroidal GR-antagonist, RU-486.