RESUMEN
The identification of a new series of RORc inverse agonists is described. Comprehensive structure-activity relationship studies of this reversed sulfonamide series identified potent RORc inverse agonists in biochemical and cellular assays which were also selective against a panel of nuclear receptors. Our work has contributed a compound that may serve as a useful in vitro tool to delineate the complex biological pathways involved in signalling through RORc. An X-ray co-crystal structure of an analogue with RORc has also provided useful insights into the binding interactions of the new series.
Asunto(s)
Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Sulfonamidas/química , Sitios de Unión , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Citocinas/biosíntesis , Agonismo Inverso de Drogas , Células HEK293 , Humanos , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/efectos de los fármacos , Simulación de Dinámica Molecular , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Unión Proteica , Estructura Terciaria de Proteína , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/toxicidadRESUMEN
Screening of the Merck compound collection identified 6 as an unusually simple, low molecular weight hit with moderate affinity for GABAA receptors. The structural novelty of 6, compared to our advanced series of GABAA alpha5 inverse agonists, made it an attractive molecule for further exploration. This paper will describe the evolution of 6 into a new series of ligands with nanomolar affinity and functional selectivity for GABAA alpha5 receptor subtypes.
Asunto(s)
Piridazinas/síntesis química , Receptores de GABA-A/efectos de los fármacos , Animales , Línea Celular , Humanos , Técnicas In Vitro , Ligandos , Masculino , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Técnicas de Placa-Clamp , Subunidades de Proteína/fisiología , Piridazinas/farmacocinética , Piridazinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores de GABA-A/fisiología , Proteínas Recombinantes/metabolismo , Relación Estructura-ActividadRESUMEN
On the basis of a spirocyclic ether screening lead, a series of acyclic sulfones have been identified as high-affinity, selective 5-HT(2A) receptor antagonists. Bioavailability lacking in the parent, 1-(2-(2,4-difluorophenyl)ethyl)-4-(phenylsulfonyl)piperidine (12), was introduced by using stability toward rat liver microsomes as a predictor of bioavailability. By this means, the 4-cyano- and 4-carboxamidophenylsulfonyl derivatives 26 and 31 were identified as orally bioavailable, brain-penetrant analogues suitable for evaluation in animal models. Bioavailability was also attainable by N substitution leading to the N-phenacyl derivative 35. IKr activity detected through counterscreening was reduced to insignificant levels in vivo with the latter compound.
Asunto(s)
Benzamidas/síntesis química , Proteínas de Transporte de Catión , Proteínas de Unión al ADN , Nitrilos/síntesis química , Piperidinas/síntesis química , Canales de Potasio con Entrada de Voltaje , Receptores de Serotonina/efectos de los fármacos , Antagonistas de la Serotonina/síntesis química , Compuestos de Espiro/síntesis química , Sulfonas/síntesis química , Transactivadores , Administración Oral , Animales , Benzamidas/química , Benzamidas/farmacocinética , Benzamidas/farmacología , Disponibilidad Biológica , Encéfalo/metabolismo , Línea Celular , Cricetinae , Evaluación Preclínica de Medicamentos , Canal de Potasio ERG1 , Electrocardiografía , Canales de Potasio Éter-A-Go-Go , Hurones , Humanos , Técnicas In Vitro , Masculino , Microsomas Hepáticos/metabolismo , Nitrilos/química , Nitrilos/farmacocinética , Nitrilos/farmacología , Piperidinas/química , Piperidinas/farmacocinética , Piperidinas/farmacología , Canales de Potasio/metabolismo , Canales de Potasio/fisiología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT2A , Antagonistas de la Serotonina/química , Antagonistas de la Serotonina/farmacocinética , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/síntesis química , Agonistas de Receptores de Serotonina/química , Agonistas de Receptores de Serotonina/farmacocinética , Agonistas de Receptores de Serotonina/farmacología , Compuestos de Espiro/química , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología , Relación Estructura-Actividad , Sulfonas/química , Sulfonas/farmacocinética , Sulfonas/farmacología , Regulador Transcripcional ERGRESUMEN
This report describes the effect of replacing the central basic amine present in many known 5-HT(2A) ligands with an aromatic residue. We targeted the isomeric phenethylpyridines 2 and 3 and these compounds proved to be excellent leads, possessing good 5-HT(2A) receptor binding affinity and selectivity over the 5-HT(2C) subtype. Optimization of one isomer led to the identification of 25, a compound with sub-nanomolar 5-HT(2A) affinity and selectivity over 5-HT(2C) of greater than 4600-fold.