RESUMEN
GPR119 is a 7-transmembrane receptor that is expressed in the enteroendocrine cells in the intestine and in the islets of Langerhans in the pancreas. Indolines and 6,7-dihydro-5H-pyrrolo[2,3-a]pyrimidines were discovered as G protein-coupled receptor 119 (GPR119) agonists, and lead optimization efforts led to the identification of 1-methylethyl 4-({7-[2-fluoro-4-(methylsulfonyl)phenyl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)-1-piperidinecarboxylate (GSK1104252A) (3), a potent and selective GPR119 agonist. Compound 3 showed excellent pharmacokinetic properties and sufficient selectivity with in vivo studies supporting a role for GPR119 in glucose homeostasis in the rodent. Thus, 3 appeared to modulate the enteroinsular axis, improve glycemic control, and strengthen previous suggestions that GPR119 agonists may have utility in the treatment of type 2 diabetes.
Asunto(s)
Hipoglucemiantes/síntesis química , Piperidinas/síntesis química , Pirimidinas/síntesis química , Pirroles/síntesis química , Receptores Acoplados a Proteínas G/agonistas , Administración Oral , Animales , Línea Celular , Colon/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Incretinas/metabolismo , Mucosa Intestinal/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Piperidinas/farmacocinética , Piperidinas/farmacología , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Pirroles/farmacocinética , Pirroles/farmacología , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The identification of novel orally active mGluR5 antagonist GSK2210875 is described.
Asunto(s)
Compuestos Heterocíclicos con 3 Anillos/química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Administración Oral , Regulación Alostérica , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Ratones , Ratas , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/metabolismo , Relación Estructura-ActividadRESUMEN
Stereorandom and diastereoselective syntheses of a novel 1,2,3,4,4a,5,6,10b-octahydro-1,10-phenanthroline ring system are described. Derivatives of all four diastereomers were prepared and isolated in >98% ee. The pure enantiomers were compared in order to determine the preferred absolute and relative configuration required for optimal anti-HIV activity. Anti-HIV potency and pharmacokinetic properties of the newly synthesized tricyclic octahydrophenanthroline inhibitors are presented and comparisons are made to previously reported bicyclic (8S)-N-methyl-5,6,7,8-tetrahydro-8-quinolinamine analogs.
Asunto(s)
Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Fenantrolinas/química , Fenantrolinas/farmacología , Receptores CXCR4/antagonistas & inhibidores , Animales , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacocinética , Línea Celular , Perros , Humanos , Modelos Moleculares , Fenantrolinas/síntesis química , Fenantrolinas/farmacocinética , Ratas , Receptores CXCR4/metabolismoRESUMEN
The discovery of new highly potent and selective triple reuptake inhibitors is reported. The new classes of 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes are described together with detailed SAR. Appropriate decoration of the scaffolds was achieved with the help of a triple reuptake inhibitor pharmacophore model detailed here. Selected derivatives showed good oral bioavailability (>30%) and brain penetration (B/B > 4) in rats associated with high in vitro potency and selectivity at SERT, NET, and DAT. Among these compounds, microdialysis and in vivo experiments confirm that derivative 15 has an appropriate developability profile to be considered for further progression.
Asunto(s)
Compuestos de Azabiciclo/farmacología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Animales , Compuestos de Azabiciclo/química , Compuestos de Azabiciclo/farmacocinética , Unión Competitiva , Monoaminas Biogénicas/metabolismo , Disponibilidad Biológica , Transporte Biológico/efectos de los fármacos , Línea Celular , Cromatografía Líquida de Alta Presión , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Humanos , Masculino , Ratones , Microdiálisis , Microsomas Hepáticos/metabolismo , Modelos Químicos , Estructura Molecular , Actividad Motora/efectos de los fármacos , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Corteza Prefrontal/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
Starting from an established series of non-steroidal glucocorticoid receptor (GR) agonists, a large array was designed where a metabolically labile benzoxazinone moiety was replaced. Initial hits bound to GR but lacked agonist activity. Following two further iterations, potent GR agonists were discovered with 20D1E1 having NFkappaB agonism pIC(50) 8.8 (103%). Other analogues such as 23D1E1 display a dissociated profile (NFkappaB pIC(50) 8.1 (103%), MMTV pEC(50) 7.02 (36%)). The tetrahydronaphthalene moiety can also be replaced with substituted aryls such as 24E1 and 25E1.
