RESUMEN
3-Aryl-5-phenyl-(1,2,4)-triazoles were identified as selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). They are active in both in vitro and an in vivo mouse pharmacodynamic (PD) model. The synthesis and structure activity relationships are presented.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Inhibidores Enzimáticos , Hidrocarburos Aromáticos , Hipoglucemiantes , Síndrome Metabólico/tratamiento farmacológico , Triazoles , Animales , Sitios de Unión , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/uso terapéutico , Hidrocarburos Aromáticos/síntesis química , Hidrocarburos Aromáticos/farmacología , Hidrocarburos Aromáticos/uso terapéutico , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/uso terapéutico , Concentración 50 Inhibidora , Ratones , Modelos Químicos , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/farmacología , Triazoles/uso terapéuticoRESUMEN
A novel series of selective ligands for the human glucocorticoid receptor (hGR) are described. Preliminary structure-activity relationships were focused on substitution at C-1 and indicated a preference for 3-, 4-, and 5-substituted aromatic and benzylic groups. The resulting analogues, e.g., 18 and 34, exhibited excellent affinity for hGR (IC(50) 1.9 nM and 2.8 nM, respectively) and an interesting partial agonist profile in functional assays of transactivation (tyrosine aminotransferase, TAT, and glutamine synthetase, GS) and transrepression (IL-6). The most potent compounds described in this study were the tertiary alcohol derivatives 21 and 25. These candidates showed highly efficacious IL-6 inhibition versus dexamethasone. The thiophenyl analogue 25 was evaluated in vivo in the mouse LPS challenge model and showed an ED(50) = 4.0 mg/kg, compared to 0.5 mg/kg for prednisolone in the same assay.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Indazoles/síntesis química , Pirazoles/síntesis química , Receptores de Glucocorticoides/metabolismo , Tiofenos/síntesis química , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Línea Celular , Cristalografía por Rayos X , Inducción Enzimática , Femenino , Glutamato-Amoníaco Ligasa/biosíntesis , Glutamato-Amoníaco Ligasa/genética , Humanos , Indazoles/química , Indazoles/farmacología , Interleucina-6/antagonistas & inhibidores , Ligandos , Ratones , Ratones Endogámicos BALB C , Conformación Molecular , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/metabolismo , Pirazoles/química , Pirazoles/farmacología , Ensayo de Unión Radioligante , Receptores de Glucocorticoides/agonistas , Estereoisomerismo , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/farmacología , Transcripción Genética/efectos de los fármacos , Activación Transcripcional/efectos de los fármacos , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Tirosina Transaminasa/biosíntesis , Tirosina Transaminasa/genéticaRESUMEN
Adamantyl triazoles were identified as selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). They are active both in in vitro and in in vivo pharmacodynamic models. The synthesis and structure-activity relationships of these inhibitors are presented.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Triazoles/síntesis química , Adamantano/síntesis química , Adamantano/farmacocinética , Adamantano/farmacología , Animales , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Síndrome Metabólico/tratamiento farmacológico , Ratones , Farmacocinética , Relación Estructura-Actividad , Triazoles/farmacocinética , Triazoles/farmacologíaRESUMEN
A novel series of selective ligands for the human glucocorticoid receptor is described. Structure-activity studies focused on variation of B-ring size, ketal ring size, and ketal substitution. These analogs were found to be potent and selective ligands for GR and have partial agonist profiles in functional assays for transactivation (TAT, GS) and transrepression (IL-6). Of these compounds, 27, 28, and 35 were evaluated further in a mouse LPS-induced TNF-alpha secretion model. Compound 28 had an ED(50) of 14.1 mg/kg compared with 0.5 mg/kg for prednisolone in the same assay.