RESUMEN
3-(Phenylcyclobutyl)-1,2,4-triazoles were identified as selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). These were active both in vitro and in an in vivo mouse pharmacodynamic (PD) model. Fluorine substitution of the cyclobutane ring improved the pharmacokinetic profile significantly. The synthesis and structure-activity relationships are presented.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Triazoles/síntesis química , Triazoles/farmacología , Administración Oral , Animales , Técnicas Químicas Combinatorias , Cortisona/análisis , Cortisona/sangre , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Humanos , Hidrocortisona/análisis , Hidrocortisona/sangre , Ratones , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Triazoles/farmacocinéticaRESUMEN
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 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.