RESUMO
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.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Inibidores Enzimáticos , Hidrocarbonetos Aromáticos , Hipoglicemiantes , Síndrome Metabólica/tratamento farmacológico , Triazóis , Animais , Sítios de Ligação , Modelos Animais de Doenças , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Hidrocarbonetos Aromáticos/síntese química , Hidrocarbonetos Aromáticos/farmacologia , Hidrocarbonetos Aromáticos/uso terapêutico , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Concentração Inibidora 50 , Camundongos , Modelos Químicos , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/farmacologia , Triazóis/uso terapêuticoRESUMO
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.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Triazóis/síntese química , Triazóis/farmacologia , Administração Oral , Animais , Técnicas de Química Combinatória , Cortisona/análise , Cortisona/sangue , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Humanos , Hidrocortisona/análise , Hidrocortisona/sangue , Camundongos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/farmacocinéticaRESUMO
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.