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
Several analogs of 2,3-diaryl pyrroles were synthesized and evaluated as inhibitors of Eimeria tenella cGMP-dependent protein kinase and in in vivo anticoccidial assays. A 4-fluorophenyl group enhances both in vitro and in vivo activities. The most potent analogs are the 5-(N-methyl, N-ethyl, and N-methylazetidine methyl) piperidyl derivatives 12, 23, and 34. These compounds have a broad spectrum of activity. Based on the in vivo efficacy and cost of synthesis, the N-ethyl analog 23 was chosen as a novel anticoccidial agent for a field trial.
Asunto(s)
Coccidiostáticos/síntesis química , Proteínas Quinasas Dependientes de GMP Cíclico/antagonistas & inhibidores , Proteínas Protozoarias/antagonistas & inhibidores , Pirroles/síntesis química , Animales , Disponibilidad Biológica , Pollos , Coccidiosis/tratamiento farmacológico , Coccidiostáticos/farmacocinética , Coccidiostáticos/farmacología , Eimeria , Semivida , Concentración 50 Inhibidora , Pirroles/farmacocinética , Pirroles/farmacología , Relación Estructura-ActividadRESUMEN
The synthesis of a number of indole GnRH antagonists is described. Oxidation of the pyridine ring nitrogen, combined with alkylation at the two position, led to a compound with an excellent in vitro activity profile as well as oral bioavailability in both rats and dogs.