RESUMEN
The synthesis and properties of the bridged piperidine (oxaazabicyclo) compounds 8, 9, and 11 are described. A conformational analysis of these structures is compared with the representative GPR119 ligand 1. These results and the differences in agonist pharmacology are used to formulate a conformation-based hypothesis to understand activation of the GPR119 receptor. We also show for these structures that the agonist pharmacology in rat masks the important differences in human pharmacology.
Asunto(s)
Compuestos de Azabiciclo/química , Compuestos de Azabiciclo/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Compuestos de Azabiciclo/síntesis química , Prueba de Tolerancia a la Glucosa , Humanos , Conformación Molecular , Pirimidinas/síntesis química , Ratas , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Especificidad de la Especie , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
As exemplified by the lead compound 2, octahydrophenanthrene-2,7-diol analogues exhibit the profile of a pathway-selective or "dissociated" agonist of the glucocorticoid receptor (GR), retaining the potent activity that glucocorticoids have for transrepression (as measured by inhibition of IL-1 induced MMP-13 expression) but showing an attenuated capacity for transactivation (as measured in an MMTV luciferase reporter assay). With the guidance of a homology model of the GR ligand binding domain, structural modifications to 2 were carried out that were successful in replacing the allyl and propynyl side chains with groups likely to be more chemically stable and less likely to produce toxic metabolites. Key to success was the introduction of an additional hydroxyl group onto the tricyclic carbon framework of the series.
Asunto(s)
Descubrimiento de Drogas , Fenantrenos/farmacología , Receptores de Glucocorticoides/agonistas , Cromatografía Líquida de Alta Presión , Cristalografía por Rayos X , Espectrometría de Masas , Modelos Moleculares , Fenantrenos/químicaRESUMEN
Nicotinamide (2) is a potent and selective inhibitor of the PDE4D isozyme and as a chemical tool selectively blocks eosinophil mediator release and chemotaxis thus linking the role of PDE4D to eosinophil function.