RESUMEN
The present report describes our efforts to convert an existing LXR agonist into an LXR antagonist using a structure-based approach. A series of benzenesulfonamides was synthesized based on structural modification of a known LXR agonist and was determined to be potent dual liver X receptor (LXR α/ß) ligands. Herein we report the identification of compound 54 as the first reported LXR antagonist that is suitable for pharmacological in vivo evaluation in rodents.
Asunto(s)
Descubrimiento de Drogas , Receptores Nucleares Huérfanos/antagonistas & inhibidores , Sulfonamidas/farmacología , Animales , Relación Dosis-Respuesta a Droga , Células HEK293 , Células Hep G2 , Humanos , Ligandos , Receptores X del Hígado , Masculino , Ratones , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , BencenosulfonamidasRESUMEN
Structural modification of a series of dual LXRα/ß agonists led to the identification of a new class of LXRß partial agonists. An X-ray co-crystal structure shows that a representative member of this series, pyrrole 5, binds to LXRß with a reversed orientation compared to 1.
Asunto(s)
Receptores Nucleares Huérfanos/agonistas , Isoformas de Proteínas/agonistas , Pirroles/síntesis química , Sitios de Unión , Células CACO-2 , Cristalografía por Rayos X , Genes Reporteros , Células HEK293 , Humanos , Receptores X del Hígado , Receptores Nucleares Huérfanos/química , Unión Proteica , Isoformas de Proteínas/química , Pirroles/farmacología , Relación Estructura-Actividad , TransfecciónRESUMEN
[reaction: see text] An efficient synthetic route to the ABC tricyclic core of 1alpha-alkyldaphnanes has been developed. The conformational bias imparted by the C6-C9 oxo-bridge of BC-ring system 12 was used to elaborate the ABC-ring system precursor including the introduction of the beta-C5 hydroxyl group. A completely diastereoselective palladium-catalyzed enyne cyclization was then employed to establish the A-ring with a C1 appendage.