RESUMEN
The structural basis of the pharmacology enabling the use of glucocorticoids as reliable treatments for inflammation and autoimmune diseases has been augmented with a new group of glucocorticoid receptor (GR) ligands. Compound 10, the archetype of a new family of dibenzoxepane and dibenzosuberane sulfonamides, is a potent anti-inflammatory agent with selectivity for the GR versus other steroid receptors and a differentiated gene expression profile versus clinical glucocorticoids (lower GR transactivation with comparable transrepression). A stereospecific synthesis of this chiral molecule provides the unique topology needed for biological activity and structural biology. In vivo activity of 10 in acute and chronic models of inflammation is equivalent to prednisolone. The crystal structure of compound 10 within the GR ligand binding domain (LBD) unveils a novel binding conformation distinct from the classic model adopted by cognate ligands. The overall conformation of the GR LBD/10 complex provides a new basis for binding, selectivity, and anti-inflammatory activity and a path for further insights into structure-based ligand design.
Asunto(s)
Antiinflamatorios no Esteroideos/química , Benzoxepinas/química , Receptores de Glucocorticoides/química , Sulfonamidas/química , Enfermedad Aguda , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/farmacología , Artritis Experimental/inducido químicamente , Artritis Experimental/tratamiento farmacológico , Benzoxepinas/farmacocinética , Benzoxepinas/farmacología , Sitios de Unión , Carragenina , Línea Celular , Enfermedad Crónica , Colágeno , Cristalografía por Rayos X , Diseño de Fármacos , Edema/inducido químicamente , Edema/tratamiento farmacológico , Humanos , Inflamación/tratamiento farmacológico , Ligandos , Masculino , Modelos Moleculares , Conformación Molecular , Ratas , Ratas Sprague-Dawley , Receptores de Glucocorticoides/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologíaRESUMEN
Structure-activity relationship studies are described, which led to the discovery of novel selective estrogen receptor modulators (SERMs) for the potential treatment of uterine fibroids. The SAR studies focused on limiting brain exposure and were guided by computational properties. Compounds with limited impact on the HPO axis were selected using serum estrogen levels as a biomarker for ovarian stimulation.