RESUMEN
SAR was used to further develop an indazole class of non-steroidal glucocorticoid receptor agonists aided by a GR LBD (ligand-binding domain)-agonist co-crystal structure described in the accompanying paper. Progress towards discovering a dissociated GR agonist guided by human in vitro assays biased the optimization of this compound series towards partial agonists that possessed excellent selectivity against other nuclear hormone receptors.
Asunto(s)
Indazoles/síntesis química , Indazoles/farmacología , Receptores de Glucocorticoides/agonistas , Amidas/química , Amidas/farmacología , Humanos , Indazoles/química , Modelos Moleculares , Unión Proteica/efectos de los fármacos , Receptores de Glucocorticoides/química , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacología , Urea/química , Urea/farmacologíaRESUMEN
Modification of a phenolic lead structure based on lessons learned from increasing the potency of steroidal glucocorticoid agonists lead to the discovery of exceptionally potent, nonsteroidal, indazole GR agonists. SAR was developed to achieve good selectivity against other nuclear hormone receptors with the ultimate goal of achieving a dissociated GR agonist as measured by human in vitro assays. The specific interactions by which this class of compounds inhibits GR was elucidated by solving an X-ray co-crystal structure.
Asunto(s)
Amidas/química , Amidas/farmacología , Descubrimiento de Drogas , Receptores de Glucocorticoides/agonistas , Sitios de Unión , Cristalografía por Rayos X , Humanos , Indazoles/química , Indazoles/farmacología , Estructura Molecular , Unión Proteica/efectos de los fármacos , Esteroides/química , Esteroides/farmacología , Relación Estructura-ActividadRESUMEN
A series of dihydro-9,10-ethano-anthracene-11-carboxamides as novel glucocorticoid receptor modulators is reported. SAR exploration identified compounds from this series displaying a promising dissociation profile in discriminating between transrepression and transactivation activities. 17a is a partial agonist of GR-mediated transactivation which elicits potent and efficacious transrepression in reporter gene assays. A hypothetical binding mode is provided which accounts for the induction of functional activity by a bridgehead methyl group.
Asunto(s)
Antracenos/farmacología , Descubrimiento de Drogas , Receptores de Glucocorticoides/metabolismo , Antracenos/química , Línea Celular , Cristalografía por Rayos X , Descubrimiento de Drogas/métodos , Glucocorticoides/química , Glucocorticoides/farmacología , Humanos , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/fisiología , Relación Estructura-ActividadRESUMEN
A series of 2,2-dimethyl-3,3-diphenyl-propanamides as novel glucocorticoid receptor modulators is reported. SAR exploration led to the identification of 4-hydroxyphenyl propanamide derivatives displaying good agonist activity in GR-mediated transrepression assays and reduced agonist activity in GR-mediated transactivation assays. Compounds 17 and 30 showed anti-inflammatory activity comparable to prednisolone in the rat carrageenan-induced paw edema model, with markedly decreased side effects with regard to increases in blood glucose and expression of hepatic tyrosine aminotransferase. A hypothetical binding mode accounting for the induction of the functional activity by a 4-hydroxyl group is proposed.