RESUMEN
We report a SAR of non-steroidal glucocorticoid mimetics that utilize indoles as A-ring mimetics. Detailed SAR is discussed with a focus on improving PR and MR selectivity, GR agonism, and in vitro dissociation profile. SAR analysis led to compound (R)-33 which showed high PR and MR selectivity, potent agonist activity, and reduced transactivation activity in the MMTV and aromatase assays. The compound is equipotent to prednisolone in the LPS-TNF model of inflammation. In mouse CIA, at 30 mg/kg compound (R)-33 inhibited disease progression with an efficacy similar to the 3 mg/kg dose of prednisolone.
Asunto(s)
Glucocorticoides/química , Glucocorticoides/farmacología , Indoles/química , Indoles/farmacología , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/metabolismo , Animales , Células HeLa , Humanos , Ratones , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
Synthesis and structure-activity relationship (SAR) of a series of nonsteroidal glucocorticoid receptor (GR) agonists are described. These compounds contain "diazaindole" moieties and display different transcriptional regulatory profiles in vitro and are considered "dissociated" between gene transrepression and transactivation. The lead optimization effort described in this article focused in particular on limiting the transactivation of genes which result in bone side effects and these were assessed in vitro in MG-63 osteosarcoma cells, leading to the identification of (R)-18 and (R)-21. These compounds maintained anti-inflammatory activity in vivo in collagen induced arthritis studies in mouse but had reduced effects on bone relevant parameters compared to the widely used synthetic glucocorticoid prednisolone 2 in vivo. To our knowledge, we are the first to report on selective glucocorticoid ligands with reduced bone loss in a preclinical in vivo model.
Asunto(s)
Huesos/efectos de los fármacos , Receptores de Glucocorticoides/agonistas , Animales , Línea Celular Tumoral , Femenino , Humanos , Espectroscopía de Resonancia Magnética , Ratones , Relación Estructura-ActividadRESUMEN
Syntheses and structure-activity relationships (SAR) of nonsteroidal glucocorticoid receptor (GR) agonists are described. These compounds contain azaindole moieties as A-ring mimetics and display various degrees of in vitro dissociation between gene transrepression and transactivation. Collagen induced arthritis studies in mouse have demonstrated that in vitro dissociated compounds (R)-16 and (R)-37 have steroid-like anti-inflammatory properties with improved metabolic side effect profiles, such as a reduced increase in body fat and serum insulin levels, compared to steroids.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Piridinas/síntesis química , Pirroles/síntesis química , Receptores de Glucocorticoides/agonistas , Esteroides/química , Tejido Adiposo/efectos de los fármacos , Animales , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/farmacología , Aromatasa/biosíntesis , Aromatasa/genética , Inhibidores de la Aromatasa/farmacología , Artritis Experimental/tratamiento farmacológico , Disponibilidad Biológica , Células Cultivadas , Inducción Enzimática , Femenino , Humanos , Enlace de Hidrógeno , Insulina/sangre , Interleucina-1/farmacología , Interleucina-6/antagonistas & inhibidores , Interleucina-6/biosíntesis , Interleucina-6/genética , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Piridinas/efectos adversos , Piridinas/farmacología , Pirroles/efectos adversos , Pirroles/farmacología , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Activación TranscripcionalRESUMEN
Compound 1, a potent glucocorticoid receptor ligand, contains a quaternary carbon bearing trifluoromethyl and hydroxyl groups. This paper describes the effect of replacing the trifluoromethyl group on binding and agonist activity of the GR ligand 1. The results illustrate that replacing the CF3 group with a cyclohexylmethyl or benzyl group maintains the GR binding potency. These substitutions alter the functional behavior of the GR ligands from agonists to antagonists. Docking studies suggest that the benzyl analog 19 binds in a similar fashion as the GR antagonist, RU486. The central benzyl group of 19 and the C-11 dimethylaniline moiety of RU486 overlay. Binding of compound 19 is believed to force helix 12 to adopt an open conformation and this leads to the antagonist properties of the non-CF3 ligands carrying a large group at the center of the molecule.