Synthetic Glucocorticoids That Dissociate Transactivation and AP-1 Transrepression Exhibit Antiinflammatory Activityin Vivo

• DOI: 10.1210/mend.11.9.9979
• Publication Date: 2014-01-08T12:30:06Z
• Authors: Béatrice M. Vayss...; Sonia Dupont; Agnès Choquart; Francis Petit; Teresa Garcia; Christian Marchan...; Hinrich Gronemeyer; Michèle Resche-Rigon
• Keywords: Transrepression; Proinflammatory cytokine; Antiglucocorticoid

Some of the most potent antiinflammatory and immunosuppressive agents are synthetic glucocorticoids. However, major side effects severely limit their therapeutic use. The development improved glucocorticoid-based drugs will require separation beneficial from deleterious effects. One possibility toward this goal is to try dissociate two main activities glucocorticoids, i.e. transactivation transrepression. Screening a library compounds using AP-1 transrepression models in transiently transfected cells identified dissociated which exert strong inhibition but little or no transactivation. Importantly, despite high ligand binding affinity, prototypic compound, RU24858, acted as weak agonist did not efficiently antagonize dexamethasone-induced transcription cells. Similar results were obtained hepatic HTC for endogenous tyrosine amino transferase gene (TAT), encodes one enzymes involved glucocorticoid-dependent stimulation neoglucogenesis. To investigate whether glucocorticoids retained potential classic several vitro vivo used. Indeed, secretion proinflammatory lymphokine interleukin-1β was inhibited by human monocytic THP 1 Moreover, models, these exerted an activity that glucocorticoid prednisolone. These may lead improvement therapies provide novel concept drug discovery.