Selective Glucocorticoid Receptor Modulators: Future of Glucocorticoid Immunosuppressive Therapy?

In1950Hench,Kendall,andReichsteinreceivedtheNobel Prize in Medicine for the characterization and isolation of glucocorticoids and the subsequent discovery of their antiinflammatory properties. To date, glucocorticoids are still widelyprescribedandplayanimportantroleinthetreatment ofavarietyofclinicaldisorders,includinginflammatorydiseases, autoimmune disorders, and hematological malignancies, as well as in the prevention of allograft rejection. Chronic glucocorticoid treatment is, however, associated with serious side effects like weight gain, hypertension, diabetes mellitus, osteoporosis, etc. In patients with Cushing’s disease,chonic(endogenous)hypercortisolismoftenleadsto irreversible changes in body composition (1, 2) and appears to be associated with an impaired quality of life (3) and an increased cardiovascular morbidity and mortality (4, 5). Therefore, patients who are chronically exposed to supraphysiological dosages of glucocorticoids are likely to be at risk for the same complications as patients with Cushing’s disease. This highlights the importance of development of glucocorticoid receptor (GR) targeting compounds with selective immunosuppressive properties but with fewer metabolic side effects. Insightinthemechanismofactionofglucocorticoidsand