Development of specific glucocorticoid receptor antagonists

Abstract

Background / Methods : Mifepristone, a potent glucocorticoid receptor (GR) and progesterone receptor (PR) antagonist, has recently become the first medication approved for the treatment of Cushing's syndrome, the archetypal illness of cortisol excess. Mifepristone is also being studied for the treatment of psychotic depression in a Phase 3 study and in numerous academic studies on diseases in which GR antagonism is thought to be potentially useful. In all cases, mifepristone utility is generated by its ability to block GR and its antagonism of PR is either irrelevant or troublesome. A selective GR antagonist may confer the same benefits of mifepristone while removing an important liability. Results : Data are provided from animal and human studies of mifepristone and animal studies of novel, selective GR antagonists in metabolic and psychiatric diseases. Conclusions : Pre-clinical studies indicate that selective GR antagonists may potentially have the same clinical utility as mifepristone in blocking cortisol while eliminating the unwanted effects of progesterone blockade.

Keywords

• mifepristone
• Cushing syndrome
• psychotic depression
• cortisol
• progesterone blockade