Development of Structurally Simplified, Non-azadecalin Glucocorticoid Antagonists which Demonstrate In Vivo Activity

Glucocorticoid receptor antagonists (GR antagonists) are a class of compounds developed to inhibit the activation of the glucocorticoid receptor and they have been used to treat a range of conditions such as Cushing's syndrome, diabetes, glaucoma, and depression. We report herein the discovery and optimization of a series of selective piperazine-based GR antagonists and discuss how key learnings from the discovery of relacorilant (CORT125134) were utilized to identify a simplified scaffold. Several compounds were identified with the desired profile and 3 key compounds were progressed to in vivo proof of concept studies.