A Non-Steroidal, Glucocorticoid Receptor Antagonist

J. N. Miner

Molecular and Cellular Biology, Section Head of Endocrinology
Ligand Pharmaceuticals Inc., San Diego, California, U.S.A.

Selective intracellular receptor antagonists are used clinically to ameliorate hormone-dependent disease states. Patients with Cushing’s syndrome have high levels of the glucocorticoid, cortisol, and suffer significant consequences from this over-exposure. This hormone is also elevated under conditions of viral infection, stress and aging. We have identified the first selective, nonsteroidal, glucocorticoid receptor antagonist. This compound is characterized by a tri-arylmethane core chemical structure. This GR-specific antagonist binds with nanomolar affinity to the glucocorticoid receptor and has no detectable binding affinity for the highly related receptors for mineralocorticoids, androgens, estrogens and progesterones. We demonstrate that this antagonist binds to the receptor and inhibits glucocorticoid-mediated transcriptional regulation. This compound binds competitively with steroids, likely occupying a similar site within the ligand binding domain. Once bound however, the compound fails to induce critical conformational changes in the receptor necessary for agonist activity.