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A Nonsteroidal Glucocorticoid Receptor Antagonist

Department of Molecular and Cell Biology (J.N.M., J.H., D.C., J.R.), New Leads Discovery (C.T., E.B., K.M.), Ligand Pharmaceuticals, Inc., San Diego, California 92121; and Abbott Laboratories (M.N., M.J.C., B.L.) D-4NB J35 Pharmaceutical Discovery, Abbott Park, Illinois 60064-3535

Address all correspondence and requests for reprints to: Jeffrey N. Miner, Ligand Pharmaceuticals, Molecular and Cellular Biology, 10275 Science Center Drive, San Diego, California 92121. E-mail: jminer{at}ligand.com.

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 overexposure. High levels of this hormone are also implicated in exacerbating diabetes and the stress response. Selectively inhibiting this hormone may have clinical benefit in these disease states. To this end, we have identified the first selective, nonsteroidal glucocorticoid receptor (GR) antagonist. This compound is characterized by a tri-aryl methane core chemical structure. This GR-specific antagonist binds with nanomolar affinity to the GR and has no detectable binding affinity for the highly related receptors for mineralocorticoids, androgens, estrogens, and progestins. We demonstrate that this antagonist 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.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  GR  |  PR  |  AR  |  TRAP100

Ligands:   Dexamethasone  |  Hydrocortisone  |  17β-Estradiol  |  Dihydrotestosterone  |  Aldosterone  |  Progesterone  |  RU486

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