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This version published online on October 17, 2002
Molecular Endocrinology, doi:10.1210/me.2002-0010
Molecular Endocrinology Vol. 0, No. 2002 200200101-
doi:10.1210/me.2002-0010
Copyright © 2002 by the Endocrine Society.
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*Compound via MeSH
*Substance via MeSH
Hazardous Substances DB
*DEXAMETHASONE

Submitted on January 8, 2002
Accepted on September 20, 2002

A Non-Steroidal, Glucocorticoid Receptor Antagonist

Jeffrey N. Miner1*, Curtis Tyree1, Junlian Hu1, Elaine Berger1, Keith Marschke1, Masaki Nakane1, Michael J. Coghlan1, Dave Clemm1, Ben Lane1, and Jon Rosen1

1 Department of Molecular and Cell Biology, New Leads Discovery, Ligand Pharmaceuticals, Inc., 10275 Science Center Drive, San Diego, Ca 92121 Abbott Laboratories, D-4NB J35 Pharmaceutical Discovery, 200 Abbott Park Rd, Abbott Park, IL 60064-3535

* To whom correspondence should be addressed. 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 over-exposure. 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 glucocorticoid receptor 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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