1. Academic Validation
  2. A nonsteroidal glucocorticoid receptor antagonist

A nonsteroidal glucocorticoid receptor antagonist

  • Mol Endocrinol. 2003 Jan;17(1):117-27. doi: 10.1210/me.2002-0010.
Jeffrey N Miner 1 Curtis Tyree Junlian Hu Elaine Berger Keith Marschke Masaki Nakane Michael J Coghlan Dave Clemm Ben Lane Jon Rosen
Affiliations

Affiliation

  • 1 Department of Molecular and Cell Biology, Ligand Pharmaceuticals, Inc, San Diego, California 92121, USA. jminer@ligand.com
Abstract

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.

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