title: A nonsteroidal glucocorticoid receptor antagonist.
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.
authors.affiliation: Department of Molecular and Cell Biology, Ligand Pharmaceuticals, Inc, San Diego, California 92121, USA. jminer@ligand.com
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Miner
authors.forename: Curtis
authors.initials: C
authors.lastname: Tyree
authors.forename: Junlian
authors.initials: J
authors.lastname: Hu
authors.forename: Elaine
authors.initials: E
authors.lastname: Berger
authors.forename: Keith
authors.initials: K
authors.lastname: Marschke
authors.forename: Masaki
authors.initials: M
authors.lastname: Nakane
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Coghlan
authors.forename: Dave
authors.initials: D
authors.lastname: Clemm
authors.forename: Ben
authors.initials: B
authors.lastname: Lane
authors.forename: Jon
authors.initials: J
authors.lastname: Rosen
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003907:Dexamethasone / Q000494:pharmacology; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000494:pharmacology; D006067:Gonanes / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology*; D006801:Humans; D009574:Nitro Compounds / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors* / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: C475562:AL082D06; D005938:Glucocorticoids; D006067:Gonanes; D006727:Hormone Antagonists; D009574:Nitro Compounds; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; C053238:onapristone