title: Indole Glucocorticoid Receptor Antagonists Active in a Model of Dyslipidemia Act via a Unique Association with an Agonist Binding Site.
abstract: To further elucidate the structural activity correlation of glucocorticoid receptor (GR) antagonism, the crystal structure of the GR ligand-binding domain (GR LBD) complex with a nonsteroidal antagonist, compound 8, was determined. This novel indole sulfonamide shows in vitro activity comparable to known GR antagonists such as mifepristone, and notably, this molecule lowers LDL (-74%) and raises HDL (+73%) in a hamster model of dyslipidemia. This is the first reported crystal structure of the GR LBD bound to a nonsteroidal antagonist, and this article provides additional elements for the design and pharmacology of clinically relevant nonsteroidal GR antagonists that may have greater selectivity and fewer side effects than their steroidal counterparts.
authors.affiliation: Eli Lilly Biotechnology Center , 10300 Campus Point Drive, Suite 200, San Diego, California 92121 United States.
authors.forename: John G
authors.initials: JG
authors.lastname: Luz
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly & Co. , Lilly Corporate Center, Indianapolis, Indiana 46285 United States.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Carson
authors.affiliation: Eli Lilly Biotechnology Center , 10300 Campus Point Drive, Suite 200, San Diego, California 92121 United States.
authors.forename: Bradley
authors.initials: B
authors.lastname: Condon
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly & Co. , Lilly Corporate Center, Indianapolis, Indiana 46285 United States.
authors.forename: David
authors.initials: D
authors.lastname: Clawson
authors.affiliation: Eli Lilly Biotechnology Center , 10300 Campus Point Drive, Suite 200, San Diego, California 92121 United States.
authors.forename: Anna
authors.initials: A
authors.lastname: Pustilnik
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly & Co. , Lilly Corporate Center, Indianapolis, Indiana 46285 United States.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Kohlman
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly & Co. , Lilly Corporate Center, Indianapolis, Indiana 46285 United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Barr
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly & Co. , Lilly Corporate Center, Indianapolis, Indiana 46285 United States.
authors.forename: James S
authors.initials: JS
authors.lastname: Bean
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly & Co. , Lilly Corporate Center, Indianapolis, Indiana 46285 United States.
authors.forename: M Joelle
authors.initials: MJ
authors.lastname: Dill
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly & Co. , Lilly Corporate Center, Indianapolis, Indiana 46285 United States.
authors.forename: Dana K
authors.initials: DK
authors.lastname: Sindelar
authors.affiliation: Eli Lilly Biotechnology Center , 10300 Campus Point Drive, Suite 200, San Diego, California 92121 United States.
authors.forename: Milan
authors.initials: M
authors.lastname: Maletic
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly & Co. , Lilly Corporate Center, Indianapolis, Indiana 46285 United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Coghlan
mesh_terms: D000818:Animals; D001665:Binding Sites; D006224:Cricetinae; D018360:Crystallography, X-Ray; D059305:Diet, High-Fat; D050171:Dyslipidemias / Q000188:drug therapy*; D005260:Female; D008024:Ligands; D008055:Lipids / Q000097:blood; D008647:Mesocricetus; D008958:Models, Molecular; D011487:Protein Conformation; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000235:genetics; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D008024:Ligands; D008055:Lipids; D011965:Receptors, Glucocorticoid; D013449:Sulfonamides