title: Trifluoromethyl group as a pharmacophore: effect of replacing a CF3 group on binding and agonist activity of a glucocorticoid receptor ligand.
abstract: Compound 1, a potent glucocorticoid receptor ligand, contains a quaternary carbon bearing trifluoromethyl and hydroxyl groups. This paper describes the effect of replacing the trifluoromethyl group on binding and agonist activity of the GR ligand 1. The results illustrate that replacing the CF3 group with a cyclohexylmethyl or benzyl group maintains the GR binding potency. These substitutions alter the functional behavior of the GR ligands from agonists to antagonists. Docking studies suggest that the benzyl analog 19 binds in a similar fashion as the GR antagonist, RU486. The central benzyl group of 19 and the C-11 dimethylaniline moiety of RU486 overlay. Binding of compound 19 is believed to force helix 12 to adopt an open conformation and this leads to the antagonist properties of the non-CF3 ligands carrying a large group at the center of the molecule.
authors.affiliation: Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877, USA. rbetager@rdg.boehringer-ingelheim.com
authors.forename: Raj
authors.initials: R
authors.lastname: Betageri
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Renee M
authors.initials: RM
authors.lastname: Zindell
authors.forename: Daniel
authors.initials: D
authors.lastname: Kuzmich
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Kirrane
authors.forename: Jörg
authors.initials: J
authors.lastname: Bentzien
authors.forename: Mario
authors.initials: M
authors.lastname: Cardozo
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Capolino
authors.forename: Tazmeen N
authors.initials: TN
authors.lastname: Fadra
authors.forename: Richard M
authors.initials: RM
authors.lastname: Nelson
authors.forename: Zofia
authors.initials: Z
authors.lastname: Paw
authors.forename: Daw-Tsun
authors.initials: DT
authors.lastname: Shih
authors.forename: Cheng-Kon
authors.initials: CK
authors.lastname: Shih
authors.forename: Ljiljana
authors.initials: L
authors.lastname: Zuvela-Jelaska
authors.forename: Gerald
authors.initials: G
authors.lastname: Nabozny
authors.forename: David S
authors.initials: DS
authors.lastname: Thomson
mesh_terms: D002478:Cells, Cultured; D005617:Chlorofluorocarbons, Methane / Q000737:chemistry* / Q000494:pharmacology; D005347:Fibroblasts; D006367:HeLa Cells; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D005617:Chlorofluorocarbons, Methane; D015850:Interleukin-6; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid; C009554:fluoroform