Trifluoromethyl group as a pharmacophore: effect of replacing a CF3 group on binding and agonist activity of a glucocorticoid receptor ligand.
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.
Betageri
Raj
R
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877, USA. rbetager@rdg.boehringer-ingelheim.com
Zhang
Yan
Y
Zindell
Renee M
RM
Kuzmich
Daniel
D
Kirrane
Thomas M
TM
Bentzien
Jörg
J
Cardozo
Mario
M
Capolino
Alison J
AJ
Fadra
Tazmeen N
TN
Nelson
Richard M
RM
Paw
Zofia
Z
Shih
Daw-Tsun
DT
Shih
Cheng-Kon
CK
Zuvela-Jelaska
Ljiljana
L
Nabozny
Gerald
G
Thomson
David S
DS
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
D005617:Chlorofluorocarbons, Methane; D015850:Interleukin-6; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid; C009554:fluoroform