ABSTRACT
We have recently reported the discovery of a novel class of glucocorticoid receptor (GR) antagonists, exemplified by 3, containing a 1,2-dihydroquinoline molecular scaffold. Further SAR studies of these antagonists uncovered chemical modifications conveying agonist functional activity to this series. These agonists exhibit good GR binding affinity and are selective against other nuclear hormone receptors.
Subject(s)
Quinolines/chemistry , Quinolines/pharmacology , Receptors, Glucocorticoid/agonists , Quinolines/metabolism , Receptors, Glucocorticoid/metabolism , Structure-Activity RelationshipABSTRACT
We report the discovery of a novel class of glucocorticoid receptor (GR) ligands based on 1,2-dihydroquinoline molecular scaffold. The compounds exhibit good GR binding affinity and selectivity profile against other nuclear hormone receptors.
Subject(s)
Quinolines/chemical synthesis , Quinolines/pharmacology , Receptors, Glucocorticoid/antagonists & inhibitors , Receptors, Glucocorticoid/metabolism , Anti-Inflammatory Agents/pharmacology , Dexamethasone/pharmacology , HeLa Cells , Humans , Interleukin-1/pharmacology , Interleukin-6/metabolism , Ligands , Mammary Tumor Virus, Mouse/genetics , Models, Molecular , Molecular Structure , Promoter Regions, Genetic/drug effects , Quinolines/chemistry , Receptors, Estrogen/drug effects , Receptors, Estrogen/metabolism , Receptors, Mineralocorticoid/drug effects , Receptors, Mineralocorticoid/metabolism , Receptors, Progesterone/drug effects , Receptors, Progesterone/metabolism , Structure-Activity Relationship , Transcription, Genetic/drug effects , Transcriptional Activation/drug effects , Transcriptional Activation/geneticsABSTRACT
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.
