Abstract
A novel class of functional ligands for the human glucocorticoid receptor is described. Substituents in the C-10 position of the tetracyclic core are essential for glucocorticoid receptor (GR) selectivity versus other steroid receptors. The C-5 position is derivatized with meta-substituted aromatic groups, resulting in analogues with a high affinity for GR (K(i) = 2.4-9.3 nM) and functional activity comparable to prednisolone in reporter gene assays of glucocorticoid-mediated gene transcription. The biological activity of these novel quinolines was also prednisolone-equivalent in whole cell assays of glucocorticoid function, and compound 13 was similar to prednisolone (po ED(50) = 2.8 mpk for 13 vs ED(50) = 1.2 mpk for prednisolone) in a rodent model of asthma (sephadex-induced eosinophil influx).
MeSH terms
-
Animals
-
Anti-Inflammatory Agents / chemical synthesis*
-
Anti-Inflammatory Agents / chemistry
-
Anti-Inflammatory Agents / metabolism
-
Anti-Inflammatory Agents / pharmacology
-
Benzopyrans / chemical synthesis*
-
Benzopyrans / chemistry
-
Benzopyrans / metabolism
-
Benzopyrans / pharmacology
-
Cell Line
-
E-Selectin / genetics
-
E-Selectin / metabolism
-
Genes, Reporter
-
Humans
-
Ligands
-
Luciferases / genetics
-
Prednisolone / pharmacology*
-
Quinolines / chemical synthesis*
-
Quinolines / chemistry
-
Quinolines / metabolism
-
Quinolines / pharmacology
-
Rats
-
Receptors, Glucocorticoid / metabolism*
-
Stereoisomerism
-
Transcriptional Activation
-
Transfection
Substances
-
1,2-dihydro-10-methoxy-2,2,4-trimethyl-5-(3-methylthiomethoxyphenyl)-5H-chromeno(3,4-f)quinoline
-
Anti-Inflammatory Agents
-
Benzopyrans
-
E-Selectin
-
Ligands
-
Quinolines
-
Receptors, Glucocorticoid
-
Prednisolone
-
Luciferases