Synthesis and characterization of non-steroidal ligands for the glucocorticoid receptor: selective quinoline derivatives with prednisolone-equivalent functional activity.
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).
Coghlan
M J
MJ
Pharmaceutical Products Division, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. coghlan_michael@lilly.com
Kym
P R
PR
Elmore
S W
SW
Wang
A X
AX
Luly
J R
JR
Wilcox
D
D
Stashko
M
M
Lin
C W
CW
Miner
J
J
Tyree
C
C
Nakane
M
M
Jacobson
P
P
Lane
B C
BC
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D008024:Ligands; D008156:Luciferases / Q000235:genetics; D011239:Prednisolone / Q000494:pharmacology*; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D013237:Stereoisomerism; D015533:Transcriptional Activation; D014162:Transfection
C435188:1,2-dihydro-10-methoxy-2,2,4-trimethyl-5-(3-methylthiomethoxyphenyl)-5H-chromeno(3,4-f)quinoline; D000893:Anti-Inflammatory Agents; D001578:Benzopyrans; D019040:E-Selectin; D008024:Ligands; D011804:Quinolines; D011965:Receptors, Glucocorticoid; D011239:Prednisolone; D008156:Luciferases