title: Synthesis and characterization of non-steroidal ligands for the glucocorticoid receptor: selective quinoline derivatives with prednisolone-equivalent functional activity.
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).
authors.affiliation: Pharmaceutical Products Division, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. coghlan_michael@lilly.com
authors.forename: M J
authors.initials: MJ
authors.lastname: Coghlan
authors.forename: P R
authors.initials: PR
authors.lastname: Kym
authors.forename: S W
authors.initials: SW
authors.lastname: Elmore
authors.forename: A X
authors.initials: AX
authors.lastname: Wang
authors.forename: J R
authors.initials: JR
authors.lastname: Luly
authors.forename: D
authors.initials: D
authors.lastname: Wilcox
authors.forename: M
authors.initials: M
authors.lastname: Stashko
authors.forename: C W
authors.initials: CW
authors.lastname: Lin
authors.forename: J
authors.initials: J
authors.lastname: Miner
authors.forename: C
authors.initials: C
authors.lastname: Tyree
authors.forename: M
authors.initials: M
authors.lastname: Nakane
authors.forename: P
authors.initials: P
authors.lastname: Jacobson
authors.forename: B C
authors.initials: BC
authors.lastname: Lane
mesh_terms: 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
chemical_list: 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