title: Nonsteroidal selective glucocorticoid modulators: the effect of C-10 substitution on receptor selectivity and functional potency of 5-allyl-2,5-dihydro-2,2,4-trimethyl-1H-[1]benzopyrano[3,4-f]quinolines.
abstract: The preparation and characterization of a series of C-10 substituted 5-allyl-2,5-dihydro-2,2,4-trimethyl-1H-[1]benzopyrano[3,4-f]quinolines as a novel class of selective ligands for the glucocorticoid receptor is described. Substitution at the C-10 position of the tetracyclic core with linear, two-atom appendages (OCH(3), OCF(2)H, NHMe, SMe, CH=CH(2), Ctbd1;CH, CH(2)OH) provided molecules of high affinity (K(i) = 2-8 nM) for the human glucocorticoid receptor (hGR) with limited cross-reactivity with other steroid receptors (PR, MR, AR, ER). Optimal analogues showed slightly less potent but highly efficacious E-selectin repression with reduced levels of GRE activation efficacy in reporter gene assays relative to prednisolone. Preliminary SAR of analogues containing substitution at the C-9 and C-10 positions identified the 9-OH, 10-OMe analogue 50 and the 9-OH, 10-Cl analogue 58 as compounds that demonstrated potent, GR-mediated inhibition in a conconavalin A stimulated T-cell proliferation assay in both rodent and human whole blood monocytes. When evaluated for their in vivo effects in carrageenan-induced paw edema in rats, 50, 58, and 10-OCF(2)H analogue 35 showed dose-dependent anti-inflammatory effects (50, ED(50) = 16 mg/kg; 58, ED(50) = 15 mg/kg; 35, ED(50) = 21 mg/kg vs ED(50) = 15 mg/kg for 18 and ED(50) = 4 mg/kg for prednisolone).
authors.affiliation: Immunologic Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6061, USA. phil.r.kym@ abbott.com
authors.forename: Philip R
authors.initials: PR
authors.lastname: Kym
authors.forename: Michael E
authors.initials: ME
authors.lastname: Kort
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Coghlan
authors.forename: Jimmie L
authors.initials: JL
authors.lastname: Moore
authors.forename: Rui
authors.initials: R
authors.lastname: Tang
authors.forename: James D
authors.initials: JD
authors.lastname: Ratajczyk
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Larson
authors.forename: Steven W
authors.initials: SW
authors.lastname: Elmore
authors.forename: John K
authors.initials: JK
authors.lastname: Pratt
authors.forename: Michael A
authors.initials: MA
authors.lastname: Stashko
authors.forename: H Douglass
authors.initials: HD
authors.lastname: Falls
authors.forename: Chun W
authors.initials: CW
authors.lastname: Lin
authors.forename: Masake
authors.initials: M
authors.lastname: Nakane
authors.forename: Loan
authors.initials: L
authors.lastname: Miller
authors.forename: Curtis M
authors.initials: CM
authors.lastname: Tyree
authors.forename: Jeffery N
authors.initials: JN
authors.lastname: Miner
authors.forename: Peer B
authors.initials: PB
authors.lastname: Jacobson
authors.forename: Denise M
authors.initials: DM
authors.lastname: Wilcox
authors.forename: Phong
authors.initials: P
authors.lastname: Nguyen
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Lane
mesh_terms: D000498:Allyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D002351:Carrageenan; D002455:Cell Division / Q000187:drug effects; D003208:Concanavalin A / Q000494:pharmacology; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D016328:NF-kappa B / Q000378:metabolism; D020033:Protein Isoforms; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D013045:Species Specificity; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D000498:Allyl Compounds; D000894:Anti-Inflammatory Agents, Non-Steroidal; D019040:E-Selectin; D008024:Ligands; D016328:NF-kappa B; D020033:Protein Isoforms; D011804:Quinolines; D011965:Receptors, Glucocorticoid; D018808:Transcription Factor AP-1; D003208:Concanavalin A; D002351:Carrageenan