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.
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).
Kym
Philip R
PR
Immunologic Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6061, USA. phil.r.kym@ abbott.com
Kort
Michael E
ME
Coghlan
Michael J
MJ
Moore
Jimmie L
JL
Tang
Rui
R
Ratajczyk
James D
JD
Larson
Daniel P
DP
Elmore
Steven W
SW
Pratt
John K
JK
Stashko
Michael A
MA
Falls
H Douglass
HD
Lin
Chun W
CW
Nakane
Masake
M
Miller
Loan
L
Tyree
Curtis M
CM
Miner
Jeffery N
JN
Jacobson
Peer B
PB
Wilcox
Denise M
DM
Nguyen
Phong
P
Lane
Benjamin C
BC
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
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