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-lh-[1]benzopyrano[3,4-f]quinolines

Journal of Medicinal Chemistry

Volumn 46, Issue 6, 2003, Pages 1016-1030

  Kym, Philip R ^a   Kort, Michael E ^a   Coghlan, Michael J ^a,c   Moore, Jimmie L ^a   Tang, Rui ^a   Ratajczyk, James D ^a   Larson, Daniel P ^a   Elmore, Steven W ^a   Pratt, John K ^a   Stashko, Michael A ^a   Douglass Falls, H ^a   Lin, Chun W ^a   Nakane, Masake ^a   Miller, Loan ^a   Tyree, Curtis M ^b   Miner, Jeffery N ^b   Jacobson, Peer B ^a   Wilcox, Denise M ^a   Nguyen, Phong ^a   Lane, Benjamin C ^a  

^a ABBOTT LABORATORIES   (United States)

^b LIGAND PHARMACEUTICALS INC   (United States)

^c ELI LILLY AND COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

10 CHLORO 9 HYDROXY 5 (2 PROPENYL) 2,5 DIHYDRO 2,2,4 TRIMETHYL 1H [1]BENZOPYRANO[3,4 F]QUINOLINE; 10 DIFLUOROMETHOXY 5 (2 PROPENYL) 2,5 DIHYDRO 2,2,4 TRIMETHYL 1H [1]BENZOPYRANO[3,4 F]QUINOLINE; 2,5 DIHYDRO 2,2,4 TRIMETHYL 1H [1]BENZOPYRANO[3,4 F]QUINOLINE; 9 HYDROXY 10 METHOXY 5 (2 PROPENYL) 2,5 DIHYDRO 2,2,4 TRIMETHYL 1H [1]BENZOPYRANO[3,4 F]QUINOLINE; ANTIINFLAMMATORY AGENT; CONCANAVALIN A; DEXAMETHASONE; ENDOTHELIAL LEUKOCYTE ADHESION MOLECULE 1; GLUCOCORTICOID RECEPTOR; PREDNISOLONE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIINFLAMMATORY ACTIVITY; ARTICLE; ASSAY; BINDING AFFINITY; CONTROLLED STUDY; DOSE RESPONSE; DRUG ACTIVITY; DRUG EFFICACY; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; GENE REPRESSION; HUMAN; HUMAN CELL; IN VIVO STUDY; LYMPHOCYTE PROLIFERATION; MONOCYTE; NONHUMAN; PAW EDEMA; RECEPTOR SENSITIVITY; REPORTER GENE; STRUCTURE ACTIVITY RELATION; T LYMPHOCYTE;

ALLYL COMPOUNDS; ANIMALS; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; BINDING, COMPETITIVE; CARRAGEENAN; CELL DIVISION; CONCANAVALIN A; E-SELECTIN; EDEMA; HUMANS; LIGANDS; NF-KAPPA B; PROTEIN ISOFORMS; QUINOLINES; RATS; RATS, SPRAGUE-DAWLEY; RECEPTORS, GLUCOCORTICOID; RESPONSE ELEMENTS; SPECIES SPECIFICITY; STRUCTURE-ACTIVITY RELATIONSHIP; T-LYMPHOCYTES; TRANSCRIPTION FACTOR AP-1; TRANSCRIPTION, GENETIC;

EID: 0037435069     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm020335m     Document Type: Article

References (32)

1. Cohen, E. M. Dexamethasone [9α-fluoro-11β,17α,21-trihydroxy-16α-methyl pregna-1,4-diene-3, 20-dione]. Anal. Profiles Drug Subst. 1973, 2, 163-197.
2. Ali, S. L. Prednisolone. Anal. Profiles Drug Subst. Excipients 1992, 21, 415-500.
3. Barnes, P. J. Anti-inflammatory actions of glucocorticoids: molecular mechanisms. Clinical Science 1998, 94, 557-572.
4. Andersson. P.-B.; Goodkin, D. E. Glucocorticosteroid therapy for multiple sclerosis: a critical review. J. Neuro. Sci. 1998, 160, 16-25.
5. Schimmer, B. P.; Parker, K. L. Adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of the synthesis and actions of adrenocortical hormones. In Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th ed.; J. G. Hardman, L. E. Limbird, P. B. Molinoff and R. W. Ruddon, Eds.; McGraw-Hill: New York, 1996; pp 1459-1485.
6. Gennari, C. Differential Effect of Glucocorticoids on calcium absorption and bone mass. Br. J. Rheumatol. 1993, 32, 11-14.
7. Andrews, R. C.; Walker, B. R. Glucocorticoids and insulin resistance: old hormones, new targets. Clin. Sci. 1999, 513-523.
8. Remesar, X.; Fernandez-Lopez, J. A.; Alemany, M. Steroid hormones and the control of body weight. Med. Res. Rev. 1993, 13(5), 623-631.
9. Adcock, I. M. Ligand-induced differentiation of glucocorticoid receptor (GR) transrepression and transactivation. Biochem. Soc. Trans. 1996, 24(2), 267S.
10. van der Burg, B.; Liden, J.; Okret, S.; Delaunay, F.; Wissink, S.; van der Saag, P. T.; Gustafsson, J.-A. Nuclear factor-kappa B repression in antiinflammation and immunosuppression by glucocorticoids. Trends Endocrinol. Metab. 1997, 8, 152-157.
11. Jonat, C.; Rahmsdorf, H. J.; Park, K. K.; Cato, A. C.; Gebel, S.; Ponta, H.; Herrlich, P. Antitumor promotion and antiinflammation: down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone. Cell 1990, 62, 1189-1204.
12. Wade, E. J.; Heck, S.; Cato, C. B. Glucocorticoid receptor-activator protein-1 interactions in drug design. Biochem. Soc. Trans. 1995, 23, 3(4), 946-52.
13. Evans, R. M. Molecular characterization of the glucocorticoid receptor. Recent Prog. Horm. Res. 1989, 45, 1-27.
14. Katzenellenbogen, J. A.; Katzenellenbogen, B. S. Nuclear hormone receptors: ligand-activated regulators of transcription and diverse cell responses. Chem. Biol. 1996, 3(7), 529-536.
15. Coghlan, M. J.; Kym, P. R.; Elmore, S. W.; Wang, A. W.; Luly, J. R.; Wilcox, D. M.; Lin, C. W.; Stashko, M. A.; Miner, J. N.; Tyree, C.; Nakane, M.; Jacobson, P. B.; Lane, B. L. Synthesis and characterization of nonsteroidal ligands for the glucocorticoid receptor: selective quinoline derivatives with prednisolone-equivalent functional activity. J. Med. Chem. 2001, 44, 2879-2885.
16. Elmore, S. W.; Coghlan, M. J., Anderson, D. D.; Pratt, J. K.; Wang, A. X.; Kym, P. R.; Green, B. E.; Stashko, M. A.; Lin, C. W.; Tyree, C. M.; Miner, J. N.; Jacobson, P. B.; Wilcox, D. M.; Luly, J. R.; Lane, B. C. Nonsteroidal selective glucocorticoid modulators: the effect of C-5 alkyl substitution on the transcriptional activation/repression profile of 2,5-dihydro-10-methoxy-dihydro-2,2,4-trimethyl-1H-[1]benzopyrano[3, 4-f]quinolines. J. Med. Chem. 2001, 44, 4481-4491.
17. Coghlan, M. J.; Kort, M. E. Novel ligands of steroid hormone receptors. Expert Opin. Ther. Pat. 1999, 9, 1523-1536.
18. Eisch, J. J.; Dluzniewski, T. Mechanism of the Skraup and Doebner-von Miller quinoline syntheses: cyclization of α,β-unsaturated N-aryliminium salts via 1,3-diazetidinium ion intermediates. J. Org. Chem. 1989, 54, 1269-1274.
19. Fokin, A. V.; Kolomiyets, A. F. Some new approaches to modifying aromatic and heteroaromatic compounds by means of fluorine-containing substituents. J. Fluorine Chem. 1988, 247-261.
20. Newman, M. S.; Karnes, H. A. Conversion of phenols to thiophenols via dialkylthiocarbamates. J. Org. Chem. 1966, 31, 3980-3984.
21. Kwart, H.; Evans, E. R.. The vapor phase rearrangement of thionocarbamates. J. Org. Chem. 1966, 31, 410-413.
22. Cacchi, Sandro; Ciattini, P.; Morera, E.; Ortar, G. Palladium-catalyzed carbonylation of aryl triflates. Synthesis of arenecarboxylic acid derivatives from phenols. Tetrahedron Lett. 1986, 27, 3931-3934.
23. Edwards, J. P.; West, S. J.; Marschke, K. B.; Mais, D. E.; Gottardis, M. M.; Jones, T. K. 5-Aryl-1,2-dihydro-5H-chromeno-[3,4-flquinolines as potent, orally active, nonsteroidal progesterone receptor agonists: the effect of D-ring substituents. J. Med. Chem. 1998, 41, 303-310.
24. Zhi, L.; Tegley, C. M.; Kallel, E. A.; Marschke, K. B.; Mais, D. E.; Gottardis, M. M.; Jones, T. K.; 5-Aryl-1,2-dihydrochromen-[3,4-f]quinolines: A novel class of nonsteroidal human progesterone receptor agonists. J. Med. Chem. 1998, 41, 291-302.
25. Thiesen, H.-J. From transient cotransfections to the transcription repressor assay (TRA). Immunol. Methods Man. 1997, 1, 315-322.
26. White, R.; Parker, M. Analysis of cloned factors. Transcr. Factors 1993, 143-179.
27. Guido, E. C.; Delorme, E. O.; Clemm, D. L.; Stein, R. B.; Rosen, J.; Miner, J. N. Determinants of promoter-specific activity by glucocorticoid receptor. Mol. Endocrinol. 1996, 10, 1178-1190.
28. Goodwin, J. S. Modulation of conconavalin-A-induced suppressor cell activation by prostaglanding E2. Cell. Immunol. 1980, 49, 421-425.
29. Wang, S.; Huang, J.; Wang, S. In vitro glucocorticoid inhibition ofsteroid-treated residual circulatory human lymphocytes. Cell. Immunol. 1981, 65, 43-51.
30. Sedgwick, A. D.; Edwards, J. C. W. Animal models Of inflammation. Immunopharmacol. Microcirc. 1994, 189-202.
31. Pathirana, C.; Stein, R. B.; Berger, T. S.; Fenical, W.; Ianiro, T.; Mais, D. E.; Torres, A.; Goldman, M. E. Nonsteroidal Human Progesterone Receptor Modulators From the Marine Alga Cymopolia Barbata. Mol. Pharmacol. 1995, 47, 630-635.
32. Cheng, Y.-C.; Prusoff, W. H. Relation Between the Inhibition Constant K1 and the Concentration of Inhibitor Which Causes Fifty Percent Inhibition (I50) of an Enzymic Reaction. Biochem. Pharmacol. 1973, 22, 3099-3108.