Quinol-4-ones as steroid A-ring mimetics in nonsteroidal dissociated glucocorticoid agonists

Journal of Medicinal Chemistry

Volumn 49, Issue 26, 2006, Pages 7887-7896

  Regan, John ^a   Lee, Thomas W ^a   Zindell, Renée M ^a   Bekkali, Younes ^a   Bentzien, Jörg ^a   Gilmore, Thomas ^a   Hammach, Abdelhakim ^a   Kirrane, Thomas M ^a   Kukulka, Alison J ^a   Kuzmich, Daniel ^a   Nelson, Richard M ^a   Proudfoot, John R ^a   Ralph, Mark ^a   Pelletier, Josephine ^a   Souza, Donald ^a   Zuvela Jelaska, Lijiljana ^a   Nabozny, Gerald ^a   Thomson, David S ^a  

^a BOEHRINGER INGELHEIM PHARMACEUTICALS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 (2,3 DIHYDROBENZOFURAN 7 YL) 2 HYDROXY 3,3 DIMETHYL N (4 METHYL 1 OXO 2,3 BENZOXAZIN 6 YL) 2 TRIFLUOROMETHYLBUTANAMIDE; CELL NUCLEUS RECEPTOR; GLUCOCORTICOID; INTERLEUKIN 6; NONSTEROID ANTIINFLAMMATORY AGENT; PREDNISOLONE; QUINOLONE DERIVATIVE; TUMOR NECROSIS FACTOR ALPHA;

AGONIST; ANIMAL EXPERIMENT; ANTIINFLAMMATORY ACTIVITY; ARTICLE; BINDING AFFINITY; CHEMICAL MODIFICATION; CHEMICAL REACTION; DRUG ACTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; FEMALE; HUMAN; HUMAN CELL; MOUSE; NONHUMAN; TRANSACTIVATION;

ANIMALS; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; AROMATASE; DEXAMETHASONE; FEMALE; FIBROBLASTS; GLUCOCORTICOIDS; HELA CELLS; HUMANS; LIPOPOLYSACCHARIDES; MICE; MICE, INBRED BALB C; MOLECULAR MIMICRY; QUINOLONES; RECEPTORS, CYTOPLASMIC AND NUCLEAR; TRANS-ACTIVATION (GENETICS); TRANS-ACTIVATORS;

EID: 33845926600     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm061273t     Document Type: Article

References (33)

1. Gupta, R.; Jindal, D. P.; Kumar, G. Corticosteroids: the mainstay in asthma therapy. Bioorg. Med. Chem. 2004, 12, 6331-6342.
2. Buttgereit, F.; Saag, K. G.; Cutolo, M.; da Silva, J. A.; Bijlsma, J. W. The molecular basis for the effectiveness, toxicity, and resistance to glucocorticoids: focus on the treatment of rheumatoid arthritis. Scand. J. Rheumatol. 2005, 34, 14-21.
3. Zhou, J.; Cidlowski, J. A. The human glucocorticoid receptor: one gene, multiple proteins and diverse responses. Steroids 2005, 70, 407-417.
4. Resche-Rigon, M.; Gronemeyer, H. Therapeutic potential of selective modulators of nuclear receptor action. Curr. Opin. Chem. Biol. 1998, 2, 501-507.
5. Adcock, I. M. Molecular mechanisms of glucocorticosteroid actions. Pulm. Pharmacol. Ther. 2000, 13, 115-126.
6. Heck, S.; Kullmann, M.; Gast. A.; Ponta, H.; Rahmsdorf, H. J.; Herrlich, P.; Cato, A. C. A distinct modulating domain in glucocorticoid receptor monomers in the repression of activity of the transcription factor AP-1. EMBO J. 1994, 13, 4087-4095.
7. Schacke, H.; Docke, W. D.; Asadullah, K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol. Ther. 2002, 96, 23-43.
8. Katzenellenbogen, J. A.; Katzenellenbogen, B. S. Nuclear hormone receptors: ligand-activated regulators of transcription and diverse cell responses. Chem. Biol. 1996, 3, 529-536.
9. Burnstein, K. L.; Cidlowski, J. A. The down side of glucocorticoid receptor regulation. Mol. Cell. Endocrinol. 1992, 83, C1-C8.
10. Coghlan, M. J.; Elmore, S. W.; Kym, P. R.; Kort, M. E. Selective Glucocorticoid Receptor Modulators. In Annual Reports in Medicinal Chemistry; Doherty, A. M., Ed.; Academic Press: New York, 2002; pp 167-176.
11. Schacke, H.; Rehwinkel, H.; Asadullah, K.; Cato, A. C. Insight into the molecular mechanisms of glucocorticoid receptor action promotes identification of novel ligands with an improved therapeutic index-amethasone. Exp. Dermatol. 2006, 15, 565-573.
12. Belvisi, M. G.; Brown, T. J.; Wicks, S.; Foster, M. L. New Glucocorticosteroids with an improved therapeutic ratio? Pulm. Pharmacol. Ther. 2001, 14, 221-227.
13. Miner, J. N. Designer glucocorticoids. Biochem. Pharmacol. 2002, 64, 355-361.
14. Schacke, H.; Schottelius, A.; Docke, W. D.; Strehlke, P.; Jaroch, S.; Schmees, N.; Rehwinkel, H.; Hennekes, H.; Asadullah, K. Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 227-232.
15. Barker, M.; Clackers, M.; Demaine, D. A.; Humphreys, D.; Johnston, M. J.; Jones, H. T.; Pacquet, F.; Pritchard, J. M.; Salter, M.; Shanahan, S. E.; Skone, P. A.; Vinader, V. M.; Uings, I.; McLay, I. M.; Macdonald, S. J. Design and synthesis of new nonsteroidal glucocorticoid modulators through application of an "agreement docking" method. J. Med. Chem. 2005, 48, 4507-4510.
16. Bledsoe, R. K.; Lambert, M. H.; Montana, V. G.; Stewart, E. L.; Xu, E. H. Structure of a Glucocorticoid Ligand Binding Domain Comprising an Expanded Binding Pocket, and Methods Using Nuclear Receptors Structure for Drug Design. Eur. Pat. Appl. 1375517, 2004.
17. Betageri, R.; Zhang, Y.; Zindell, R. M.; Kuzmich, D.; Kirrane, T. M.; Bentzien, J.; Cardozo, M.; Capolino, A. J.; Fadra, T. N.; Nelson, R. M.; Paw, Z.; Shih, D. T.; Shih, C. K.; Zuvela-Jelaska, L.; Nabozny, G.; Thomson, D. S. Trifluoromethyl group as a pharmacophore: effect of replacing a CF3 group on binding and agonist activity of a glucocorticoid receptor ligand. Bioorg. Med. Chem. Lett. 2005, 15, 4761-4769.
18. Abraham, M. H.; Duce, P. P.; Prior, D. V.; Barratt, D. G.; Morris, J. J.; Taylor, P. J. Hydrogen bonding. Part 9. Solute proton donor and proton acceptor scales for use in drug design. J. Chem. Soc., Perkin Trans. 2 1989, 1355-1375.
19. Bekkali, Y.; Cardozo, M.; Kirrane, T. M.; Kuzmich, D.; Proudfoot, J. R.; Takahashi, H.; Thomson, D.; Wang, J.; Zindell, R.; Harcken, C. H. J. J.; Razavi, H. Glucocorticoid Mimetics, Methods of Making Them, Pharmaceutical Compositions, and Uses Thereof. WO 03/082787, 2003.
20. Proudfoot, J. R.; Regan, J. R.; Thomson, D. S.; Kuzmich, D.; Lee, T. W-H.; Hammach, A.; Ralph, M. S.; Zindell, R.; Bekkali, Y. 1-Propanol and 1-Propylamine Derivatives and Their Use as Glucocorticoid Ligands. WO 04/063163, 2004.
21. Harper, N.; Chignell, C.; Kirk, G. F. Synthesis of some N-substituted 3,5-dimethyl-4-piperdinols and their derivatives as potential analgesics. J. Med. Chem. 1964, 7, 726-728.
22. McCabe, P. H.; Milne, N. J.; Sim, G. A. Conformational study of bridgehead lactams. Preparation and x-ray structural analysis of 1-azabicyclo[3.3.1]nonane-2,6-dione. J. Chem. Soc., Perkin Trans. 2 1989, 10, 1459-1462.
23. 50 standard deviations of 20-40% about the mean. See the Experimental Section for complete details.
24. Waage, A.; Slupphaug, G.; Shalaby, R. Glucocorticoids inhibit the production of IL6 from monocytes, endothelial cells and fibroblasts. Eur. J. Immunol. 1990, 20, 2439-2443.
25. 50 standard deviations of 20-30% about the mean. See the Experimental Section for complete details.
26. 50 standard deviations of 30-50% about the mean. See the Experimental Section for complete details.
27. 50 values are determined by nonlinear curve fitting of the data from duplicate eight-point concentration-response curves. Repeated testing of reference compounds in these assays demonstrates a 30% coefficient of variation. See the Experimental Section for complete details.
28. Thompson, C. F.; Quraishi, N.; Ali, A.; Tata, J. R.; Hammond, M. L.; Balkovec, J. M.; Einstein, M.; Ge, L.; Harris, G.; Kelly, T. M.; Mazur, P.; Pandit, S.; Santoro, J.; Sitlani, A.; Wang, C.; Williamson, J.; Miller, D. K.; Yamin, T. T.; Thompson, C. M.; O'Neill, E. A.; Zaller, D.; Forrest, M. J.; Carballo-Jane, E.; Luell, S. Novel heterocyclic glucocorticoids: in vitro profile and in vivo efficacy. Bioorg. Med. Chem. Lett. 2005, 15, 2163-2167.
29. Smith, C. J.; Ali, A.; Balkovec, J. M.; Graham, D. W.; Hammond, M. L.; Patel, G. F.; Rouen, G. P.; Smith, S. K.; Tata, J. R.; Einstein, M.; Ge, L.; Harris, G. S.; Kelly, T. M.; Mazur, P.; Thompson, C. M.; Wang, C. F.; Williamson, J. M.; Miller, D. K.; Pandit, S.; Santoro, J. C.; Sitlani, A.; Yamin, T. T.; O'Neill, E. A.; Zaller, D. M.; Carballo-Jane, E.; Forrest, M. J.; Luell, S. Novel ketal ligands for the glucocorticoid receptor: in vitro and in vivo activity. Bioorg. Med. Chem. Lett. 2005, 15, 2926-2931.
30. Bourguet, W.; Germain, P.; Gronemeyer, H. Nuclear receptor ligand-binding domains: three-dimensional structures, molecular interactions and pharmacological implications. Trends Pharmacol. Sci. 2000, 21, 381-388.
31. Bledsoe, R. K.; Stewart, E. L.; Pearce, K. H. Structure and function of the glucocorticoid receptor ligand binding domain. Vitam. Horm. 2004, 68, 49-91.
32. Berkovitz, G. D.; Bisat, T.; Carter, K. M. Aromatase activity in microsomal preparations of human genital skin fibroblasts: influence of glucocorticoids. J. Steroid Biochem. 1989, 33, 341-347.
33. Vayssiere, B. M.; Dupont, S.; Choquart, A.; Petit, F.; Garcia, T.; Marchandeau, C.; Gronemeyer, H.; Resche-Rigon, M. Synthetic glucocorticoids that dissociate transactivation and AP-1 transrepression exhibit antiinflammatory activity in vivo. Mol. Endocrinol. 1997, 11, 1245-1255.