Design and synthesis of new nonsteroidal glucocorticoid modulators through application of an "agreement docking" method

Journal of Medicinal Chemistry

Volumn 48, Issue 14, 2005, Pages 4507-4510

  Barker, Mike ^a   Clackers, Margaret ^a   Demaine, Derek A ^a   Humphreys, Davina ^a   Johnston, Michael J ^a   Jones, Haydn T ^a   Pacquet, Francois ^a   Pritchard, John M ^a   Salter, Mark ^a   Shanahan, Stephen E ^a   Skone, Philip A ^a   Vinader, Victoria M ^a   Uings, Iain ^a   McLay, Iain M ^a   Macdonald, Simon J F ^a  

^a GLAXOSMITHKLINE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

BENZOSUBERAN DERIVATIVE; BENZOXAZINONE DERIVATIVE; DEXAMETHASONE; FLUTICASONE PROPIONATE; GLUCOCORTICOID; GLUCOCORTICOID RECEPTOR; GLUCOCORTICOID RECEPTOR ANTAGONIST; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INDAN DERIVATIVE; MIFEPRISTONE; NONSTEROID ANTIINFLAMMATORY AGENT; PARTIAL AGONIST; PREDNISOLONE; TETRALIN DERIVATIVE; UNCLASSIFIED DRUG;

ANTIINFLAMMATORY ACTIVITY; ARTICLE; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG ANTAGONISM; DRUG BINDING SITE; DRUG DESIGN; DRUG POTENTIATION; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; HUMAN CELL; IC 50; LUNG ALVEOLUS EPITHELIUM; MOUSE MAMMARY TUMOR ONCOVIRUS; PROMOTER REGION; REPORTER GENE; TRANSACTIVATION;

ANIMALS; ANTI-INFLAMMATORY AGENTS; CELL LINE; CELL LINE, TUMOR; HUMANS; LIGANDS; MICE; MODELS, MOLECULAR; RECEPTORS, GLUCOCORTICOID; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; TETRAHYDRONAPHTHALENES; TRANS-ACTIVATION (GENETICS); TRANSCRIPTION, GENETIC;

EID: 22244432464     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm050345y     Document Type: Article

References (22)

1. Schimmer, B. P.; Parker, K. L. Adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogues: inhibitors of the synthesis and actions of adrenocortical hormones. In Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th ed; Hardman, J. G., Limbird, L. E., Molinoff, P. B., Ruddon, R. W., Eds.; McGraw-Hill: New York, 1996; pp 1459-1485.
2. Resche-Rigon, M.; Gronemeyer, H. Therapeutic potential of selective modulators of nuclear receptor action. Curr. Opin. Chem. Biol. 1998, 2, 501-507.
3. Barnes, P. J., Anti-inflammatory actions of glucocorticoids: molecular mechanisms. Clin. Sci. 1998, 94, 557-572.
4. Kym, P. R.; Kort, M. E.; Coghlan, M. J.; Moore, J. L.; Tang, R.; Ratajczyk, J. D.; Larson, D. P.; Elmore, S. W.; Pratt, J. K.; Stashko, M. A.; Falls, H. D.; Lin, C. W.; Nakane, M.; Miller, L.; Tyree, Curtis, M.; Miner, J. N.; Jacobson, P. B.; Wilcox, D. M.; Nguyen, P.; Lane, B. C. 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. J. Med. Chem. 2003, 46, 1016-1030 and references therein.
5. 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. Nat. Acad. Sci. U.S.A. 2004, 101, 227-32.
6. Ali, A.; Thompson, C. F.; Balkovec, J. M.; Graham, D. W.; Hammond, M. L.; Quraishi, N.; Tata, J. R.; Einstein, M.; Ge, L.; Harris, G.; Kelly, T. M.; Mazur, P.; Pandit, S.; Santoro, J.; Sitlani, A.; Wang, C.; Williamson, J.; Miller, D. K.; Thompson, C. M.; Zaller, D. M.; Forrest, M. J.; Carballo-Jane, E.; Luell, S. Novel N-arylpyrazolo[3,2-c]-Based ligands for the glucocorticoid receptor: Receptor binding and in vivo activity. J. Med. Chem. 2004, 47, 2441-2452.
7. Marshall, D. R. 3-Sulfonamidoethylindole derivatives for use as glucocorticoid mimetics in the treatment of inflammatory, allergic and proliferative diseases. PCT Int. Appl. WO 019935, 2004. Other patents include WO (2003) 059899, 082280, 082787, 101932, 104195; WO (2004) 018429, 063163, 075864.
8. Shah, N.; Scanlan, T. S. Design and evaluation of novel nonsteroidal dissociating glucocorticoid receptor ligands. Bioorg. Med. Chem. Lett. 2004, 14, 5199-5203.
9. Kauppi, B.; Jakob, C.; Farnegardh, M.; Yang, J.; Ahola, H.; Alarcon, M.; Galles, K.; Engstrom, O.; Harlan, J.; Muchmore, S.; Ramqvist, A.-K.; Thorell, S.; Ohman, L.; Greer, J.; Gustafsson, J.-A.; Carlstedt-Duke, J.; Crlquist, M. The three-dimensional structures of antagonistic and agonistic forms of the glucocorticoid receptor ligand-binding domain. J. Biol. Chem. 2003, 22748-22754.
10. Link, J. T.; Sorensen, B. K.; Lai, C.; Wang, J.; Fung, S.; Deng, D.; Emery, M.; Carroll, S.; Grynfarb, M.; Goos-Nilsson, A.; von Geldern, T. Synthesis, activity, metabolic stability and pharmacokinetics of glucocorticoid receptor modulator-statins hybrids. Bioorg. Med. Chem. Lett. 2004, 14, 4173-4178 and references therein.
11. Morgan, B. P.; Liu, K. K.-C.; Dalvie, D. K.; Swick, A. G.; Hargrove, D. M.; Wilson, T. C.; LaFlamme, J. A.; Moynihan, M. S.; Rushing, M. A.; Woodworth, G. F.; Li, J.; Trilles, R. V.; Yang, X.; Harper, K. W.; Carroll, R. S.; Martin, K. A.; Nardone, N. A.; O'Donnell, J. P.; Faletto, M. B.; Vage, C.; Soliman, V. Discovery of potent, non-steroidal and highly selective glucocorticoid receptor antagonists with anti-obesity activity. Lett. Drug Des. Discovery 2004, 1, 1-5.
12. Bledsoe, R. K.; Montana, V. G.; Stanley, T. B.; Delves, C. J.; Apolito, C. J.; McKee, D. D.; Consler, T. G.; Parks, D. J.; Stewart, E. L.; Willson, T. M.; Lambert, M. H.; Moore, J. T.; Pearce, K. H.; Xu, H. E. Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition. Cell 2002, 110, 93-105.
13. Bledsoe, R. K.; Lambert, M. H.; Montana, V. G.; Stewart, E. L.; Xu, E. H. Structure of a glucocorticoid receptor ligand binding domain comprising an expanded binding pocket, and methods using nuclear receptors structure for drug design. Eur. Pat. Appl. 1375517, 2004.
14. Lehmann, M.; Krolikiewicz, K.; Skuballa, W.; Strehkle, P.; Kalkbrenner, F.; Ekerdt, R.; Giesen, C. WO Patent Appl. 32584, 2000. Compounds not described as potent binders in this application are presumed to be potent binders based on their GR agonism activity when tested in our assays (data not shown).
15. McMartin, C. FLO+, version Feb02, mcdock+ facility; Thistlesoft (P.O. Box 227, Colebrook, CT 06021). All dockings were performed using 600 Monte Carlo steps and generating five docking poses for each compound.
16. SYBYL, version 7.0; Tripos Inc. (1699 South Hanley Rd, St. Louis, MO, 63144).
17. Lehmann, M.; Schollkopf, K.; Strehlke, P.; Heinrich, N.; Fritzemeier, K.; Muhn, H.; Krattenmacher, R. Non-steroidal (hetero)-cyclically substituted acylanilides with mixed gestagenic and androgenic activity. PCT Int. Appl. WO 9854159, 1998.
18. The diastereomers have been consistently assigned on the basis of the order of elution from analytical reverse-phase LC/MS where diastereomer 1 elutes first. The enantiomers have been assigned on the basis of the order of elution from normal-phase analytical chiral HPLC where enantiomer 1 elutes first.
19. Ray, K. P.; Farrow, S.; Daly, M.; Talabot, F.; Searle, N. Induction of the E-selectin promoter by interleukin 1 and tumour necrosis factor alpha, and inhibition by glucocorticoids. Biochem. J. 1997, 328, 707-715.
20. Austin, R. J. H.; Maschera, B.; Walker, A.; Fairbain, L.; Meldrum, E.; Farrow, S. N.; Uings, I. J. Mometasone furoate is a less specific glucocorticoid than fluticasone propionate. Eur. Respir. J. 2002, 20, 1386-1392.
21. 1H NMR spectra of the active isomers of 9 and 15 does not allow conclusions to be drawn about similarities in the stereochemistry of the active isomers.
22. Barker, M. D.; Demaine, D. A.; House, D.; Inglis, G. G. A.; Johnston, M. J.; Jones, H. T.; Macdonald, S. J. F.; McLay, I. M.; Shanahan, S.; Skone, P. A.; Vinader, M. V. Preparation of heterocycle-substituted N- benzoxazinylpropanamides as glucocorticoid receptor binders and agonists for the treatment of inflammatory, allergic and skin diseases. PCT Int. Appl. WO 071389, 2004.