Tetrahydronaphthalenes
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 26 6533
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. 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. D.;
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.
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. M.; Pandit, S.; Santoro,
J. C.; Sitlani, A.; Yamin, T. D.; 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.
56D1E2 (Enantiomer 2 of Diastereomer 2). Analytical chiral
HPLC (25 cm × 0.46 cm Chiralpak AD column, 60% ethanol in
heptane, eluting at 1 mL/min): tR ) 5.68 min. LCMS: tR ) 3.37
min; MH+ 415
Acknowledgment. We thank Ryan P Trump and Eugene
Stewart for helpful discussions, particularly regarding the
mutation studies.
Supporting Information Available: Additional experimental
and spectroscopic data for various analogues are detailed. This
material is available free of charge via the Internet at http://
pubs.acs.org.
References
(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
and Gilman’s The Pharmacological Basis of Therapeutics, 10th ed.;
Hardman, J. G., Limbird, L. E., Gilman, A. G., Eds.; McGraw-Hill:
New York, 2001; pp 1649–1677.
(2) Buttgereit, F.; Straub, R. H.; Wehling, M.; Burmester, G.-R. Gluco-
corticoids in the Treatment of Rheumatic Disease. Arthritis Rheum.
2004, 50, 3408–3417.
(3) Schacke, H.; Docke, W. D.; Asdullah, K. Mechanisms Involved in
the Side Effects of Glucocorticoids. Pharmacol. Ther. 2002, 96, 23–
43.
(4) Resche-Rigon, M.; Gronemeyer, H. Therapeutic potential of selective
modulators of nuclear receptor action. Curr. Opin. Chem. Biol. 1998,
2, 501–507. Barnes, P. J. Anti-inflammatory actions of glucocorticoids:
molecular mechanisms. Clin. Sci. 1998, 94, 557–572. Buckbinder, L.;
Robinson, R. P. The Glucocorticoid Receptor: Molecular Mechanism
and New Therapeutic Opportunities. Curr. Drug Targets: Inflammation
Allergy 2002, 1, 127–136.
(8) Boehringer Ingelheim. For leading references, see the following: Regan,
J.; Lee, T. W.; Zindell, R. M.; Bekkali, Y.; Bentzien, J.; Gilmore, T.;
Hammach, A.; Kirrane, T. M.; Kukulka, A. J.; Kuzmich, D.; Nelson,
R. M.; Proudfoot, J. R.; Ralph, M.; Pelletier, J.; Souza, D.; Zuvela-
Jelaska, L.; Nabozny, G.; Thomson, D. S. Quinol-4-ones as Steroid
A-Ring Mimetics in Nonsteroidal Dissociated Glucocorticoid Agonists.
J. Med. Chem. 2006, 49, 7887–7896. 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.
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.
(5) Abbott/Ligand. For leading references, see the following: Ardecky,
R. J.; Hudson, A. R.; Phillips, D. P.; Tyhonas, J. S.; Deckhut, C.;
Lau, T. L.; Li, Y.; Martinborough, E. A.; Roach, S. L.; Higuchi, R. I.;
Lopez, F. J.; Marschke, K. B.; Miner, J. N.; Karanewsky, D. S.; Negro-
Vilar, A.; Zhi L. 5(Z)-Benzylidene-1,2-dihydro-9-hydroxy-10-methoxy-
2,2,4-trimethyl-5H-1-aza-6-oxa-chrysenes as non-steroidal glucocor-
ticoid receptor modulators. Bioorg. Med. Chem. Lett., in press. Elmore,
S. W.; Coghlan, M. J.; Anderson, D. D.; Pratt, J. K.; Green, B. E.;
Wang, A. X.; Stashko, M. A.; Lin, C. W.; Tyree, C. M.; Miner, J. N.;
Jacobson, P. B.; Wilcox, D. M.; 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-2,2,4-trimethyl-1H-[1]benzopyrano[3,4-f]quinolines. J. Med.
Chem. 2001, 44, 4481–4491. 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. Elmore, S. W.; Pratt, J. K.; Coghlan, M. J.;
Mao, Y.; Green, B. E.; Anderson, D. D.; Stashko, M. A.; Lin, C. W.;
Falls, D.; Nakane, M.; Miller, L.; Tyree, C. M.; Miner, J. N.; Lane,
B. Differentiation of in Vitro Transcriptional Repression and Activation
Profiles of Selective Glucocorticoid Modulators. Bioorg. Med. Chem.
Lett. 2004, 14, 1721–1727.
(6) Schering. 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.
Jaroch, S.; Rehwinkel, H.; Schacke, H.; Schmees, N.; Skuballa, W.;
Schneider, M.; Hubner, J.; Petrov, O. 5-Substituted Quinoline and
Isoquinoline Derivatives, a Method for the Production Thereof and
Their Use as Antiphlogistics. PCT Int. Appl. WO 050998, 2006.
(7) Merck. For leading references, see the following: Thompson, C. F.;
Quraishi, N.; Ali, A.; Mosley, R. T.; 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. D.; Thompson, C. M.; O’Neill, E. A.; Zaller, D.;
Forrest, M. J.; Carballo-Jane, E.; Luell, S. Novel Glucocorticoids
Containing a 6,5-Bicyclic Core Fused to a Pyrazole Ring: Synthesis,
in Vitro Profile, Molecular Modeling Studies, and in Vivo Experiments.
Bioorg. Med. Chem. Lett. 2007, 17, 3354–3361. Ali, A.; Thompson,
C. F.; Balkovec, J. M.; Graham, D. W.; Hammond, M. L.; Quraishi,
(9) University of California. Shah, N.; Scanlan, T. S. Design and
Evaluation of Novel Nonsteroidal Dissociating Glucocorticoid Recep-
tor Ligands. Bioorg. Med. Chem. Lett. 2004, 14, 5199–5203.
(10) Karo Bio/Abbott. Kauppi, B.; Jakob, C.; Farnegardh, M.; Yang, J.;
Ahola, H.; Alarcon, M.; Calles, 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. 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 Hy-
brids. Bioorg. Med. Chem. Lett. 2004, 14, 4173–4178, and references
therein.
(11) Pfizer. 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) Barker, M.; Clackers, M.; Demaine, D. A.; Humphreys, D.; Johnston,
M. J.; Jones, H. T.; Pacquet, F.; Pritchard, J. M.; Shanahan, S. E.;
Skone, P. A.; Vinader, V. M.; Uings, I.; McLay, I. M.; Macdonald,
S.J.F. Design and Synthesis of New Non-Steroidal Glucocorticoid
Modulators through Application of an “Agreement Docking” Method.
J. Med. Chem. 2005, 48, 4507–4510.
(13) 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.
(14) Barker, M.; Clackers, M.; Copley, R.; Demaine, D. A.; Humphreys,
D.; Inglis, G.G.A.; Johnston, M. J.; Jones, H. T.; Haase, M. V.; House,
D.; Loiseau, R.; Nisbet, L.; Pacquet, F.; Skone, P. A.; Shanahan, S. E.;
Tape, D.; Vinader, V. M.; WA, M.; Uings, I.; Upton, R.; McLay,
I. M.; Macdonald, S.J.F. Dissociated Non-Steroidal Glucocorticoid
Receptor Modulators; Discovery of the Agonist Trigger in a Tetrahy-
dronaphthalene–Benzoxazine Series. J. Med. Chem. 2006, 49, 4216–
4231.
(15) 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.;