4544 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 11
Yates et al.
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. (b) 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-Aryl-
pyrazolo[3,2-c]-Based Ligands for the Glucocorticoid Receptor: Re-
ceptor Binding and in Vivo Activity. J. Med. Chem. 2004, 47, 2441–
2452. (c) 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 Gluco-
corticoids: In Vitro Profile and in Vivo Efficacy. Bioorg. Med. Chem.
Lett. 2005, 15, 2163–2167. (d) 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.
4216–4231. (b) Biggadike, K.; Boudjelal, M.; Clackers, M.; Coe, D. M.;
Demaine, D. A.; Hardy, G. W.; Humphreys, D.; Inglis, G. G. A.; Johnston,
M. J.; Jones, H. T.; House, D.; Loiseau, R.; Needham, D.; Skone, P. A.;
Uings, I.; Veitch, G.; Weingarten, G. G.; McLay, I. M.; Macdonald, S. J. F.
Nonsteroidal Glucocorticoid Agonists: Tetrahydronaphthalenes with Alter-
native Steroidal A-Ring Mimetics Possessing Dissociated (Transrepression/
Transactivation) Efficacy Selectivity. J. Med. Chem. 2007, 50, 6519–6534.
(11) Clackers, M.;Coe, D. M.;Demaine, D. A.;Hardy, G. W.;Humphreys,
D.; Inglis, G. G. A.; Johnston, M. J.; Jones, H. T.; House, D.; Loiseau,
R.; Minick, D. J.; Skone, P. A.; Uings, I.; McLay, I. M.; Macdonald,
S. J. F. Non-steroidal glucocorticoid agonists;The discovery of aryl
pyrazoles as A-ring mimetics. Bioorg. Med. Chem. Lett. 2007, 17, 4737–
4745.
(12) Miller, D. D.; Mohler, M. L.; He, Y.; Wu, Z.; Hong, S.-S. Expert
Opin. Ther. Pat. 2007, 17, 59–81.
(13) Welles, B. Drug Dev. Res. 2006, 67, 570–573.
(14) (a) Herzig, S; Long, F.; Jhala, U. S.; Hedrick, S.; Quinn, R.; Bauer,
A.; Rudolph, D.; Schutz, G.; Yoon, C.; Puigserver, P.; Spiegelman,
B.; Montminy, M. Nature 2001, 413, 179–183. (b) Yoon, J. C.;
Puigserver, P.; Chen, G.; Donovan, J.; Wu, Z.; Rhee, J.; Adelmant, G.;
Stafford, J.; Kahn, C. R.; Granner, D. K.; Newgard, C. B.; Spiegelman,
B. M. Nature 2001, 413, 131–138.
(15) Chrousos, G. P.; Kino, T. Glucocorticoid action networks and
complex psychiatric and/or somatic disorders. Stress 2007, 10, 213–
219.
(16) Karo Bio/Abbott: (a) 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. (b) 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 .
(17) 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 Gluco-
corticoid Receptor Antagonists with Anti-Obesity Activity. Lett.
Drug Des. Discovery 2004, 1, 1–5.
(8) Boehringer Ingelheim. For leading references, see the following: (a)
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 Dis-
sociated Glucocorticoid Agonist. J. Med. Chem. 2006, 49, 7887–
7896. (b) 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. (c) Marshall, D. R. 3-Sulfonamidoethylindole Deriva-
tives for Use as Glucocorticoid Mimetics in the Treatment of Inflam-
matory, 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.
(9) (a) Shah, N.; Scanlan, T. S. Design and Evaluation of Novel
Glucocorticoid Dissociating Glucocorticoid Receptor Ligands.
Bioorg. Med. Chem. Lett. 2004, 14, 5199–5203. (b) De Bosscher,
K.; Vanden Berghe, W.; Beck, I. M.; Van Molle, W.; Hennuyer, N.;
Hapgood, J.; Libert, C.; Staels, B.; Louw, A.; Haegeman, G. A Fully
Dissociated Compound of Plant Origin for Inflammatory Gene Repres-
sion. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 15827–15832. (c)
Robinson, R. P.; Buckbinder, L.; Haugeto, A. I.; McNiff, P. A.; Mill-
ham, M. L.; Reese, M. R.; Schaefer, J. F.; Abramov, Y. A.; Bordner, J.;
Chantigny, Y. A.; Kleinman, E. F.; Laird, E. R.; Morgan, B. P.; Murray,
J. C.; Salter, E. D.; Wessel, M. D.; Yocum, S. A. Octahydrophenan-
threne-2,7-diol Analogues as Dissociated Glucocorticoid Receptor
Agonists: Discovery and Lead Exploration. J. Med. Chem. 2009, 52,
1731–1743. (d) Yang, B. V.; Vacarro, W.; Doweyko, A.; Doweyko,
L.; Huynh, T.; Tortolani, D.; Nadler, S.; McKay, L.; Somerville, J.;
Holloway, D. A.; Habte, S.; Weinstein, D. S.; Barrish, J. Discovery of
Novel Dihyro-9,10-ethano-anthracene Carboxamides As Glucocorti-
coid Receptor Modulators. Bioorg. Med. Chem. Lett. 2009, 19, 2139–
2143. (e) Xiao, H.-Y.; Wu, D.-R.; Malley, M. F.; Gougoutas, J. Z.;
Habte, S. F.; Cunningham, M. D.; Somerville, J. E.; Dodd, J. H.;
Barrish, J. C.; Nadler, S. G.; Dhar, T. G. M. A Novel Synthesis of the
Hexahydroimidazo[1,5b]isoquinoline Scaffold: Application to the
Synthesis of Glucocorticoid Receptor Modulators. J. Med. Chem.
2010, 53, 1270–1280.
(18) Rafferty, S. W.; Caldwell, R. D.; Gray, D. W.; Hoekstra, W. J.;
Pahel, G. L.; Stewart, E. L.; Turnbull, P. S.; Wingler, L.; Yang, B.
Identification of Hexahydropyridazines as Glucocorticoid Anta-
gonists. Manuscript in preparation.
(19) Sun, D.; Whitty, A.; Papadatos, J.; Newman, M.; Donnelly, J.;
Bowes, S.; et al. Adopting a Practical Statistical Approach for
Evaluating Assay Agreement in Drug Discovery. J. Biomol.
Screening 2005, 10, 508–516.
(20) Trump, R. P.; Blanc, J.-B. E.; Stewart, E. L.; Brown, P. J.; Caivano,
M.; Gray, D. W.; Hoekstra, W. J.; Willson, T. M.; Han, B.;
Turnbull, P. Design and Synthesis of an Array of Selective Andro-
gen Receptor Modulators. J. Comb. Chem. 2007, 9, 107–114.
(21) (a) Rusinko, A. S., Balducci, R.; Pearlman, R. S. CONCORD:
Rapid Generation of High Quality Approximate 3-Dimensional
Molecular Structures. Presented at the 192nd National Meeting of
the American Chemical Society, 1986. (b) CONCORD, version
5.1.2; Tripos, Inc.: St. Louis, MO, 2003. (c) OMEGA, version 1.8.1;
OpenEye Scientific Software: Santa Fe, NM, 2004.
(22) (a) ROCS, version 2.0; OpenEye Scientific Software: Santa Fe, NM,
2004.(b) Grant, J. A.; Pickup, B. T. J. Phys. Chem. 1995, 99, 3503–
3510. (c) Grant, J. A.; Gallardo, M. A.; Pickup, B. T. J. Comput. Chem.
1996, 17, 1653–1666. (d) Masek, B. B.; Merchant, A.; Matthew, J. B.
J. Med. Chem. 1993, 36, 1230–1238.
(10) (a) 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.; Washington, M.; Uings, I.; Upton, R.;
McLay, I. M.; Macdonald, S. J. F. Dissociated Nonsteroidal Gluco-
corticoid Receptor Modulators: Discovery of the Agonist Trigger in a
Tetrahydronaphthalene-Benzoxazine Series. J. Med. Chem. 2006, 49,
(23) Lambert, M. H. Docking Conformationally Flexible Molecules
into Protein Binding Sites. In Practical Application of Computer-
Aided Drug Design; Marcel-Dekker: New York, 1997; pp 243-303.
(24) 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. Cell 2002, 110, 93–105.