5030
D. Kuzmich et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5025–5031
Upton, R.; McLay, I. M.; Macdonald, S. J. F. J. Med.
Chem. 2006, 49, 4216.
profile. Movement of the cyano group to the 2-postion
gave compound 41 which binds to GR with equal po-
tency compared to 40, however 41 was not as potent
and efficacious as 40 in the cellular assays. Compound
41 is however sixfold more potent in the transrepression
assay, while maintaining similar efficacy, compared to
the transactivation assay. Thus, compound 41 is a novel
GR ligand that is dissociated based upon potency.
15. De Bosscher, K.; Berghe, W. V.; Beck, I. M. E.; Molle, W. V.;
Hennuyer, N.; Hapgood, C. L.; Staels, B.; Louw, A.;
Haegeman, G. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 15827.
16. Shah, N.; Scanlan, T. S. Bioorg. Med. Chem. Lett. 2004,
14, 5199.
17. 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. J. Med. Chem. 2004, 47, 2441.
18. Coghlan, M. J.; Kym, P. R.; Elmore, S. W.; Wang, A. X.;
Luly, J. R.; Wilcox, D.; Stashko, M.; Lin, C. W.; Miner,
J.; Tyree, C.; Nakane, M.; Jacobson, P.; Lane, B. C. J.
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In conclusion, we have described a new class of non-ste-
roidal glucocorticoid receptor ligands. We have pro-
posed a binding mode for this scaffold which was used
to guide and is supported by our SAR studies. This
model suggests that the methoxyfluorophenyl ring ex-
tends above and sits over the dexamethasone D-ring
binding region while the benzyl group adjacent to the
chiral center occupies the A-ring portion of the binding
pocket. We have shown that GR binding potency can be
improved via the introduction of either lipophilic or po-
lar groups to the phenyl group that occupies the steroid
A-ring binding site. However, to improve the functional
activity of this scaffold the introduction of both polar
and lipophilic groups is required. Finally, it should be
noted that small structural changes can alter functional
activity and dissociated functional activity in unpredict-
able ways. Taken all together, these observations have
made this series highly attractive for further studies
and will be subject of future reports.
19. Lin, X.; Hueber, V. Curr. Opin. Drug Discovery Dev. 2000,
3, 383.
20. 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. Bioorg. Med. Chem. Lett. 2004, 14,
1721.
21. Lin, C. W.; Makane, M.; Stashko, M.; Falls, D.; Kuk, J.;
Miller, L.; Huang, R.; Tyree, C.; Miner, J. N.; Rosen, J.;
Kym, P. R.; Coghlan, M. J.; Carter, G.; Lane, B. C. Mol.
Pharmacol. 2002, 62, 297.
22. 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,
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test compound and
a fluorescently labeled receptor
ligand, or probe. IC50 values were determined by fitting
the fluorescence polarization signal data to a 4-param-
eter logistic equation. All IC50 values shown represent
means of at least two independent determinations.
Repeated testing of reference compounds in these
assays demonstrated typical IC50 standard deviations
of 20–40% about the mean. The ER fluorescence
polarization competitive binding assays were performed