S. L. Roach et al. / Bioorg. Med. Chem. Lett. 21 (2011) 168–171
171
Table 2
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11. (a) 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.;
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4216.
Cross-reactivity for selected new ligandsa
Compdb GR binding Ki
PR binding Ki
MR binding Ki
(nM)
AR binding Ki
(nM)
(nM)
(nM)
3
12
13
22
0.6 0.1
1.7 0.4
13
1
21
800 140
890
57
7
1200 200
1300 180
1100 150
900 200
915
400 170
16
10
4
3
1200 100
a
Standard errors (SEM) represent the mean value of at least three separate
experiments with triplicate determinations. If no SEM is noted, value is from a
single determinant.
b
Except where noted, compounds were tested as racemates.
served to diminish off-target receptor (PR, MR, AR) binding, thus
improving GR selectivity within the series. For example, 12 showed
good GR selectivity over PR (ꢀ700-fold), MR (ꢀ470-fold), and AR
(ꢀ530-fold).
In summary, we report our results based on A-ring SAR of
6-indole tetrahydroquinoline 3 which identified 12 as a selective
non-steroidal GR agonist with TR activity (E-selectin and IL-6)
similar to prednisolone. Polar functionality was successfully incor-
porated into the A-ring via addition of a C3 hydroxyl group, which
resulted in commitment improvements in receptor cross-reactiv-
ity, IL-6 repression activity, and lipophilicity with respect to 3.
Further SAR of this bicyclic 6-indole tetrahydroquinoline series
focusing on improvements in hepatic microsomal stability and
subsequent demonstration of in vivo efficacy will follow.
12. (a) Yates, C. M.; Brown, P. J.; Stewart, E. L.; Patten, C.; Austin, R. J. H.; Holt, J. A.;
Maglich, J. M.; Angell, D. C.; Sasse, R. Z.; Taylor, S. J.; Uings, I. J.; Trump, R. P. J.
Med. Chem. 2010, 53, 4531; (b) Biggadike, K.; Caivano, M.; Clackers, M.; Coe, D.
M.; Hardy, G. W.; Humphreys, D.; Jones, H. T.; House, D.; Miles-Williams, A.;
Skone, P. A.; Uings, I.; Weller, V.; McLay, I. M.; Macdonald, S. J. F. Bioorg. Med.
Chem. Lett. 2009, 19, 4846; (c) Biggadike, K.; Bledsoe, R. K.; Coe, D. M.; Cooper,
T. W. J.; House, D.; Iannone, M. A.; Macdonald, S. J. F.; Madauss, K. P.; McLay, I.
M.; Shipley, T. J.; Taylor, S. J.; Tran, T. B.; Uings, I. J.; Weller, V.; Williams, S. Proc.
Natl. Acad. Sci. U.S.A. 2009, 106, 18114; (d) Clackers, M.; Coe, D. M.; Demaine, D.
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room temperature.
17. Enantiomers of analog 12 were separated on
a Chiracel OJ column
(2 cm  25 cm ID) using 35% EtOH in hexanes as eluent at a flow rate of
2.5 mL/min. (À)12, tR = 15 min, (+)12, tR = 23 min. Absolute configuration of
(À)12 and (+)12 have not been determined.
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ratio of approximately 1:9.
20. Synthesized from 5-chloro-2-methylphenol following the procedure of
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