318
D. R. Marshall et al. / Bioorg. Med. Chem. Lett. 17 (2007) 315–319
Table 7. NR selectivity of phenyl sulfonamides
Table 6. Study of indole substitution
R
H
O
O
N
Indole
S
R
O
O
N
S
H
N
R
H
R
Compound 6
Indole
R
hGR IC50 (lM)
Compound
R
hGR IC50 hPR IC50 hMR IC50
(lM)
H
(lM)
(lM)
N
a
Me
Cl
>2.0
Dex
1a
1e
2f
—
0.0034
>2.00
>2.00
1.00
0.033
4-t-Bu
4-i-Pr
2,4-Cl2
2,6-Cl2
0.735
0.750
0.480
0.240
0.710
0.064
0.040
0.067
>2.00
0.029
1.07
1.40
>2.00
0.170
0.440
0.570
1.40
0.850
1.60
1.00
N
2g
3e
3f
b
>2.0
2,4,5-Cl3
2,4,6-Cl3
2,4,6-Me3
2,4,6-i-Pr3
2,4,6-Me3
2,4,6-Me3
0.130
0.290
>2.00
0.520
1.00
3g
3h
5f
>2.00
>2.00
1.20
H
N
c
d
e
Cl
0.57
0.49
0.12
5g
H
fonamide provided a hGR selective compound. There-
fore, this effort has led to the discovery of a novel,
potent, and selective hGR ligand.
N
Me
Me
H
N
Acknowledgment
We thank Oliver Deeg.
H
N
References and notes
f
Me
Me
0.065
0.079
1. Coghlan, M. J.; Elmore, S. W.; Kym, P. R.; Kort, M. E.
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F
2. (a) Wagner, B. L.; Pollio, G.; Giangrande, P.; Webster, J.
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H
N
g
F
H
N
h
Cl
>2.0
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OMe
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In conclusion, a uHTS campaign identified methyltryp-
tamine sulfonamides as novel hGR ligands. Utilizing
parallel synthesis, the hGR potency was increased 17-
fold. 2,4,6-Tri-substituted phenyl sulfonamides, with al-
kyl or halogen substituents, were found to be the most
potent ligands. The sulfonamide proved to be crucial
for hGR binding and the tryptamine chain substituent
was required to be lipophilic in nature. Resolution of
the a-methyltryptamine moiety revealed an enantiomer-
ic preference with hGR binding affinity residing in one
enantiomer. Independent synthesis of each enantiomer
identified the (S)-configuration as being the preferred
stereocenter. The selectivity of the tryptamine sulfona-
mides was also improved. Placement of sterically
demanding groups at the 2, 4, and 6 positions of the sul-