α-Methyltryptamine sulfonamide derivatives as novel glucocorticoid receptor ligands

Article abstract of DOI:10.1016/j.bmcl.2006.10.058

α-Methyltryptamine sulfonamides were identified as human glucocorticoid receptor (hGR) ligands in an ultra high throughput screening (UHTS) campaign. Described will be the hit-to-lead activities, including parallel and single point analog synthesis to map the scaffold. Ligands were identified that exhibited 30 nM binding to hGR. The SAR and selectivity of these compounds will be discussed.

Full text of DOI:10.1016/j.bmcl.2006.10.058

Bioorganic & Medicinal Chemistry Letters 17 (2007) 315–319
a-Methyltryptamine sulfonamide derivatives as novel
glucocorticoid receptor ligands
Daniel R. Marshall,* Gus Rodriguez, David S. Thomson,
Richard Nelson and Allison Capolina
Boehringer Ingelheim Pharmaceuticals, Inc. 900 Ridgebury Rd/PO Box 368, Ridgefield, CT 06877-0368, USA
Received 18 August 2006; revised 12 October 2006; accepted 23 October 2006
Available online 25 October 2006
Abstract—a-Methyltryptamine sulfonamides were identified as human glucocorticoid receptor (hGR) ligands in an ultra high
throughput screening (UHTS) campaign. Described will be the hit-to-lead activities, including parallel and single point analog syn-
thesis to map the scaffold. Ligands were identified that exhibited 30 nM binding to hGR. The SAR and selectivity of these com-
pounds will be discussed.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Glucocorticoid receptor modulators are among the most
widely prescribed drugs (Fig. 1). Indications for agonists
include rheumatoid arthritis, bronchial asthma, and se-
vere psoriasis.1 Antagonists have the potential to be
used to treat a multitude of disorders, including diabetes
and obesity.2 However, the use of steroidal glucocorti-
coid receptor modulators in chronic disease treatment
can result in the occurrence of serious side-effects, such
as skin thinning, osteoporosis, hypotension, and shock.3
The discovery of novel classes of non-steroidal agents
that interact with the human glucocorticoid receptor
(hGR) in the role of agonists4 or antagonists5 may lead
to the identification of novel therapeutics with dimin-
ished side-effects.
To this end, we embarked on an ultra high throughput
screening (uHTS) campaign to identify novel, non-
steroidal hGR ligands.6 Due to the reported biological
consequences of human nuclear receptor activity,7
a
counterscreen against the human progesterone receptor
(hPR) was run to indicate preliminary selectivity.
a-Methyltryptamine sulfonamide 1a was identified and
displayed binding affinities of 0.70 lM against hGR
and greater than 2.0 lM against hPR (Fig. 2). These
findings compelled us to more thoroughly examine
this series, with the goals of increasing potency and
selectivity.
HO
O
To explore the effects of phenyl sulfonamide substitu-
tion, a parallel synthesis array was employed, coupling
racemic a-methyl tryptamine with 88 sulfonyl chlorides
under basic conditions8 to rapidly access a variety of
sulfonamide analogs. The SAR of mono-substituted
OH
HO
H
F
H
O
Dexamethasone (Dex)
hGR Binding: 0.0034 µM
H
N
O
O
Figure 1. Marketed hGR modulator.
S
N
H
Keywords: Glucocorticoid receptor; Non-steroidal; Human nuclear
receptor.
*
Corresponding author. Tel.: +1 203 791 6055; fax: +1 203 791
6072; e-mail: dmarshal@rdg.boehringer-ingelheim.com
Figure 2. Methyltryptamine sulfonamide uHTS hit.
0960-894X/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.10.058

316
D. R. Marshall et al. / Bioorg. Med. Chem. Lett. 17 (2007) 315–319
Table 3. Tri-substituted phenyl sulfonamides
phenyl sulfonamides is displayed in Table 1. Unsubsti-
tuted phenyl sulfonamide, 1b, was shown to have no
binding affinity to hGR up to 10 lM. Substitution with
lipophilic substituents at the 4-position led to an in-
crease in binding potency compared to 1b (compounds
1c, 1d, and 1e). Substituting with chloro, 1h, or phenyl,
1j, at the 4-position provided compounds that were 2.1
and 2.6 lM, respectively. A 3-position methyl substitu-
ent, 1l, demonstrated no binding, while substituting with
a chloro at the same position, 1 m, gave an affinity of
4.1 lM. 2-Chlorophenyl sulfonamide, 1n, exhibited a
binding potency of 4.1 lM. Of the limited number of po-
lar groups surveyed (1f, 1g, 1i, 1k, and 1o), substitution
with a moderately polar functionality at the 2, 3, and 4
positions did not lead to compounds exhibiting binding
potency of less than 10 lM.
H
N
O
O
R
S
N
R
H
R
Compound 3
R
hGR IC50 (lM)
a
b
c
d
e
f
2,5-F2-4-Br
2,5-Me2-4-Cl
3,5-Cl2-2-OH
2,3,4-Cl3
3.6
1.8
>10
1.9
2,4,5-Cl3
2,4,6-Cl3
0.99
0.064
0.040
0.067
g
h
2,4,6-Me3
2,4,6-i-Pr3
Introduction of a second substituent on the phenyl
sulfonamide led to the identification of more potent
ligands (Table 2). 2,3-Dichlorophenyl sulfonamide 2b
demonstrated equivalent potency to the original hit 2a,
while 3,4-dichloro or 3,5-dichloro combinations (2d
and 2e) were less potent analogs. 2,4-Dichlorophenyl
sulfonamide 2f demonstrated a modest 3-fold increase
in binding affinity over 2a, while 2,6-dichlorophenyl sul-
fonamide 2g was 0.24 lM (6-fold increase). This indi-
cates an additive effect for these positions. Compounds
2c and 2h demonstrate that methyl is interchangeable
with chloro in this manifold.
Table 1. Mono-substituted phenyl sulfonamides
H
N
O
O
S
N
R
H
The study of tri-substituted phenyl sulfonamides provid-
ed ligands with improved binding affinity and a further
preferred substituent pattern (Table 3). 2,3,4- and
2,4,5-tri-substituted sulfonamides exhibited micromolar
potency (compounds 3a, 3b, 3d, and 3e) and hydroxy
substitution at the ortho position was not tolerated.
However, when the 2, 4, and 6 positions were substitut-
ed with non-polar groups (alkyl or halogen), the binding
affinity increased to less than 0.10 lM (compounds 3f
and 3g). These results indicate that the phenyl sulfon-
amide is situated in a large lipophilic pocket as 2,4,6-
tri-iso-propylphenyl sulfonamide 3h binds at 0.067 lM.
Compound 1
R
H
hGR IC50 (lM)
b
c
d
e
f
>10
5.7
4-Me
4-n-Pr
4-i-Pr
4-OMe
4-NO2
4-Cl
1.6
0.75
>10
>10
2.1
g
h
i
4-NHC(O)Me
4-Ph
3-CN
>10
2.6
j
k
l
>10
>10
4.1
3-Me
3-Cl
m
n
o
2-Cl
2-NO2
4.1
>10
We next explored the substitution and replacement of
the sulfonamide moiety to probe its role as linker and
interactive functionality. The 2,4,6-tri-substituted pat-
tern was locked while modulating the linkage to the
tryptamine portion of the molecule (Table 4). Methyla-
tion of the sulfonamide nitrogen, compound 4a,9 led to
a 20-fold loss of binding potency. Replacement of the
sulfonamide also proved detrimental. Amide and urea
replacements (4b10 and 4c11) did not exhibit binding
affinity up to the highest concentrations tested. Similar-
ly, replacing the sulfonamide with a methylene amine,
4d,12 resulted in a dramatic loss of potency.
Table 2. Di-substituted phenyl sulfonamides
H
N
O
O
S
N
R
H
R
Compound 2
R
hGR IC50 (lM)
We then investigated the substitution effects of a-substi-
tution (R2) to the sulfonamide nitrogen to probe the
nature of this position (Table 5). Deletion of the methyl
group (5a) resulted in complete loss of binding affinity.
Ethyl substitution was tolerated, 5b13, while substitution
with polar functionality was not. Methylene hydroxy
5c14 or esters 5d and 5e15 exhibited a lack of binding
potency up to 2.0 lM. The stereochemical orientation
a
b
c
d
e
f
2,5-Cl2
2,3-Cl2
1.3
1.2
2-Me-3-Cl
3,4-Cl2
3,5-Cl2
0.82
6.9
4.6
2,4-Cl2
2,6-Cl2
2-Me-6-Cl
0.48
0.24
0.28
g
h

D. R. Marshall et al. / Bioorg. Med. Chem. Lett. 17 (2007) 315–319
Table 4. Sulfonamide substitution and replacement
317
H
OMs
H
N
HO
N
O
O
H
R
R
S
N
a,b,c
N
*
H2N
H
*
X
H
R
N
O
O
S
Compound 4
X
R
hGR IC50 (lM)
d
N
*
H
O
O
S
a
Me
Me
1.3
N
Scheme 1. Synthesis of enantiomeric pair 5f/5g. Reagents and Con-
ditions: (a) TMSCN, TEA, CH2Cl2, rt, 16 h; (b) Mesitylene sulfonyl
chloride, TEA, CH2Cl2, rt, 16 h; (c) MsCl, TEA, CH2Cl2, rt, 16 h; (d)
LiBHEt3, THF, 40 ꢁ C, 16 h.
O
b
c
d
>2.0
>2.0
>2.0
N
H
O
H
H
N
N
Cl
N
H
N
O
O
O
O
H
S
S
N
N
H
H
Me
N
H
5f
Figure 3. Enantiomers of 3g.
5g
Table 5. Study of tryptamine chain substitution
of the indole nitrogen (6b) also led to loss of binding
potency, while methyl substitution at the 2-position
(6c) resulted in 10-fold loss of affinity. Methylation of
the indole phenyl ring at the 6-position (6d) also
adversely affected the binding, while 7-methyl substitu-
tion (6e) exhibited a 3-fold loss of potency. Fluoroin-
doles 6d and 6f were equipotent to unsubstituted 3g
(0.069 and 0.079 lM, respectively) and 5-methoxy sub-
stitution was not tolerated.
H
R2
R1
N
O
O
S
N
*
H
R1
Compound 5
R1
R1
R2
hGR IC50 (lM)
a
Me
Cl
H
Et
>2.0
0.064
>2.0
>2.0
>2.0
>2.0
0.029
b
Having identified compounds with hGR binding of less
than 0.100 lM, the selectivity of these compounds
against other human nuclear receptors (hNR) was ex-
plored.19 A select panel of compounds screened against
hPR and human mineralcorticoid receptor (hMR) is
shown below (Table 7).20 Compound 1a, our starting
point, demonstrates weak selectivity against the hNR
panel. 2,6-Dichlorophenyl sulfonamide, 2g, shows a
6-fold selectivity over hMR, and no selectivity against
hPR, while 2,4-dichloro substitution (2f) elicits at least
a 4-fold selectivity over hPR and equivalent cross reac-
tivity with hMR. 2,4,6-Trichlorophenyl sulfonamide,
3f selectively binds to hGR over hPR (8-fold), while
selectivity is poor against hMR. 2,4,5-Trichloro substi-
tution (compound 3e) does not retain hPR selectivity.
2,4,6-Trimethyl derivative 3g exhibits 35-fold increase
of selectivity against hPR, while hMR selectivity
increases (7-fold). Finally, tri-iso-propylphenyl sulfon-
amide 3h exhibited the highest degree of selectivity in
the hNR panel. When the stereocenter is resolved, the
hMR selectivity is affected. Enantiomer 5f, the com-
pound lacking hGR potency, retains its hMR cross reac-
tivity, while 5g is 34-fold selective against hMR. Other
changes to the tryptamine chain substitution or modula-
tion of the indole substituent pattern had little effect on
the selectivity profile. Based on these data, it appears as
though the selectivity profile of these compounds is
dependent on steric environment of the phenyl ring as
well as orientation of the chiral center.
c
Me
Me
Me
Me
Me
CH2OH
(R)-COOMe
(S)-COOMe
Me*
d
e
fa
gb
Me*
a (R)-configuration.
b (S)-configuration.
of the tryptamine substituent proved to be of conse-
quence. Racemic methyltryptamine sulfonamide 3g
was subjected to resolution on a chiral HPLC column
(Chiracel OD) to provide enantiomeric pairs 5f/5g.16
These enantiomers illustrate that there is a stereochem-
ical component to the binding affinity of this series.
One enantiomer binds at 0.029 lM while the other dem-
onstrates no binding at the highest concentration tested.
Stereoisomers 5f and 5g were independently synthesized
to reveal the absolute configuration of the active enan-
tiomer, starting from enantiopure D- or L-tryptophanol
(Scheme 1). It was found that the compound with the
(S)-configuration, 5g, was the enantiomer demonstrat-
ing potent binding (Fig. 3).17
A brief study of the effect of indole substitution on
binding affinity is presented in Table 6.18 The isomeric,
2-substituted indole 6a did not demonstrate binding
affinity at the highest concentration tested. Methylation

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
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g
F
H
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h
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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, C. M.; Miner, J. M.;
Jacobson, P. B.; Wilcox, D. M.; Nguyen, P.; Lane, B. C.
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-

D. R. Marshall et al. / Bioorg. Med. Chem. Lett. 17 (2007) 315–319
319
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Natl. Acad. Sci. U.S.A. 2004, 101, 227.
11. a-Methyltryptamine was treated with 2,4,6-tri-chlorophe-
nyl isocyanate in THF at 50 ꢁC overnight.
12. a-Methyltryptamine was treated with 1.5 equiv 2,4,6-
trimethylbenzaldehyde in C2H4Cl2 at 180 ꢁC with lW
irradiation for 3 min. To this were added EtOH and 1.5
equiv NaBH4. The mixture was concentrated after 20 min.
13. (a) 3-Indole carboxaldehyde, nitropropane, AcOH, soni-
cation, rt, 4; (b) Nitro olefin, BH3/THF, TMSCl, rt, 14 h;
(c) Crude amine, TEA, sulfonyl chloride, rt, 16 h.
14. (a) a-Methyltryptamine, TMSCN, TEA, CH2Cl2, rt, 16 h;
(b) Mesitylene sulfonyl chloride, TEA, CH2Cl2, rt, 16 h.
15. 5d and 5e: tryptophan methyl ester was treated with 2
equiv TEA and mesitylene sulfonyl chloride in CH2Cl2
overnight.
5. Miner, J. M.; Tyree, C.; Hu, J.; Burger, E.; Marshke, K.;
Nakane, M.; Coghlan, M. J.; Clem, D.; Lane, B.; Rosen,
J. Mol. Endocrinol. 2003, 17, 117.
6. Goldrick, S. E.; Nelson, R. M.; Crute, J. J.; Wasti, R. C.;
Nabozny, G. H.; Proudfoot, J. R.; Thomson, D. S. WO
02/095354, 2002.
7. (a) Novac, N.; Heinzel, T. Curr. Drug Targets: Infammat.
Allergy 2004, 3, 335; (b) Shiau, A. K.; Coward, P.;
Schwartz, M.; Lehmann, J. M. Curr. Opin. Drug Discovery
Dev. 2001, 4, 575.
8. a-Methyltryptamine (780 mg, 4.40 mmol) and triethyl-
amine (1.25 mL, 8.98 mmol) was dissolved in 18 mL
CH2Cl2. This solution (0.2 mL) was dispensed into 88
wells of a 96-well microtiter plate. To each was added
0.5 mL of a solution of the specified sulfonyl chloride
(0.1 mmol) in CH2Cl2. The plate was sealed and placed on
a shaker for 48 h. The plate was transferred to the
automated Gilson 215 SPE instrument where each well
was passed through a CH2Cl2 pre-washed NH2/CBA-
layered solid-phase extraction cartridge (100 mg sorbent
each, Varian Bond-elut). The cartridge was washed with
2· 0.3 mL CH2Cl2. The filtrates were concentrated in
vacuo and the residues dissolved into 0.5 mL CH2Cl2.
Fifty microliters of each well was transferred to a
collection plate for LC–MS analysis.
16. Racemate 3g (19.0 mg, 0.05 mmol) was dissolved into
8 mL of a 10% IPA/hexane solution. 2.0 mL of this
solution was injected onto an HPLC (column: Chiracel
OD 1.0 mm, flowrate: 5 mL/min). 5f was collected at
30.8 min and 5g collected at 35.2 min. This cycle was
repeated three more times to give 15.0 of 5f (48% yield)
and 15.5 mg of 5g (50% yield).
17. >95% ee for each enantiomer.
18. General experimental for compounds 6c–6h: (a) 3-indole
carboxaldehyde, nitroethane, AcOH, sonication, rt, over-
night. See Ref. 13.
19. GR, PR, and MR binding assays were performed in a
fluorescence polarization format that measures competi-
tion for binding to the nuclear receptor, present in lysates
of baculovirus-infected insect cells, between a test com-
pound and a fluorescently labeled receptor ligand, or
probe. IC50 values were determined by fitting the fluores-
cence polarization signal data to a 4-parameter logistic
equation.
9. (a) Compound 3g was treated with the following condi-
tions: (a) DMAP, (BOC)2O, CH3CN, rt, 16 h; (b) K2CO3,
MeI, DMF, 50 ꢁC, 16 h; (c) lW, 180 ꢁC, 20 min, repeat 3
times.
10. a-Methyltryptamine was treated with 2 equiv TEA and
2,4,6-tri-methylbenzoyl chloride in CH2Cl2 overnight.
20. All compounds in this series are >2.00 lM against human
estrogen receptor (hER).