Discovery of 5-arylsulfonamido-3-(pyrrolidin-2-ylmethyl)-1H-indole derivatives as potent, selective 5-HT6 receptor agonists and antagonists

Article abstract of DOI:10.1021/jm049243i

5-Arylsulfonylamido-3-(pyrrolidin-2-ylmethyl)-1H-indoles have been identified as high-affinity 5-HT₆ receptor ligands. Within this class, several of the (R)-enantiomers were potent agonists having EC ₅₀ values of 1 nM or less and functioning as full agonists while the (S)-enantiomers displayed moderate antagonist activity.

Full text of DOI:10.1021/jm049243i

J. Med. Chem. 2005, 48, 353-356
353
Chart 1. Structures of 5-HT6 Receptor Ligands
Discovery of 5-Arylsulfonamido-3-
(pyrrolidin-2-ylmethyl)-1H-indole
Derivatives as Potent, Selective 5-HT6
Receptor Agonists and Antagonists
Derek C. Cole,*,† William J. Lennox,†
Sabrina Lombardi,† John W. Ellingboe,†
Ronald C. Bernotas,‡ Gregory J. Tawa,§
Hossein Mazandarani,# Deborah L. Smith,#
Guoming Zhang,# Joseph Coupet,# and
Lee E. Schechter#
Chemical and Screening Sciences, Wyeth Research,
401 N. Middletown Road, Pearl River, New York 10965,
Chemical and Screening Sciences, Wyeth Research,
500 Arcola Road, Collegeville, Pennsylvania 19426,
Chemical and Screening Sciences, Wyeth Research,
Princeton, New Jersey 08852, and Neurosciences,
Wyeth Research, Princeton, New Jersey 08852
SB-357134 (4),9 were subsequently revealed by Smith-
Kline-Beecham. More recently, N,N-dimethyl-1-benzene-
sulfonyl-5-methoxytryptamine (6)10 and the first non-
sulfonamide antagonist 4-(2-bromo-6-pyrrolidine-1-yl-
pyridine-4-sulfonyl)phenylamine (7)11 were reported
(Chart 1).
Received September 16, 2004
Abstract: 5-Arylsulfonylamido-3-(pyrrolidin-2-ylmethyl)-1H-
indoles have been identified as high-affinity 5-HT6 receptor
ligands. Within this class, several of the (R)-enantiomers were
potent agonists having EC50 values of 1 nM or less and
functioning as full agonists while the (S)-enantiomers dis-
played moderate antagonist activity.
These compounds have been used to probe the thera-
peutic potential of 5-HT6 receptor ligands. Bentley et
al. showed that the 5-HT6 receptor blockade with Ro-
04-6790 produced a dose-dependent stretching that was
blocked by the muscarinic receptor antagonist atropine
suggesting that the 5-HT6 receptor may regulate central
cholinergic neurotransmission.12 Ro-04-6790 also inhib-
ited atropine- and scopolamine-induced ipsilateral rota-
tions but not L-Dopa-induced contralateral rotations in
rats with 6-OHDA lesions in the medial forebrain
indicating that 5-HT6 receptors may play a role in
normal and dysfunctional memory.13 While in vivo
studies with Ro-04-6790, SB-271046, and SB-357134
showed no enhancement in learning, some results
suggested enhanced memory retention in rats indicating
that blocking 5-HT6 receptor function may be involved
in cognitive processes.9,14 However, interpretation of
these results has been somewhat controversial.15 Daw-
son et al. demonstrated increased levels of glutamate
and aspartate in rat frontal cortex and hippocampus,
respectively, after treatment with SB-271046, support-
ing the hypothesis that the 5-HT6 receptor may regulate
glutamatergic neurons and that this could be involved
in the no-otropic effect seen with 5-HT6 receptor an-
tagonists.16
There are now approximately 15 different human
serotonin (5-HT) receptors that have been cloned and
divided into 7 subclasses (5-HT1-7).1 The 5-HT6 receptor
is one of the latest to have been identified and belongs
to the G-protein coupled receptor (GPCR) superfamily.
The rat 5-HT6 receptor was first cloned in 1993 and
found to consist of a 438-residue peptide chain with
<40% homology with other 5-HT receptors.2 The human
receptor was cloned in 1996, shares 89% homology with
the rat receptor, and is positively coupled to adenylyl
cyclase.3,4
In situ hybridization studies indicate that the 5-HT6
receptor mRNA is localized exclusively in the central
nervous system, with highest densities in the cerebral
cortex, nucleus accumbens, caudate-putamen, and hip-
pocampus and with moderate densities in the thalamus
and substantia nigra.5 Binding studies have shown
certain tricyclic antidepressants and antipsychotic drugs
have high affinity for 5-HT6 receptors.6 The central
nervous system (CNS) localization of 5-HT6 receptors
and their affinity for CNS drugs have created intense
interest in identifying selective 5-HT6 receptor modula-
tors as tools for studying the receptor and as potential
therapeutic agents.5
Identification of selective 5-HT6 receptor agonists has
proven very challenging. One of the few agonists
reported, 2-ethyl-5-methoxy-N,N-dimethyltryptamine
(6),17 has 16 nM affinity for the 5-HT6 receptor but is
In 1998, scientists at Roche described a series of
pyrimidinyl- and pyridinylsulfonamides, Ro-04-6790 (1)
and Ro-63-0563 (2),7 which were among the first selec-
tive 5-HT6 receptor antagonists. A series of piperazi-
nylbenzenesulfonamides, including SB-271046 (3)8 and
only 10-, 20-, and 30-fold selective over 5-HT1A, 5-HT1D
,
and 5-HT7 receptors, respectively.
As part of a project to develop 5-HT6 receptor modula-
tors at Wyeth, we identified N1-arylsulfonyltryptamine
derivatives 8 as high-affinity 5-HT6 receptor ligands.10,17,18
We examined conformationally restricted aminoethyl
side chains focusing on the 3-(pyrrolidin-2-ylmethyl)
group.19 Indeed, the N1-arylsulfonamido-3-(pyrrolidin-
2-ylmethyl)-1H-indoles 9 had low-nanomolar affinity for
* To whom correspondence should be addressed. Phone: 845-602-
4619. Fax: 845-602-5561. E-mail:coledc@wyeth.com.
† Wyeth Research, NY.
‡ Wyeth Research, PA.
§ Chemical and Screening Sciences, Wyeth Research, Princeton,
NJ.
# Neurosciences, Wyeth Research, Princeton, NJ.
10.1021/jm049243i CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/21/2004

354 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 2
Letters
Chart 2. Design of 5-Arylsulfonamido-3-
(pyrrolidin-2-ylmethyl)-1H-indoles
Scheme 2a
a Reagents: (a) LiBH4, THF, ∆; (b) H2, Pd(OH)2, (Boc)2O, EtOH;
(c) NH4OH‚HCl, Et3N, i-PrOH, water, ∆; (d) ArSO2Cl, Et3N, THF;
(e) HCl, dioxane.
Scheme 1a
Table 1. 5-HT6 Receptor Binding Affinity of
5-Arylsulfonamido-3-(pyrrolidin-2-ylmethyl)-1H-indoles
Ki (nM)a
a Reagents: (a) LiAlH4, THF, ∆; (b) NH4OH‚HCl, Et3N, i-PrOH,
water, ∆; (c) ArSO2Cl, Et3N, THF.
R ) Me
(R)-13 (S)-13
R ) H
(R)-15 (S)-15
Ar
5-HT6 receptors. We had also found that tryptamine
type cores with lipophilic groups in the 5-position, e.g.,
5-benzyloxytryptamine, had high affinity for the 5-HT6
receptor. Thus, we thought that moving the sulfonamido
group from the 1- to the 5-position, as in 10 (Chart 2),
might also lead to 5-HT6 receptor ligands.
The compounds were found to have high 5-HT6
receptor affinity and to be potent modulators of 5-HT6
receptor dependent cyclase activity. Surprisingly, potent
agonists and antagonists were identified within this
single series; one enantiomeric series provided potent
agonists, while compounds of the opposite chirality were
potent antagonists. Herein, we describe the synthesis
and remarkable biological activities of 5-arylsulfona-
mido-3-(pyrrolidin-2-ylmethyl)-1H-indoles as 5-HT6 re-
ceptor modulators.
5-Amino-3-[(N-methyl-pyrrolidine-2-yl)methyl]-1H-in-
dole (R)-12 was prepared via a literature procedure20
by protection of 5-aminoindole as the 2,5-dimethylpyr-
role, Grignard promoted coupling with Cbz-D-proline
acid chloride to give (R)-11, followed by reduction with
LiAlH4 and deprotection of the amine to give (R)-12
(Scheme 1).
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
Ph
1.0 ( 0.3 16 ( 2
1.0 ( 0.1
1.0 ( 0.0 22 ( 2
5 ( 1
4.0 ( 0.4
4.0 ( 0.4
3.0 ( 0.4
2-F-Ph
2-Cl-Ph
2-Br-Ph
2-I-Ph
1.0 ( 0.1
2.0 ( 0.2 36 ( 1
4 ( 1
4 ( 1
3 ( 1
3.0 ( 0.2 57 ( 6
1.0 ( 0.1
4 ( 1
3-Cl-Ph
3-CF3-Ph
4-F-Ph
4-Cl-Ph
4-Br-Ph
4-I-Ph
0.4 ( 0.1 11 ( 1
1.0 ( 0.2 12 ( 2
1.0 ( 0.2
74%b
9 ( 1
0.3 ( 0.0
1.0 ( 0.0
1.0 ( 0.1 34 ( 4
0.4 ( 0.0 10 ( 2
1.0 ( 0.2 8 ( 2
1.0 ( 0.2 3.0 ( 0.2 1.0 ( 0.1
1.0 ( 0.1 1.0 ( 0.2
2.0 (0.2
4-Me-Ph
4-MeO-Ph
64%b
4-CF3-Ph
4-CF3O-Ph
4-(2-Pr)-Ph
2-Naph
5 ( 1
2-(3-Me-5-Cl-
benzothiophene)
2,4-diF-Ph
2-Cl-4-F-Ph
3,4-diCl-Ph
3-Cl-6-MeO-Ph
s
t
u
v
w
8 ( 1
9 ( 2
3.0 ( 0.3
131 ( 19
35 ( 5
1.0 ( 0.2 7 ( 1
24 ( 3
4-(3,5-diMe-isoxazole) 1.0 ( 0.2
a Displacement of [3H]-LSD binding to cloned h5-HT6 receptors
stably expressed in HeLa cells. Ki values were determined in
triplicate. b % inhibition at 1000 nM.
This 5-aminoindole core (R)-12 was converted into an
array of sulfonamides (R)-13a-w in parallel fashion by
treatment with a set of arylsulfonyl chlorides and
subsequent purification by high-throughput RP-HPLC.21
Corresponding (S)-enantiomers (S)-13a-w were pre-
pared in similar fashion, starting from Cbz-L-proline
acid chloride.
A somewhat modified route was used to prepare the
N-H pyrrolidinyl analogues (Scheme 2). The 2-(5-
amino-1H-indol-3-ylmethyl)-N-Boc-pyrrolidine core (R)-
14 was synthesized by selective reduction of (R)-11 with
lithium borohydride in refluxing THF. This milder
reducing agent effected the keto-to-methylene transfor-
mation while leaving the Cbz group intact. A Boc for
Cbz protecting group exchange was achieved in a single
pot by hydrogenation over palladium hydroxide in the
presence of di-tert-butyl dicarbonate in ethanol. Depro-
tection of the 5-amino group then gives the Boc-
protected core (R)-14. Sulfonamide array synthesis is
accomplished as for the N-methyl series. The Boc group
was then removed by treatment with HCl in dioxane,
affording the sulfonamide array (R)-15a-w. The (S)-
enantiomers were prepared analogously starting from
Cbz-L-proline, acid chloride.
Many 5-HT6 receptor antagonists (e.g., 1-4) share a
pharmacophore consisting of a sulfonamide separated
from a basic amine by an aryl group and linker. Indeed,
our initial targets, N-sulfonyl-3-pyrrolidin-2-ylmethyl-
1H-indoles (9), contained this pharmacophore and had
high affinity for 5-HT6 receptors (data not shown).
Gratifyingly, moving the sulfonamide from the indole
N1-position to the 5-amino position also provided high-
affinity 5-HT6 receptor ligands 13 and 15 (Table 1). In
general, the (S)-enantiomers in 13 and 15 have signifi-
cantly weaker affinity compared to the corresponding
(R)-enantiomers with a single exception: (R)-13q and
(S)-13q in which Ar ) 2-naphthyl were equipotent at
5-HT6 receptors (Ki ) 1 nM).
Similarly, there is a trend in which the N-methylpyr-
rolidines (R)-13 have ∼4-fold higher affinity relative to

Letters
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 2 355
Table 2. Antagonism of cAMP Productiona
Table 4. Selectivity Binding Affinity for Serotonin and
Dopamine Receptors, Ki (nM)a
Ar
IC50 (nM) Imax (%)
receptor
5-HT6
(R)-13c
1 ( 0
(R)-13f
(R)-15c
(R)-15e
(S)-13d 2-Br-Ph
(S)-13g 3-CF3-Ph
0.8 ( 0.2
14.1 ( 4.7
1.6 ( 0.1
21.6 ( 0.6
25.8 ( 0.3
21.1 ( 2.7
10.4 ( 0.4
75 ( 1
78 ( 1
85 ( 1
78 ( 1
85 ( 1
76 ( 1
95 ( 0
91 ( 1
0.4 ( 0.1 3.0 ( 0.4
1.0 ( 0.1
234 ( 35
9.3 ( 8.5
65 ( 28
(S)-13j
4-Br-Ph
5-HT1A
5-HT1B
5-HT1D
5-HT1F
170 ( 17 200 ( 28 552 ( 63
(S)-13n 4-CF3-Ph
(S)-13o 4-CF3O-Ph
(S)-13p 4-(2-Pr)-Ph
(S)-13q 2-Naph
15 ( 5
4.3 ( 1.2 88 ( 10
29.5b
4.7b
>1000
16 ( 10
2.7 ( 1.7 12.3 ( 0.9 17.8 ( 2.5
5-HT2A (agonist) 367 ( 43 269 ( 33 NDd
42%c
(S)-13r 2-(3-Me-5-Cl-benzothiophene) 1.1 ( 0.1
5-HT2c
5-HT7
D2
289 ( 39 231 ( 18 566 ( 4
235 ( 1
329 ( 42
>2000
>5000
>5000
74 ( 12
>2000
>1000
>5000
24 ( 2
>2000
NDd
a Antagonism of 5-HT stimulated cAMP production in HeLa
cells stably transfected with human 5-HT6 receptors. IC50 and Imax
values were determined in triplicate.
>5000
D3
D4
930 ( 46 >5000
>5000
>5000
Table 3. Agonism of cAMP Productiona
a Receptors were all human clones stably expressed in CHO cells
(5-HT receptors) or CHO-K1 cells (D receptors). Radioligands were
Ar
EC50 (nM)
Emax (%)
as follows. 5-HT1A: 8-hydroxy-[3H]-DPAT. 5-HT1B, 5-HT1D, 5-HT1F
,
5-HT2C: [3H]-5-HT. 5-HT2A: [125I]DOI. 5-HT6, 5-HT7: [3H]-LSD.
Dopamine D2, D3, and D4: [3H]spiperone. Ki values were deter-
mined in triplicate except for those indicated by footnote b. b Ki
values were determined with n ) 1. c % inhibition at 1000 nM.
d ND ) not determined.
(R)-13b
(R)-13c
(R)-13f
(R)-13g
(R)-13h
(R)-13k
(R)-13l
(R)-13m
(R)-13n
(R)-13o
(R)-13w
(S)-13o
(R)-15a
(R)-15c
(R)-15e
(R)-15f
(R)-15g
(R)-15i
(R)-15o
(R)-15s
2-F-Ph
1.3 ( 0.1
1.1 ( 0.2
1.6 ( 0.2
3.2 ( 0.8
1.1 ( 0.1
2.7 ( 0.5
1.3 ( 0.0
2.2 ( 0.2
4.5 ( 0.6
2.9 ( 0.7
0.8 ( 0.1
180 ( 3
1.4 ( 0.0
1.3 ( 0.4
0.4 ( 0.1
1.0 ( 0.2
5.8 ( 0.9
4.5 ( 1.2
4.2 ( 0.8
5.2 ( 0.4
91 ( 1
100 ( 0
100 ( 0
90 ( 1
85 ( 5
72 ( 2
79 ( 7
83 ( 2
85 ( 2
94 ( 2
77 ( 1
68 ( 1
73 ( 0
100 ( 1
100 ( 0
92 ( 1
77 ( 1
99 ( 1
86 ( 2
78 ( 2
2-Cl-Ph
3-Cl-Ph
3-CF3-Ph
4-F-Ph
4-I-Ph
4-Me-Ph
13f vs (R)-15f). Many compounds behave as essentially
full agonists with EC50 values in the low-nanomolar or
even subnanomolar range.
4-MeO-Ph
4-CF3-Ph
4-CF3O-Ph
4-(3,5-diMe-isoxazole)
4-CF3O-Ph
Ph
(R)-13c, (R)-13f, (R)-15c, and (R)-15e were examined
further for selectivity against several serotonergic and
dopaminergic receptors (Table 4). All four compounds
2-Cl-Ph
2-I-Ph
were greater than 50-fold selective over 5-HT1A, 5-HT2A
,
3-Cl-Ph
3-CF3-Ph
4-Cl-Ph
5-HT2C, 5-HT7, and dopamine (D2, D3, and D4) receptors
but show significant affinity for the 5-HT1B, 5-HT1D, and
5-HT1F receptors.
4-CF3O-Ph
2,4-diF-Ph
In summary, our exploration of the SAR of N1-
arylsulfonyltryptamine derivatives relative to the 5-HT6
receptor led to the finding that the aminoethyl group
of the tryptamine could be replaced with the conforma-
tionally restricted pyrrolidin-2-ylmethyl group. Further
structural manipulations led to the important finding
that the indole N1-arylsulfonyl group could be moved
to a 5-amino substitutent on the indole, providing
5-arylsulfonamido-3-(pyrrolidin-2-ylmethyl)-1H-in-
doles 13 and 15 as high-affinity 5-HT6 receptor ligands.
Surprisingly, while the (R)- and (S)-enantiomer series
had good affinity for 5-HT6 receptors, they had es-
sentially opposite functional activity. Specifically, (S)-
enantiomers showed moderate antagonist activity while
many of the (R)-enantiomers function as essentially full
agonists with several compounds having EC50 values of
1 nM or less. Some of the highest affinity agonists are
relatively selective against several other 5-HT and
dopamine receptors. This new series of 5-HT6 receptor
modulators, especially the agonists, may be useful tools
in elucidating potential therapeutic uses for 5-HT6
receptor ligands.
a Agonism of cAMP production in HeLa cells stably transfected
with human 5-HT6 receptors. IC50 and Imax values were determined
in triplicate.
the corresponding N-H analogues (R)-15. More subtle
effects on 5-HT6 receptor affinities can also be discerned.
For example, N-[3-(1-methylpyrrolidin-2-ylmethyl)-1H-
indol-5-yl]benzenesulfonamide (R)-3a with no substitu-
tion on the phenyl group binds with 1 nM affinity.
Substitution on the phenyl at the 2-, 3-, or 4-position
with small groups, e.g., halogen, methyl, methoxy,
resulted in similar or modestly increased receptor
affinity. Some disubstituted phenyl groups were also
tolerated. Replacing the phenyl group with lipophilic
heterocycles such as 4-(3,5-dimethylisoxazole ((R)-13w)
also afforded high-affinity ligands, as did bicyclic aro-
matic groups ((R)-13q and (R)-13r).
Compounds with Ki < 15 nM were further evaluated
for their ability to modulate 5-HT6 receptor function in
a cyclase assay measuring production of cyclic AMP
(cAMP) at various concentrations of ligand. None of the
(S)-enantiomers (S)-13 or (S)-15 had significant intrinsic
(agonist) activity at 5-HT6 receptors, with the exception
of the weak partial agonist (S)-13o. However, when
these compounds were tested for the ability to block
serotonin-induced stimulation of cAMP, several of the
(S)-enantiomers (S)-13 were antagonists with low na-
nomolar IC50 values and Imax ) 75-95% (Table 2).
Acknowledgment. We thank Mario D. Gonzalez,
Organix, Inc., for synthesis of intermediates, and we
thank Xidong Feng, Michael Kelly, and Mairead Young
for HRMS, LCMS, and chiral HPLC and SFC analysis.
In contrast, the (R)-enantiomers proved to be potent
agonists at 5-HT6 receptors (Table 3). Pyrrolidine N-
substitution had little effect on intrinsic activity because
(R)-13 (N-Me) and (R)-15 (N-H) analogues have
similar activity (compare (R)-13c vs (R)-15c and (R)-
Supporting Information Available: Experimental de-
tails for the binding and functional assays and the synthetic
procedures. This material is available free of charge via the
Internet at http://pubs.acs.org.

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