Phenyl benzenesulfonamides are novel and selective 5-HT6 antagonists: Identification of N-(2,5-dibromo-3-fluorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide (SB-357134)

Article abstract of DOI:10.1016/S0960-894X(00)00597-7

Substituted N-phenyl-4-methoxy-3-piperazin-1-ylbenzenesulfonamides and conformationally restricted analogues have been identified as high affinity and selective 5-HT₆ antagonists. Compounds from this series had a range of pharmacokinetic profiles in rat and in general there was a correlation between clearance and CNS penetration. Based on its overall biological profile 2 (SB-357134) was selected for further pre-clinical evaluation. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0960-894X(00)00597-7

Bioorganic & Medicinal Chemistry Letters 11 (2001) 55±58
Phenyl Benzenesulfonamides are Novel and Selective 5-HT6
Antagonists: Identi®cation of N-(2,5-Dibromo-3-¯uorophenyl)-
4-methoxy-3-piperazin-1-ylbenzenesulfonamide (SB-357134)
Steven M. Bromidge,a,* Stephen E. Clarke,b Tracey Gager,c Kerry Grith,a
Phillip Je€rey,b Andrew J. Jennings,a Graham F. Joiner,a Frank D. King,a
Peter J. Lovell,a Stephen F. Moss,a Helen Newman,c Graham Riley,c
Derek Rogers,c Carol Routledge,c Halina Sera®nowskaa and Douglas R. Smithb
aDiscovery Chemistry Europe, SmithKline Beecham Pharmaceuticals, Discovery Research,
New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
bDepartment of Drug Metabolism and Pharmacokinetics, SmithKline Beecham Pharmaceuticals,
Discovery Research, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
cDepartment of Neurosciences Research, SmithKline Beecham Pharmaceuticals, Discovery Research,
New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
Received 21 August 2000; revised 16 October 2000; accepted 20 October 2000
AbstractÐSubstituted N-phenyl-4-methoxy-3-piperazin-1-ylbenzenesulfonamides and conformationally restricted analogues have
been identi®ed as high anity and selective 5-HT6 antagonists. Compounds from this series had a range of pharmacokinetic pro®les
in rat and in general there was a correlation between clearance and CNS penetration. Based on its overall biological pro®le 2 (SB-
357134) was selected for further pre-clinical evaluation. # 2000 Elsevier Science Ltd. All rights reserved.
The 5-HT6 receptor is the latest serotonin receptor to be
identi®ed by molecular cloning. The intriguing distribu-
tion in the brain, together with its high anity for a wide
range of drugs used in psychiatry, has stimulated sig-
ni®cant recent interest.1 In particular a possible role for
5-HT6 antagonists in the treatment of learning and mem-
ory disorders has been suggested.1 3 We have recently
disclosed2,4 the sulfonamide 1 (SB-271046) as a potent and
selective 5-HT6 antagonist which is currently in phase 1
clinical trials for the treatment of cognitive disorders. This
compound has been demonstrated to selectively enhance
excitatory transmission within the frontal cortex5 and to
enhance the retention of memory in rats.3
Chemistry
We now report the discovery and structure±activity
relationships (SAR) of a structurally distinct series of N-
phenyl-4-methoxy-3-piperazin-1-ylbenzenesulfonamides
such as 2 (SB-357134) which are also high anity and
selective 5-HT6 receptor antagonists with good oral
bioavailability in rats.
The ®nal compounds were prepared according to
Scheme 1.6 1-(2-Methoxyphenyl)-4-trichloroacetylpiper-
azine, prepared from commercially available 1-(2-meth-
oxyphenyl)piperazine, was treated with chlorosulfonic
acid to give the key intermediate sulfonyl chloride 3 in
79% overall yield. Coupling of 3 with the appropriate
anilines a€orded the trichloroacetylsulfonamides 4 in
reaction times and yields that were dependent on the
reactivity of the anilines. Removal of the protecting
*Corresponding author. Tel.: +44-1279-627684; fax: +44-1279-
622550; e-mail: steve_bromidge-1@sbphrd.com
0960-894X/01/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00597-7

56
S. M. Bromidge et al. / Bioorg. Med. Chem. Lett. 11 (2001) 55±58
Scheme 1. Reagents and conditions: (i) CCl3COCl/iPr2NEt, CH2Cl2, rt, 18 h (84%); (ii) ClSO3H, 0 ꢀC, 1 h (94%); (iii) pyridine, CH2ClCH2Cl,
re¯ux, 1±48 h (25±95%); (iv) 1 M aq KOH, THF, rt, 18 h (90%).
group under basic conditions a€orded the ®nal com-
pounds (2, 5±33) in ecient yields. Compounds 34±43
were prepared similarly by reacting 3 with the appro-
priately substituted indolines, tetrahydroquinolines and
tetrahydroisoquinolines.6 All the amines and anilines
were commercially available or prepared by methods
known in the literature.
binding pro®les (11±15). In contrast, 2,4- and 3,4-di-
substitution was less favoured (18±20) as was incor-
poration of polar substituents (17). A number of these
compounds were demonstrated to be antagonists in a
functional model of 5-HT6 receptor activation.4
Table 1. 5-HT6 receptor binding anity and selectivitya of sub-
stituted phenyl benzenesulfonamides 2, 5±33
Results and Discussion
As part of our SAR studies around bisaryl sulfonamides
such as 1, we investigated a number of modi®cations to
the sulfonamide linker group including simply reversing
the linker. Molecular modelling indicated that such
compounds could adopt a low energy conformation
very similar to that obtained with 1 (Fig. 1) although
signi®cant di€erences in electrostatic properties were
anticipated.
R
pKi
5-HT6
Selectivity versus 13
receptor subtypes
Compound
2
3
4
5
6
5
6
7
8
Br
iPr
8.8
9.0
8.9
8.9
9.3
8.7
9.2
9.3
9.0
8.9
9.1
8.4
7.7
7.6
8.1
8.6
6.8
8.7
8.3
8.7
8.6
8.5
8.7
8.4
8.6
8.4
8.6
8.5
8.5
7.5
400
500
630
630
400
160
1250
1600
2000
400
1000
60
Ð
Ð
<50
200
Ð
400
500
500
400
320
800
320
400
250
320
1300
1600
Ð
Cl
Br
I
A wide range of variously substituted N-aryl-4-meth-
oxy-3-piperazin-1-ylbenzenesulfonamides were prepared
by parallel synthesis and many of these compounds
were found to demonstrate excellent binding pro®les. In
this series substituted phenyl left-hand sides (LHS) were
optimal and a selection of these is illustrated in Table 1.
A range of lipophilic aromatic LHS groups were toler-
ated giving compounds with high 5-HT6 anity and
>100-fold selectivity over other serotinergic and dopa-
minergic receptors (totalling 13 subtypes: see Table 4).
Halogen substitution at the 2- or 3-positions (e.g., 5, 7±
9) was favourable compared to 4-substitution (10) and
3,5- and 2,5-disubstitution gave particularly impressive
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
2
I
Cl
Br
Cl
Br
Br
Cl
Br
OMe
Me
OMe
Me
I
CF3
NO2
CF3
Br
Cl
Me
Cl Cl
Br
F
OMe
Cl
F
Cl Me
Cl
Cl
Cl
Br
Cl
Cl
Br
Br
Br
Br
Br
Br
F
Cl
Cl
Br
Cl
Br
Cl
Br
Cl
Br
F
Br
Br
Cl
Cl
Cl
Br
F
Br
Cl
32
33
F
F
Cl
aSelectivity was determined against the 13 receptor subtypes detailed
in Table 4.
Figure 1. Overlap of low energy conformations of 1 (dark) and 8 (light).

S. M. Bromidge et al. / Bioorg. Med. Chem. Lett. 11 (2001) 55±58
Table 2. The pharmacokinetic pro®les of bisaryl sulfonamides in rat
57
The pharmacokinetic pro®le of several of these com-
pounds was assessed in rats (Table 2). Monosubstituted
analogues such as 5, 6 and 9 were very rapidly cleared
in vivo. In contrast, the 3,5-dichloro-analogue 11
demonstrated very low clearance and excellent oral
bioavailability. However, the brain to blood ratio at
steady state (n=3, following 8 h iv infusion) was very low
(2%). In contrast, the 2,5-dibromo-analogue 13, which
had a similar in vitro binding pro®le to 11, was found to
have much improved CNS penetration (38%) but sig-
ni®cantly higher clearance.
Compound
CLb iva
(mL/min/Kg)
AUC/dose po
(mM min/mmol)
Fpo
(%)
Brain:
blood
1
2
5
6
8
14
60
52
58
4
43
2
73
83
76
300 Æ 80b
130Æ11c
82Æ16b
65Æ11c
0.10
0.19
0.24
NQf
0.13
0.02
0.38
0.02
0.41
NQ
9
11
13
24
36
41
42
450Æ60d
17Æ4e
51Æ9d
20 est.e
>80 est.e
2450Æ200e
In an e€ort to combine the metabolic stability of the 3,5-
disubstituted analogues with the apparently enhanced
CNS penetration of the ortho-substituted analogues, a
series of 2,3,5-trisubstituted analogues was prepared
(Table 1). Most of these compounds had good 5-HT6
anity and exceptional selectivity, and several were
further pro®led in vivo (Table 2). The 2,3,5-trichloro
sulfonamide 24 demonstrated a similar pharmacokinetic
pro®le to 11 with extremely low clearance (2 mL/min/
kg) but correspondingly low brain to blood ratio
(2%). In contrast, the 2,5-dibromo-3-¯uoro-analogue 2
showed markedly improved CNS penetration (19%)
combined with increased but still low clearance (14 mL/
min/kg) and excellent oral bioavailability. The 2,4,5-
analogues 22±23 and the 2,4,6-analogue 21 had reduced
5-HT6 anity and selectivity.
0.10
aMeasured at steady-state following iv infusion at 0.6 mg/kg/h (n=1);
blood drug levels were determined by LC/MS/MS.
b
eFollowing oral (suspension) dose (n=3); blood drug levels were
determined by LC/MS/MS.
b10 mg/kg in 10% (w/v) EncapsinTM and 2% DMSO (v/v) aq.
c2 mg/kg in 1% methylcellulose (v/v) aq.
d10 mg/kg in 1% methylcellulose (v/v) aq.
e3 mg/kg in 1% methylcellulose (v/v) aq.
fNQ, non quanti®able.
Table 3. 5-HT6 receptor binding anity and selectivitya of con-
formationally restricted bisaryl sulfonamides 34±43
In an attempt to further increase the brain penetration of
these compounds, conformationally restricted indoline,
tetrahydroquinoline and tetrahydroisoquinoline analogues
Table 4. Receptor binding pro®le of compounds 2, 13, 24 and 34a
Anity (pKi)
Compound
Ar
pKi 5-HT6
Selectivity versus 13
receptor subtypes
Receptor
2
13
24
5.4
<5.0
<5.5
<5.0
<5.0
<5.0
5.7
34
6.3
5.9
6.7
<5.0
<5.1
<5.4
6.2
6.2
5.4
34
35
36
37
38
39
40
9.5
8.4
8.4
9.1
9.5
8.5
9.1
630
60
5-HT1A
5-HT1B
5-HT1D
5-HT1E
5-HT1F
5-HT2A
5-HT2B
5-HT2C
5-HT4
<5.2
<5.4
<5.4
<5.0
<5.0
<5.1
<5.4
<5.3
<5.3
8.54Æ0.03
(n=9)
<5.0
<5.1
<5.3
<5.3
<5.5
<5.3
<5.8
<5.0
<5.0
<5.0
<5.5
<5.3
5.5
8.99Æ0.08
(n=6)
<5.4
<5.7
<5.0
<5.3
160
1000
400
200
250
6.0
<5.0
8.7Æ0.03
(n=3)
<5.0
<5.4
<5.0
<5.4
5-HT6
9.5Æ0.1
(n=3)
7.0
5-HT7
Adrenergic a1B
Dopaminergic D2
Dopaminergic D3
6.0
5.6
6.0
aAll values represent the mean of at least two determinations, with
each determination lying within 0.2 log unit of the mean. Receptors
and radioligands used in binding assay: 5-HT1A (human cloned
receptors in HEK 293 cells; [3H]-8-OH-DPAT); 5-HT1B (human
cloned receptors in CHO cells; [3H]-5-HT); 5-HT1D (human cloned
receptors in CHO cells; [3H]-5-HT); 5-HT1E (human cloned receptors
in CHO cells; [3H]-5-HT); 5-HT1F (human cloned receptors in CHO
cells; [3H]-5-HT); 5-HT2A (human cloned receptors in HEK 293 cells;
[3H]-ketanserin); 5-HT2B (human cloned receptors in HEK 293 cells;
[3H]-5-HT); 5-HT2C (human cloned receptors in HEK 293 cells; [3H]-
mesulergine); 5-HT6 (human cloned receptors in HeLa cells; [3H]-
LSD); 5-HT7 (human cloned receptors in HEK 293 cells; [3H]-5CT);
D2 (human cloned receptors in CHO cells; [125I]-iodosulpride); D3
(human cloned receptors in CHO cells; [125I]-iodosulpride).
41
42
8.9
9.3
200
800
43
8.8
100
aSelectivity was determined against the 13 receptor subtypes detailed
in Table 4.

58
S. M. Bromidge et al. / Bioorg. Med. Chem. Lett. 11 (2001) 55±58
were prepared in the expectation that replacing the
polar sulfonamide NH would increase CNS pene-
tration. A number of these analogues maintained
excellent binding anity and selectivity (Table 3) and
the 6-iodoindoline 34 and the 7-bromotetrahydro-quin-
oline 38 demonstrated the highest 5-HT6 anities yet
achieved. Unfortunately, compounds from this series
such as 36, 41 and 42 had in vivo clearances in rat equal
or greater than liver blood-¯ow (Table 2). In general in
this series, attempts to increase CNS penetration by
increasing lipophilicity have also led to increases in the
in vivo clearance.
kinetic pro®les in rat and in general there was a positive
correlation between clearance and CNS penetration.
Based on its overall biological pro®le 2 (SB-357134) was
selected for further pre-clinical evaluation.
References
1. Branchek, T. A.; Blackburn, T. P. Annu. Rev. Pharmacol.
Toxicol. 2000, 40, 319.
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Hirst, W. D.; Newman, H.; Riley, G.; Gager, T.; Brown, A.
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J.; Routledge, C.; Hagan, J. J. Br. J. Pharmacol. 1999, 127
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Summary
4. Bromidge, S. M.; Brown, A. M.; Clarke, S. E.; Dodgson,
K.; Gager, T.; Grassam, H. L.; Je€rey, P. M.; Joiner, G. F.;
King, F. D.; Middlemiss, D. N.; Moss, S. F.; Newman, H.;
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September, 1999.
A number of substituted N-phenyl-4-methoxy-3-piper-
azin-1-ylbenzenesulfonamides and conformationally
restricted analogues have been identi®ed with excellent
5-HT6 anity and selectivity over a range of ser-
otonergic and dopaminergic receptors (Table 4). In a
human 5-HT6 functional assay they were found to be
full antagonists with no evidence of intrinsic activity.
Compounds from this series had a range of pharmaco-