(Arylpiperazinyl)cyclohexylsufonamides: Discovery of α1a/1d-selective adrenergic receptor antagonists for the treatment of Benign Prostatic Hyperplasia/Lower Urinary Tract Symptoms (BPH/LUTS)

Article abstract of DOI:10.1016/j.bmcl.2007.04.008

Benign Prostatic Hyperplasia/Lower Urinary Tract Symptoms (BPH/LUTS) can be effectively treated by α₁-adrenergic receptor antagonists. Unfortunately, all currently marketed α₁ blockers produced CV related side effects that are caused by the subtype non-selective nature of the drugs. To overcome this problem, it was postulated that a α_1a/1d subtype selective antagonist would bring more benefit for the treatment of BPH/LUTS. In developing selective α_1a/1d ligands, (arylpiperazinyl)cyclohexylsulfonamides were synthesized and their binding profiles against three cloned human α₁-adrenergic receptor subtypes were evaluated. Many compounds show equal affinity for both α_1a and α_1d subtypes with good selectivity against the α_1b subtype. They also overcome the problem of dopamine receptor affinity that previous analogues had exhibited.

Full text of DOI:10.1016/j.bmcl.2007.04.008

Bioorganic & Medicinal Chemistry Letters 17 (2007) 3292–3297
(Arylpiperazinyl)cyclohexylsufonamides: Discovery of
1a/1d-selective adrenergic receptor antagonists for the treatment
of Benign Prostatic Hyperplasia/Lower Urinary Tract
Symptoms (BPH/LUTS)
a
George Chiu,*, Shengjian Li,à Peter J. Connolly,à Virginia Pulito,§ Jingchun Liu
and Steven A. Middleton–
Johnson & Johnson Pharmaceutical Research and Development L.L.C., PO Box 300, 1000 Route 202 South, Raritan, NJ 08869, USA
Received 6 January 2007; revised 31 March 2007; accepted 4 April 2007
Available online 10 April 2007
Abstract—Benign Prostatic Hyperplasia/Lower Urinary Tract Symptoms (BPH/LUTS) can be effectively treated by a1-adrenergic
receptor antagonists. Unfortunately, all currently marketed a1 blockers produced CV related side effects that are caused by the sub-
type non-selective nature of the drugs. To overcome this problem, it was postulated that a a1a/1d subtype selective antagonist would
bring more benefit for the treatment of BPH/LUTS. In developing selective a1a/1d ligands, (arylpiperazinyl)cyclohexylsulfonamides
were synthesized and their binding profiles against three cloned human a1-adrenergic receptor subtypes were evaluated. Many
compounds show equal affinity for both a1a and a1d subtypes with good selectivity against the a1b subtype. They also overcome
the problem of dopamine receptor affinity that previous analogues had exhibited.
Ó 2007 Elsevier Ltd. All rights reserved.
The increasing elderly population within society has
caused healthcare givers and the pharmaceutical indus-
try to spend more effort on age related diseases such
as Benign Prostatic Hyperplasia (BPH). The prostate
is a male sex auxiliary gland situated just below the blad-
der and surrounding the urethra. Excessive growth of
the prostate with age will result in BPH, which causes
obstruction of the bladder outlet and eventually leads
to Lower Urinary Tract Symptoms (LUTS). These
symptoms include increased urinary frequency, de-
creased urine stream, increased urgency and feeling of
irritation, and sensation of incomplete bladder empty-
ing.1,2 As a urological disorder, BPH/LUTS is not a
life-threatening disease, but it has adverse impacts on
the patient’s life style.
Several methods for the treatment of BPH/LUTS may
be chosen, depending on the severity of the disease. In
addition to surgery (prostatectomy), drug interventions
are also available. Since there are two pathological com-
ponents in BPH, namely the increased size and elevated
muscle tone of prostate gland, medication for BPH/
LUTS has been classified into two categories. The first
category, 5-a-reductase inhibitors (finasteride and
dutasteride), work by reducing the size of prostate;
another category, a1-adrenergic receptor antagonists
(tamsulosin and terazosin), work by relaxing prostate
smooth muscle. Unlike 5-a-reductase inhibitors that
take considerable time to show results, the a1 blockers
can provide effective relief of symptoms in very short
period of time. Unfortunately, the advantage of using
a1 blockers for treatment of BPH/LUTS is limited by
the fact that all a1 drugs currently on the market also
produce significant side effects, specifically, the cardio-
vascular-associated orthostatic hypotension.3,4
Keywords: BPH/LUTS; a1-Adrenergic receptors; a1a/1d Subtype selec-
tive antagonist; (Arylpiperazinyl)cyclohexylsulfonamides.
*
Corresponding author. Tel.: +1 908 231 2925; fax: +1 908 231
4203; e-mail: George.Chiu@sanofi-aventis.com
Present address: Sanofi-Aventis, 1041 Route 202–206, PO Box 6800,
Bridgewater, NJ 08807, USA.
à
Present address: Johnson & Johnson Pharmaceutical Research and
Development L.L.C., 8 Clark Drive, Cranbury, NJ 08512, USA.
§
Present address: Wyeth Research, 865 Ridge Road, Monmouth
Junction, NJ 08852, USA.
–
Present address: Hoffmann-La Roche, Inc., 340 Kingsland Street,
Bldg. 76/5E11, Nutley, NJ 07110, USA.
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.04.008

G. Chiu et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3292–3297
3293
Since late 1980s, molecular biology studies have identi-
fied three a1-adrenergic receptor subtypes, classified as
a1a, a1b, and a1d.5–7 Current a1 blocking drugs are
known to bind to all of them relatively indiscriminately.8
It is speculated that orthostatic hypotension is caused by
the subtype non-selective nature of present a1 blockers.8
Further studies also revealed that among three a1 sub-
types, the a1a-adrenoceptor subtype plays a dominant
role in controlling human prostatic smooth muscle con-
traction,8 but the exact contribution of each subtype to
the orthostatic hypotension is not yet clearly deter-
mined. Many a1a-adrenoceptor subtype selective antag-
onists have since been discovered, and they have
demonstrated the ability to relax prostate muscle in ani-
mals without producing cardiovascular side effects.9a–c
Surprisingly, in subsequent clinical trials, these a1a selec-
tive compounds have not proven to be effective in reliev-
ing LUTS, especially the symptom of irritation. This is
in sharp contrast to their subtype non-selective counter-
parts10 and strongly suggests that, in addition to the a1a
subtype, other a1 receptor subtype(s) may be implicated
in BHP/LUTS.
a1a/1d subtype selective antagonists, with superior selec-
tivity profile compared to marketed drug tamsulosin.
In our previous papers,14 we reported the discovery of
a series of (phenylpiperazinyl)cyclohexylphthalimides
(2). These compounds showed equal affinity for both
a1a and a1d subtypes, with good selectivity against the
a1b subtype. Unfortunately, they also interacted with
the dopamine D2 receptor.15 In this paper, we report
our efforts to overcome this problem through the design
and synthesis of a series of (arylpiperazinyl)cyclohexyl-
sulfonamides (3), and the evaluation of their subtype
selectivities for cloned human a1a-, a1b-, and a1d-adren-
ergic receptors. As will be shown, compounds not only
possess excellent a1a/1d affinity and selectivity, but also
show much reduced dopamine activity (Fig. 1).
The (phenylpiperazinyl)cyclohexylsulfonamides (X =
CH) were prepared by the following general sequence
(Scheme 1). The appropriately substituted phenylpiper-
t
azine was subjected to reductive amination with Boc
protected 4-aminocyclohexanone to give a cis/trans mix-
ture of diaminocyclohexane intermediates. Treatment
with TFA produced the corresponding free amine,
which was sulfonylated by various sulfonyl chlorides.
Final chromatographic separation gave the individual
isomer.16,18 The related (pyridine-2-ylpiperazinyl)cyclo-
hexylsulfonamides (X = N) were prepared by the same
synthetic route starting from substituted (pyridine-2-
yl)piperazines.17
For the past several years, many studies have provided
evidence indicating that the a1d subtype is involved in
the mediation of LUTS.11a–c There are also experimental
data suggesting that a1b subtype may be associated with
CV related side effects.12 On the other hand, tamsulosin
(1), a moderately a1a/1d selective drug is capable of treat-
ing both BPH and LUTS. These results led to the forma-
tion of new hypothesis that, rather than non-selective or
pure a1a selective drug, an antagonist with balanced a1a/1d
selectivity profile will be efficacious yet produce less side
effects, hence rendering optimum benefit for BPH/LUTS
patients.13a–e Unfortunately, providing convincing proof
for this hypothesis has been unsuccessful, due to the fact
that no a1 antagonist with high selectivity for the a1a/1d
subtypes is currently available.
We first investigated analogues with mono-substituted
sulfonamide aryl ring (4). In addition to binding affinity
for the a1-adrenoceptor subtypes, each analogue’s dopa-
mine D2 affinity was evaluated. For this series, we ob-
served striking differences in affinity and selectivity
profiles between cis and trans isomers (e.g., cis-5 vs
trans-5, cis-9 vs trans-9, and cis-13 vs trans-13). Gener-
ally speaking, trans isomers had relatively weaker affin-
ity toward the a1d subtype. This made cis-isomers more
desirable compounds since they had a1a/1d selectivity
profiles closer to the desired 1:1 ratio. Although it is
difficult to outline any SAR from such limited number
of compounds, several analogues with electron
We initiated a research program to validate this hypoth-
esis by first discovering a1a/1d selective compounds, then
studying them in established animal models. Our pri-
mary goal was to design and synthesize potent and
SO2NH2
O
O
O
O
N
N
N
R
N
H
O
O
2
tamsulosin (1)
O
S
R1
N
N
N
O
X
H
R2
3
Figure 1. The structure of tamsulosin, compound 2 and 3.

3294
G. Chiu et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3292–3297
O
NHBoc
b
N
N
NHBoc
N
NH
a
X
R1
X
R1
O
S
N
H
R2
c
O
N
N
NH2
N
N
X
X
R1
R1
d
O
O
R2
+
R2
S
S
H
O
O
N
N
N
N
N
N
X
H
R1
X
R1
Scheme 1. Reagents and conditions: (a) Na(AcO)3BH, HOAc, CH2Cl2, rt, 8 h, 40–65% yield; (b) CF3CO2H/CH2Cl2, rt, 2 h, 90–100% yield;
(c) sulfonyl chloride/CH2Cl2/Na2CO3 (aq), rt, 8 h, 60–90% yield; (d) SiO2 column or prep. TLC.
Table 1. Binding profiles of analogues with mono-substituted sulfonamide aryl ring 4 (Ki, nM)
O
O
X
S
O
N
N
N
H
4
Compound
Configuration
X
a1a
0.19
13.7
a1b
a1d
0.2
5.2
55
D2
1
5
2.0
111
Cis16
Trans16
Cis
H
191
34
H
2.7
9.6
487
217
31
6
2-CN
2-CN
2-F
2-F
6.3
3.2
2.4
55
Trans
Cis
0.77
5.6
2.4
7
103
385
201
236
108
545
222
334
150
301
195
392
174
1254
149
31
Trans
Cis
0.88
6.3
30
2.5
27
8
2-NO2
2-NO2
3-F
51
86
Trans
Cis
1.0
3.5
9
3.3
24.5
1.4
35
74
64
Trans
Cis
3-F
0.73
10
11
12
13
3-CF3
3-CF3
4-F
14
20
5.6
118
39
Trans
Cis
4.8
36
69
27
Trans
Cis
4-F
1.3
4.8
7.5
4-SO2Me
4-SO2Me
4-OCF3
4-OCF3
3.4
22
122
14
Trans
Cis
Trans
17
100
2.1
430
58
111
withdrawing groups showed equal affinity for a1a and
a1d subtypes, with good selectivity against the a1b sub-
type (6, 8, 9, and 12). Their a1a/a1b ratios ranged from
23- to 40-fold, and their a1d/a1b ratios ranged from 33-
to 80-fold. This represents an improvement over the
10-fold a1a/a1b ratio shown by commercial drug tamsul-
osin (1). Perhaps the most encouraging trend we
observed was that many (phenylpiperazinyl)cyclohexyl-
sulfonamides had much reduced dopamine affinities,
which were difficult to remove from our previously
investigated a1a/1d selective antagonists15 (Table 1).
We next concentrated our efforts on analogues with di-
substituted sulfonamide aryl ring (4). The binding study
results are summarized in Table 2. Once again, cis iso-
mers exhibit more favorable a1a/1d selectivity ratios
(i.e., closer to the desired 1:1 ratio) than trans isomers,
although again no apparent relationship between substi-
tution pattern and affinity was observed. However, com-
pared with the mono-substituted series, di-substituted
analogues showed an even better selectivity profile, espe-
cially compounds 14, 18, and 23. Their a1a/a1b ratios
ranged from 70-fold to more than 300-fold, and their

G. Chiu et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3292–3297
3295
Table 2. Binding profiles of analogues with di-substituted sulfonamide aryl ring 4 (Ki, nM)
O
O
X
S
O
N
N
N
H
4
Compound
Configuration
X
a1a
1.6
23
8.7
a1b
a1d
1.0
24
5.1
D2
94
14
Cis
3,4-diOMe
3,4-diOMe
2,5-diOMe
2,5-diOMe
2-MeO-5-Me
2-MeO-5-Me
2-MeO-5-F
2-MeO-5-F
2-MeO-5-Cl
2-MeO-5-Cl
2-MeO-5-Br
2-MeO-5-Br
109
126
153
424
162
218
162
714
78
Trans
Cis
62
81
15
16
17
18
19
20
21
22
23
24
25
Trans
Cis
17
18
56
7
62
110
50
Trans
Cis
0.9
6.0
11
31
5.0
66
0.75
11
0.8
173
139
101
78
Trans
Cis
1.0
3.8
1.6
Trans
Cis
250
42
37
36
Trans
Cis
10
131
473
258
85
38
14
15
2-MeO-5-CF3
2-MeO-5-CF3
2-MeO-5-NO2
2-MeO-5-NO2
3-Cl-4-Me
3-Cl-4-Me
2,4-diCl
36
25
194
Trans
Cis
1.9
4.3
1.0
11
2.2
45
18
Trans
Cis
173
167
193
177
596
120
348
101
243
22
11
16
60
52
Trans
Cis
1.5
4.5
1.6
0.64
42
76
Trans
Cis
2,4-diCl
3-Cl-2-F
8.6
6.2
12
0.56
11
3.0
198
271
130
42
Trans
Cis
3-Cl-2-F
4-Cl-2-F
4-Cl-2-F
24
1.5
19
Trans
a1d/a1b ratios ranged from 60- to 270-fold. 3,4-dime-
thoxy substituted compound cis-14 and 2-methoxy-5-
chloro substituted compound cis-18 also showed very
good selectivity against the D2 receptor. These com-
pounds are the a1a/a1d selective antagonist that met
our initial goal. Their structural features lay a solid
foundation for the further development of new BPH/
LUTS drugs.
able PK properties, we decided to incorporate a
pyridine group into the scaffold. Several analogues
were designed following the best substitution patterns
in sulfonamide portion. In this series, only the cis iso-
mers were prepared and are reported in Table 3. Judg-
ing from these binding data, it was very clear that in
most cases, replacement of the phenyl ring with pyrid-
inyl has a detrimental effect on binding affinity; even
the best analogue in this series, 27 is much weaker
than its phenyl counterpart 18. It is possible that
under physiological conditions, this part of receptor
To increase water solubility of (phenylpiperazi-
nyl)cyclohexylsulfonamides and potentially gain favor-
Table 3. Binding profiles of pyridine containing analogues 26–31 (Ki, nM)
R
O
O
X
S
O
N
N
N
H
N
Compound
R
X
a1a
a1b
112
a1d
D2
26
27
28
29
30
31
i-Pr
i-Pr
3,4-diOMe
2-MeO-5-Cl
2-F-5-Cl
61
11
19
12
15
64
48
44
810
259
356
123
588
425
399
1855
364
i-Pr
45
c-PrCH2
c-PrCH2
c-PrCH2
3,4-diOMe
2-MeO-5-Cl
2-F-5-Cl
189
19
601
952
36

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G. Chiu et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3292–3297
Table 4. Binding profiles of compounds 32–35 (Ki nM)
N
O
O
O
O
S
S
O
O
N
N
N
H
N
N
N
H
33
32
Br
Cl
O
N
N
O
O
O
O
S
S
O
O
N
N
N
N
N
H
N
H
34
35
Compound
Configuration
a1a
1.2
a1b
a1d
3.6
D2
32
Cis
82
200
400
192
169
268
125
279
24
71
15
55
92
43
61
80
Trans
Cis
3.9
5.0
12
46
33
34
35
Trans
Cis
5.8
4.9
5.5
9.4
76
0.14
14.6
Trans
Cis
13.4
14.4
3.5
Trans
does not favor a positively charged aromatic ring. We
speculated that the iso-propoxy group could be a
metabolic weak point for these molecules, and there-
fore we decided to replace it with cyclopropylmethoxy
group. The binding data show that compounds with a
cyclopropylmethoxy group are slightly inferior to their
iso-propoxy counterparts, perhaps due to a strict size
or electronic requirement in this part of the a1a and
a1d binding pockets.
selectivity for these compounds were evaluated in
cloned human a1a-, a1b-, and a1d-adrenergic receptor
subtypes. The effect of aromatic substitution on their
affinity and selectivity was investigated. We discovered
several compounds (cis-8, -9, -12, -14, -18, and -23)
that showed equally high affinity for both a1a- and
a1d-adrenoceptor subtypes, with good selectivity
against the a1b subtypes. Among these compounds,
cis-14 and -18 also had respectable selectivity over
the dopamine D2 receptor in addition to their excel-
lent a1a/1d selectivity. This selectivity profile is a great
improvement over the commercial drug tamsulosin,
and we believe this discovery has enriched our knowl-
edge about a1 blockers and will eventually lead to the
development of a1a/1d selective drug for the treatment
of BPH/LUTS. Future work will be concentrating on
improvement of PK properties and progress will be re-
ported in due course.
Finally, we prepared and tested several related com-
pounds, including benzylsulfonamide 32 and pyridyl-
sulfonamides 33, 34, and 35 (Table 4). Extending
phenylsulfonamide 5 by one carbon unit gave benzyl-
sulfonamide 32, which had better affinity and selectiv-
ity than phenylsulfonamide 5. Unfortunately, this
change also gave the compound higher dopamine
affinity. To increase the compound’s water solubility,
we replaced the sulfonamide phenyl ring in 5 with a
pyridine. The resulting unsubstituted compound cis-
33 lost substantial a1d affinity. Interestingly, the trans
isomer of 33 is a better a1a/1d antagonist than cis iso-
mer, a very rare phenomenon. Addition of a methoxy
group to 33 gave 34, which improved the affinity (cis-
34 vs cis-33), but still was inferior to our benchmark
compounds cis-14 and -18. Introduction of chloro
and bromo groups to the pyridine gave 35, which
resulted in loss of affinity in the a1a subtype.
Acknowledgments
We want to express our gratitude to Ms Sally Varga, Ms
Aida Howells, and Dr. Alexandra Shedlow for their
technical assistance in this research.
Supplementary data
In conclusion, to discover an a1a/1d selective antago-
nist as a new drug for the treatment of BPH/LUTS,
we have designed and synthesized a series of (arylpip-
erazinyl)cyclohexylsulfonamides. Binding affinity and
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.bmcl.
2007.04.008.

G. Chiu et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3292–3297
3297
16. The isomer with the higher Rf value by TLC is the cis
isomer. The isomer with lower Rf value is the trans isomer.
This has been determined by 2-D NMR and confirmed by
X-ray structure determination.
References and notes
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18. NMR and MS data of representative compounds. Cis-5
NMR: d (CDCl3) 1.32 (d, J = 6.0 Hz, 6H), 1.47 (m, 2H),
1.55 (m, 2H), 1.68 (m, 4H), 2.22 (m, 1H), 2.65 (m, 4H),
3.08 (br s, 4H), 3.45 (m, 1H), 4.56 (m, 1H), 4.92 (d,
J = 6.5 Hz, NH, 1H), 6.8–8.0 (m, 9H). MS: 458 (M+1).
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Trans-5 NMR:
d (CDCl3) 1.22 (m, 4H), 1.33 (d,
J = 6.1 Hz, 6H), 1.90 (m, 4H), 2.23 (m, 1H), 2.67 (m,
4H), 3.08 (br s, 5H), 4.57 (m, 1H), 4.65 (d, J = 7.0 Hz, NH,
1H), 6.8–8.0 (m, 9H). MS: 458 (M+1). Cis-14 NMR: d
(CDCl3) 1.32 (d, J = 6.1 Hz, 6H), 1.4–1.8 (m, 8H), 2.21 (m,
1H), 2.63 (br s, 4H), 3.06 (br s, 4H), 3.39 (m, 1H), 3.92 (s,
3H), 3.94 (s, 3H), 4.60 (m, 1H), 4.82 (d, J = 6.5 Hz, NH,
1H), 6.8–7.6 (m, 7H). MS: 558 (M+). Trans-14 NMR: d
(CDCl3) 1.24 (m, 4H), 1.34 (d, J = 6.2 Hz, 6H), 1.92 (m,
4H), 2.22 (m, 1H), 2.68 (m, 4H), 3.05 (br s, 5H), 3.92 (s,
3H), 3.94 (s, 3H), 4.62 (m, 1H), 4.75 (d, J = 6.5 Hz, NH,
1H), 6.8–7.6 (m, 7H). MS: 558 (M+1). Cis-17 NMR: d
(CDCl3) 1.33 (d, J = 6.2 Hz, 6H), 1.45 (m, 2H), 1.60 (m,
2H), 1.71 (m, 4H), 2.27 (m, 1H), 2.71 (br s, 4H), 3.14 (br s,
4H), 3.39 (m, 1H), 3.98 (s, 3H), 4.62 (m, 1H), 5.05 (d,
J = 7.0 Hz, NH, 1H), 6.8–7.8 (m, 7H). MS: 506 (M+1).
Trans-17 NMR: d (CDCl3) 1.24 (m, 4H), 1.35 (d,
J = 6.1 Hz, 6H), 1.94 (m, 4H), 2.27 (m, 1H), 2.70 (m,
4H), 3.10 (br s, 5H), 3.98 (s, 3H), 4.57 (m, 1H), 4.82 (d,
J = 6.5 Hz, NH, 1H), 6.8–7.8 (m, 7H). MS: 506 (M+1).
Cis-18 NMR: d (CDCl3) 1.32 (d, J = 6.1 Hz, 6H), 1.47
(m, 2H), 1.59 (m, 2H), 1.71 (m, 4H), 2.22 (m, 1H), 2.68 (m,
4H), 3.09 (br s, 4H), 3.40 (m, 1H), 3.95 (s, 3H), 4.57 (m,
1H), 4.83 (d, J = 6.9 Hz, NH, 1H), 6.8–8.0 (m, 7H). MS:
522 (M+1). Trans-18 NMR: d (CDCl3) 1.23 (m, 4H), 1.34
(d, J = 6.0 Hz, 6H), 1.89 (m, 4H), 2.23 (m, 1H), 2.68 (m,
4H), 3.05 (br s, 5H), 3.96 (s, 3H), 4.58 (m, 1H), 4.80 (d,
J = 7.0 Hz, NH, 1H), 6.8–8.0 (m, 7H). MS: 522 (M+1).
Cis-32 NMR: d (CDCl3) 1.33 (d, J = 6.0 Hz, 6H), 1.55 (m,
4H), 1.64 (m, 2H), 1.78 (m, 2H), 2.22 (m, 1H), 2.66 (m,
4H), 3.08 (br s, 4H), 3.41 (m, 1H), 4.20 (d, J = 7.1 Hz, NH,
1H), 4.22 (s, 2H), 4.58 (m, 1H), 6.8–7.5 (m, 9H). MS: 472
(M+1). Trans-32 NMR: d (CDCl3) 1.20 (m, 4H), 1.33 (d,
J = 6.1 Hz, 6H), 1.95 (bd, 2H), 2.05 (bd, 2H), 2.23 (m,
1H), 2.70 (m, 4H), 3.03 (m, 1H), 3.10 (br s, 4H), 3.95 (d,
J = 7.1 Hz, NH, 1H), 4.23 (s, 2H), 4.56 (m, 1H), 6.8–7.5
(m, 9H). MS: 472 (M+1).
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15. Unpublished results.