Analgesic agents without gastric damage: Design and synthesis of structurally simple benzenesulfonanilide-type cyclooxygenase-1-selective inhibitors

Article abstract of DOI:10.1016/j.bmc.2006.10.029

In order to create novel analgesic agents without gastric disturbance, structurally simple cyclooxygenase-1 (COX-1) inhibitors with a benzenesulfonanilide skeleton were designed and synthesized. As a result, compounds 11f and 15a, which possess a p-amino group on the benzenesulfonyl moiety and p-chloro group on the anilino moiety, showed COX-1-selective inhibition. Moreover compound 11f, which is the most potent compound in this study showed more potent analgesic activity than that of aspirin at 30 mg/kg by po. The anti-inflammatory activity and gastric damage, however, were very weak or not detectably different from aspirin. Since the structure of our COX-1 inhibitors are very simple, they may be useful as lead compounds for superior COX-1 inhibitors as analgesic agents without gastric disturbance.

Full text of DOI:10.1016/j.bmc.2006.10.029

Bioorganic & Medicinal Chemistry 15 (2007) 1014–1021
Analgesic agents without gastric damage: Design and synthesis
of structurally simple benzenesulfonanilide-type
cyclooxygenase-1-selective inhibitors
Xiaoxia Zheng,a Hiroyuki Oda,a Kayo Takamatsu,a Yukio Sugimoto,a Akihiro Tai,a
Eiichi Akaho,c Hamed Ismail Ali,c Toshiyuki Oshiki,b Hiroki Kakutaa,* and Kenji Sasakia
aDivision of Pharmaceutical Sciences, Okayama University Graduate School of Medicine,
Dentistry and Pharmaceutical Sciences, 1-1-1, Tsushima-Naka, Okayama 700-8530, Japan
bDivision of Chemistry and Biochemistry, Okayama University Graduate School of Natural Science and Technology,
3-1-1, Tsushima-Naka, Okayama 700-8530, Japan
cFaculty of Pharmaceutical Sciences, High Technology Research Center (Life Science Center), Kobe Gakuin University,
518 Arise, Ikawadani-cho, Nishi-ku, Kobe 651-2180, Japan
Received 26 August 2006; revised 11 October 2006; accepted 14 October 2006
Available online 18 October 2006
Abstract—In order to create novel analgesic agents without gastric disturbance, structurally simple cyclooxygenase-1 (COX-1)
inhibitors with a benzenesulfonanilide skeleton were designed and synthesized. As a result, compounds 11f and 15a, which possess
a p-amino group on the benzenesulfonyl moiety and p-chloro group on the anilino moiety, showed COX-1-selective inhibition.
Moreover compound 11f, which is the most potent compound in this study showed more potent analgesic activity than that of aspi-
rin at 30 mg/kg by po. The anti-inflammatory activity and gastric damage, however, were very weak or not detectably different from
aspirin. Since the structure of our COX-1 inhibitors are very simple, they may be useful as lead compounds for superior COX-1
inhibitors as analgesic agents without gastric disturbance.
Ó 2006 Published by Elsevier Ltd.
1. Introduction
gastric disturbance was thought to be due to inhibi-
tion of COX-1 on the stomach mucous membrane
by NSAIDs.4 Furthermore, it was thought that the
anti-inflammatory effect of NSAIDs arises from the
inhibition of COX-2 in the inflamed region.5 Conse-
quently, COX-2-selective inhibitors drew much atten-
tion as candidates of anti-inflammatory agents with
reduced side effects.6 However, very recently, rofecoxib
(VioxxTM),7 a COX-2-selective inhibitor, was with-
drawn from the market because of possible association
with an increased incidence of cardiovascular events,
such as heart attack and stroke.8
Patients with cancer or rheumatism suffer from physical
and mental pains due to anxiety produced by the dis-
ease. Therefore, it is very important to reduce these
pains for the patients to achieve a better quality of life.
One of the current methods to relieve their physical
pains is the usage of non-steroidal anti-inflammatory
drugs (NSAIDs), for example, aspirin, acetaminophene,
ibuprofen and so on. However, these NSAIDs produce a
serious problem, gastric disturbance.
In general, most NSAIDs inhibit cyclooxygenases
(COXs), which catalyze the synthesis of prostaglani-
dins from arachidonic acid. They have three subtypes,
COX-1, COX-2, and COX-3.1–3 Until recently, the
Meanwhile, NSAID-induced gastric damage was
reported to be caused by the inhibition of both
COX-1 and COX-2.9 Moreover, it has been suggested
that COX-1 may play an important role in pain pro-
cessing and sensitization of the spinal cord and gracile
nucleus after surgery.10 Therefore, COX-1-selective
inhibitors are anticipated to be candidates as novel
analgesic agents with reduced gastroenteric distur-
bance. For example, mofezolac (1)11 and FR122047
Keywords: Cyclooxygenase-1; COX-1-selective inhibitors; Molecular
design; Analgesic effects; Sulfonamides; Gastric damages; Structure–
activity relationship study; Docking study.
*
Corresponding author. Tel.: +81 86 251 7977; fax: +81 86 251
7926; e-mail: kakuta@pharm.okayama-u.ac.jp
0968-0896/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.bmc.2006.10.029

X. Zheng et al. / Bioorg. Med. Chem. 15 (2007) 1014–1021
1015
few well-known COX-1-selective inhibitors are avail-
able at this point. These factors motivated us to
search for new COX-1-selective inhibitors as novel
analgesic agents without gastric disturbance.
MeO
HO2C
MeO
MeO
O
N
N
S
O
N
In Figure 1, representative COX-1 inhibitors are
shown. These compounds possess the characteristic
structure, which contains two para-substituted phenyl
groups which oriented in a cis-conformation. The
structural similarity of these COX-1 inhibitors led us
to invent novel COX-1 inhibitors by modifying syn-
thesized analogues with a similar chemical structure.
Thus we chose benzenesulfonanilide (5), which con-
tains two phenyl groups bridged by a SO2-NH unit,
as a simple model compound, because sulfonamide
derivatives were reported to orient the substituents
in an s-cis conformation16 and to show various bioac-
tivities.17 To elucidate the conformation of the two
phenyl groups of 5, an X-ray crystallographic analysis
was carried out (Tables 1 and 2). The molecular struc-
ture is shown in Figure 2. The torsional angle of
C(1)–S(1)–N(1)–C(7) is 58.1(3)° indicating that two
phenyl groups of 5 are in s-cis form. Based on the
above ideas, we selected 5 as a novel COX-1-selective
inhibitor framework and performed molecular design
by the introduction of various substituents (e.g., car-
boxyl, nitro, amino and methanesulfonamide groups)
onto each phenyl group of 5 (Fig. 3).
MeO
MeO
NMe
FR122047 (2)
mofezolac (1)
HO2C
MeO
Me
N
N
N
CF3
O
Cl
Cl
SC-560 (3)
indomethacin (4)
Figure 1. Chemical structures of representative COX-1 inhibitors 1–3
and a COX-1 relatively selective inhibitor 4.
(2),12 two representative COX-1-selective inhibitors,
show analgesic activity and are recognized to reduce
hyperplastic polyp. In addition, COX-1-selective inhib-
itors have started to garner attention as anti-tumor
agents because of their anti-angiogenesis activity.13
For example, low-dose aspirin, which inhibits mainly
COX-1, is reported to decrease intestinal cancer inci-
dence by 40–50% as compared with non-aspirin
usage14 and has also been applied in a clinical setting
as an anti-thrombotic agent.15 Thus, COX-1 is also
thought to be a therapeutic target. However, very
2. Chemistry
The benzenesulfonanilide skeleton was obtained by
coupling benzenesulfonyl chlorides and anilines in pyr-
idine. Most compounds except for carboxy derivatives
6 were obtained in at least 60% yield. N-Methylation
of the benzenesulfonanilide moiety was performed
with compound 7, followed by reduction of the nitro
group to afford 11. For compounds bearing halogen
atoms, reduction of the nitro group was carried out
with tin and hydrogen chloride because halogen atoms
except for fluorine departed under palladium on car-
bon reduction conditions. The structures of all the
compounds were confirmed by spectroscopy (1H
NMR, IR, and mass spectrometry) and elemental
analyses.
N(1)
C(7)
NH
S(1)
SO2
C(1)
5
Figure 2. Chemical structure and ORTEP drawing of benzenesulfo-
nanilide (5).
MeO
MeO
MeO
MeO
HO2C
O
N
N
S
O
N
R
NMe
Design
FR122047 (2)
SO2
mofezolac (1)
N
R = NH2, NO2, NHMs...
R' = H, Me...
R'
MeO
R" = H, Me, Cl...
N
R"
N
CF3
Cl
SC-560 (3)
Figure 3. Molecular design strategy of COX-1-selective inhibitors with a benzenesulfonanilide skeleton.

1016
X. Zheng et al. / Bioorg. Med. Chem. 15 (2007) 1014–1021
Table 1. Crystallographic data for 5
4. Molecular docking
Formula
Crystal system
Space group
C12H11NO2S
The docking program used was AutoDock 3.05 devel-
oped by Morris et al.18 The 3D coordinate structure of
COX-1 (1PGF) was retrieved from the Brookhaven Pro-
tein Data Bank: URL*http://www.rcsb.org/pdb/ Welco-
me.do. and water molecules and ions were removed
before the docking.
Tetragonal
P41212(#92)
8.7746(8)
30.037(2)
30312.6(3)
8
˚
a (A)
˚
c (A)
3
˚
v (A )
Z value
D (g/cmꢀ1
)
1.340
1627
No. of obsd reflns
No. of variables
R1;wR2
179
0.037, 0.087
5. In vivo assay
5.1. Animals
˚
Male mice and male rats, weighting 15–30 and 170–
200 g, respectively, were acquired from the Charles Riv-
er Co. Ltd. Only water was provided ad libitum during
the 12 h before experimentation. The study was con-
ducted according to internationally accepted principles
of laboratory animal use.
Table 2. Selected bond distances (A) and angles (°) for 5
C(1)–S(1)
S(l)–O(l)
N(1)–C(7)
1.756(3)
1.434(2)
1.448(3)
106.3(1)
108.5(1)
119.4(1)
105.7(1)
115(2)
S(1)–N(1)
S(1)–O(2)
N(1)–H(11)
1.618(3)
1.424(2)
1.12(4)
C(1)–S(1)–O(1)
C(1)–S(1)–O(2)
O(1)–S(1)–O(2)
N(1)–S(1)–O(2)
S(l)–N(l)–H(ll)
C(1)–S(1)–O(2)
C(1)–S(1)–N(1)
N(1)–S(1)–O(1)
S(1)–N(1)–C(7)
C(7)–N(1)–H(11)
108.5(1)
108.9(1)
107.8(1)
121.7(2)
110(1)
5.2. Writhing test12
Groups of mice (n = 9–11) were treated with the solu-
tions of compound 11f, aspirin at a dose of 30 mg/kg,
and the solvent (1% ethanol and 0.5% CMC (carboxym-
ethyl cellulose) in milliQ water) at a dose of 0.3 mL/10 g
of animal via po. The muscular contraction was induced
by an ip administration of 0.7% acetic acid at a dose
0.1 mL/10 g for 30 min after the treatment. The number
of muscular contractions was counted starting at 10 min
after injection for a period of 10 min. Data represent
average of the total writhes observed.
3. Biology
The biological activity of the compounds was assessed
with a colorimetric COX (ovine) inhibitory screening as-
say kit (Cayman Chemical; catalog No. 760111) accord-
ing to the supplier’s protocol. Each experiment was
initially performed at 100 lM of the test compound (fi-
nal concentration). IC50 values were calculated for only
potent compounds discovered in this assay system.
Lineweaver–Burk plot analysis was performed with the
same assay kit described above at 100 lM (final concen-
tration) of the compound and arachidonic acid was used
as a substrate at a concentration of 25, 50, 100, 200, and
400 lM, respectively. Each experiment was performed
at least twice and their mean value was calculated.
5.3. Rat paw edema induced by carrageenan19
Groups of rats (n = 3–8) were treated with solutions of
compound 11f, aspirin (30 mg/kg, each), and indometh-
acin (4) (10 mg/kg). The solvent (1% ethanol and 0.5%
CMC in milliQ water) at a dose of 1 mL/200 g of animal
Table 3. COX-inhibitory activity of indomethacin (4) and compounds 6–9
R
SO
2
NH
R'
Compound
R0
% Inhibition of COX at 100 lM
7 (R = NO2) 8 (R = NH2)
COX-1 COX-2 COX-1 COX-2
6 (R = CO2H)
COX-1 COX-2
9 (R = NHMs)
COX-1 COX-2
4
a
b
c
d
e
f
—
H
90
11
21
0
90
0
90
0
90
0
90
0
90
0
90
0
90
0
2-Me
3-Me
4-Me
3,5-DiMe
4-OMe
4-CF3
3,5-DiCF3
4-Cl
6
0
4
5
0
0
0
19
n.t.
n.t.
0
3
0
8
2
3
0
n.t.
n.t.
3
44
0
0
52
13
n.t.
14
30
70
15
28
n.t.
35
49
50
12
0
0
0
0
0
0
8
13
0
g
h
i
0
12
8
1
1
8
25
n.t.
19
6
19
0
0
11
0
n.t.
4
n.t., not tested.

X. Zheng et al. / Bioorg. Med. Chem. 15 (2007) 1014–1021
1017
Table 5. COX-inhibitory activity of indomethacin (4), compounds 13
and 15
Table 4. COX-inhibitory activity of compounds 8 and 11
m
H N
2
p
R
H N
2
SO
2
R'
N
N
R
SO
R'
2
Cl
Compound
NH2
R
R0
% Inhibition of
COX at 100 lM
Compound
R
% Inhibition of COX at 100 lM
13 (R0 = H) 15 (R0 = Me)
COX-1 COX-2 COX-1 COX-2
COX-1
COX-2
4
—
p
p
p
p
p
p
p
p
p
p
p
p
p
m
p
p
p
p
—
H
—
90
70
18
53
6
90
50
16
8
8i
4-CI
3-CI
2-CI
2,4-DiCI
4-F
8j
8k
H
4
a
b
c
—
H
90
3
90
4
90
68
77
73
n.t.
90
24
5
H
81
H
12
26
25
50
16
16
4
Me
OMe
CF3
7
28
22
23
8m
8n
H
15
23
18
48
21
6
1
44
n.t.
H
4-Br
4-I
d
7
8o
H
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j
11k
Me
Me
Me
Me
Me
Me
Me
Et
H
n.t., not tested.
4-Me
4-OMe
4-CF3
4-F
9
6
and aspirin (30 mg/kg) were orally administered to
the rats (n = 3–5), respectively. Five hours later, the
rats were anesthetized with diethyl ether. The stomach
was taken out and viewed using a stereoscopic micro-
scope. The stomach damage images were captured by
hemorrhagic damage analysis using a CCD camera
(Monicam2000, Motic China Group) and analyzed
using Motic Images Plus 2.0S software. The damage
scoring was performed by measuring the lengths of
the ulcers in millimeters, and the sum of the damage
values gave an overall gastric damage score for each
rat.
0
5
4-CI
4-CI
4-CI
4-CI
4-Br
4-I
78
39
10
0
29
4
19
5
Pr
Me
Me
21
18
8
45
was administered via po or ip. Paw edema was induced
by 0.1 mL of 1% carrageenan in saline solution into the
hind paw of a rat 1 h after the administration of the
solution.19 Edema was measured with a thickness gauge
(Mitsutoyo Co. Ltd., Tokyo, No. 7331).
5.5. Statistical analysis
5.4. Acute gastric damage scoring9
All data were expressed as means SEM. Comparisons
among groups of data were performed using a one-way
analysis of variance followed by the Dunnett’s multiple
comparison test. An associated probability (p value) of
<5% was considered to be significant.
An acute gastric damage experiment was performed
according to Wallace et al.9 The 0.5% CMC vehicle,
indomethacin (10 mg/kg), compound 11f (30 mg/kg),
R
R
R
SO2Cl
a
d
SO2
NH
SO2
N
NH2
X
R'
R'
R'
R"
R"
R"
5;
6;
10;
11;
14;
15;
R, R' = H
R
= NO2, R' = H, Me, OMe...
R" = H, X = Me, Et...
= NH2, R' = H, Me, OMe...
R" = H, X = Me, Et...
= Cl, R' = NO2
R" = H, Me, OMe, X = Me
= Cl, R' = NH2
R" = H, Me, OMe, X = Me
b
b
R
= CO2H, R' = H, Me, OMe...
R" = H
R
7;
8;
R
= NO2, R' = H, Me, OMe...
R" = H
b
c
R
R
= NH2
R' = H, Me, OMe...
R" = H
R
9;
R
= NHMs
R' = H, Me, OMe...
R" = H
10;
11;
R
= Cl, R' = NO2
R" = H, Me, OMe...
= Cl, R' = NH2
R" = H, Me, OMe...
b
R
Scheme 1. Reagents and conditions: (a) pyridine, (b) H2, Pd/C, EtOH or Sn, HCl, EtOH, (c) MsCl, pyridine, (d) MeI, NaH, DMF.

1018
X. Zheng et al. / Bioorg. Med. Chem. 15 (2007) 1014–1021
Table 6. COX-inhibitory activity of indomethacin (4), aspirin, and
compounds 8i, 11f, and 15a–c
R
X
R'
N
SO2
Y
Compound
X
Y
R
R1
IC50 (lM)
COX-1
COX-2
Si
Cl
Cl
NH2
NH2
Cl
H
H
H
H
12.0
3.2
>100
>100
>100
>100
>100
11f
15a
15b
15c
Me
Me
Me
Me
NH2
NH2
NH2
9.2
Cl
Cl
Me
OMe
26.0
20.0
Aspirin
100
0.03
>100
7.7
4
Amino group is needed
H2N
Figure 6. Potential binding mode of 11f (colored by element, stick) in
the COX-1 active site. 2H-bonds are indicated with green dotted lines.
Sulfonamide group is reversible
N-methylation is needed
SO2
N
Me
halogen derivatives 8m,8n, and 8o were prepared and
assessed. (Table 4). However, these compounds pos-
sessed little COX-inhibitory activity. Thus this COX-
inhibitory activity was thought to be specific to chloro
derivatives. Moreover, although chlorine regioisomers
8j and 8k were prepared, p-isomer 8i was more potent
than these chlorine regioisomers. Next, in order to in-
crease the hydrophobicity of the compounds, N-alkyl-
ation of the sulfonanilide skeleton was performed
(Table 4, compounds 11). Compound 11f, the N-
methylated derivative of 8i, showed the most potent
and COX-1-selective inhibitory activity. In addition,
compound 11a, which has no substituted group on
the N-aromatic ring, showed moderate COX-1-inhibi-
tory activity. Other halogen derivatives 11e, 11j ,
and 11k did not possess COX-inhibitory activity.
Other N-alkylated compounds 11h and 11i also did
not show COX-inhibitory activity. Additionally, m-
amino derivative 11g showed a weak COX-1-inhibito-
ry activity. These results suggested that p-chlorine, N-
methyl, and p-amino groups are important to exhibit
a COX-inhibitory activity and a COX-1 sub-type
selectivity Scheme 1.
X
Halogen atom is important
Cl gives the most potent inhibitory activity
Figure 4. Important factors for benzenesulfonanilide-type COX-1
inhibitors.
Figure 5. Lineweaver–Burk plot analysis for compounds 11f and 15a.
DMSO (circle), 11f (square), and 15a (triangle), respectively. The
compound concentration is 100 lM.
Moreover, compounds with the sulfonamide group re-
versed in the structure and compounds bearing vari-
ous substituents on the aniline moieties were also
prepared (synthetic scheme not shown) (Table 5). As
a result, the N-methylated compounds showed a po-
tent COX-1-inhibitory activity. Then, the IC50 values
were assessed as shown in Table 6. One of sulfon-
amide-reversed compounds 15a possessed a COX-1-se-
lective inhibitory activity as observed in compound
11f. On the other hand, introduction of substituents
to aniline moieties made COX-inhibitory activity
slightly weaker.
6. Results and discussion
The inhibitory activities toward individual COX
isozymes are shown in Table 3. Most of the
compounds showed no COX-inhibitory activity, but
amino derivatives, for example, 8d and 8i, were shown
to be active (Table 3). The chloro compound 8i
showed a potent COX-inhibitory activity. Since chloro
compound 8i showed COX-inhibitory activity, other

X. Zheng et al. / Bioorg. Med. Chem. 15 (2007) 1014–1021
1019
25
20
15
2.5
**
*
2.0
1.5
1.0
0.5
*
10
5
0
0
vehicle
aspirin
11f
vehicle
indomethacin
aspirin
11f
Figure 7. Analgesic effect on acetic acid-induced writhing response in
mice. Data shown are the average of the total writhes observed (n = 9–
11) SEM. *p < 0.05 , **p < 0.01.
Figure 9. Gastric damaging effects of indomethacin (4) (10 mg/kg),
aspirin (30 mg/kg) and 11f (30 mg/kg). The gastric damage score was
calculated by measuring the lengths, in millimeters, and summing the
values for each rat. *p < 0.05, **p < 0.01. Data shown are means
(n = 3–5/group) SEM.
Based on these results, the structure–activity relation-
ship of benzenesulfonanilide COX-1-inhibitory activity
is summarized in Figure 4. In order to produce COX-
1-selective inhibitory activity, sulfonanilide derivatives
need to possess a p-chlorine or p-amino group on each
aromatic ring, whose sulfonamide moiety should be N-
methylated. Though sulfonamide-type COX inhibitors
have been reported, their inhibitory activities are less
than those of our compounds.20 The reason might come
from lack of the SAR conditions discussed above.
In order to examine the inhibitory mode of these com-
pounds to COX-1, Lineweaver–Burk plot analysis was
performed. It is difficult to calculate the appropriate
a
b
Figure 8. Effect of COX inhibitors on carrageenan-induced edema. (a) Administered via po, (b) administered via ip. Single doses of vehicle (circle),
30 mg/kg 11f (triangle), 30 mg/kg aspirin (square) or 10 mg/kg indomethacin (4) (open circle) were administered by oral gavage 1 h before initiation
of inflammation with carrageenan. Edema was measured 4 h after carrageenan injection. Data shown are means (n = 3–8) SEM. *p < 0.05 ,
**p < 0.01.

1020
X. Zheng et al. / Bioorg. Med. Chem. 15 (2007) 1014–1021
amount of reacted arachidonic acid in this assay system.
Therefore, the vertical axis (1/V) was represented with
the amount of OD change at 595 nm used in this assay.
As shown in Figure 5, the 1/Vmax (y intercept) values of
each inhibitor are as same as that of no inhibitor, sug-
gesting that each inhibitor reduced the affinity of
COX-1 for its substrate, arachidonic acid. These results
suggest that the investigated compounds are competitive
COX-1 inhibitors, which bind to the catalytic site of
COX-1.
Acknowledgments
The authors are grateful to the SC-NMR Laboratory of
Okayama University for 300 MHz NMR experiment.
The work described in this paper was partially support-
ed by a Grants-in-Aid for Scientific Research from the
Ministry of Education, Culture, Sports, Science and
Technology, Japan. The authors are also grateful to
Dr. James Fuchs for helpful discussion in the prepara-
tion of this manuscript.
Furthermore, to understand the binding mode in COX-
1, a docking study was performed. As shown in Figure
6, compound 11f binds to the catalytic site of COX-1.
In addition, the amino group of compound 11f exhibited
two hydrogen bonds with Tyr385 and Ser530, support-
ing the importance of the amino group on these benze-
nesulfonanilide COX-1 inhibitors.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.bmc.2006.10.029.
Since mofezolac (1) and FR122047 (2) show the anal-
gesic activity, the analgesic effect of our COX-1-selec-
tive inhibitor 11f was assessed by the acetic acid-
induced writhing test in mice (Fig. 7). As a result,
moderate analgesic activity similar to that of aspirin
was recognized.
References and notes
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Meanwhile, the anti-inflammatory effect of compound
11f is shown in Figure 8. No anti-inflammatory effect
was detected for compound 11f in either po or iv as com-
pared with that of indomethacin (4). Since mofezolac
(1), FR122047 (2), and SC-560 (3) are reported not to
possess a potent anti-inflammatory effect, this result is
considered to be appropriate.
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tric ulcers or not. As shown in Figure 9, indomethacin
(4) induced visible gastric ulcers when administered
orally at 10 mg/kg and aspirin also induced small gas-
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very easy, this compound may be useful as a lead
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which were also not observed in the case of COX-1-
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Recently, COX-1-selective inhibitors have also started
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