Methanesulfonamide group at position-4 of the C-5-phenyl ring of 1,5-diarylpyrazole affords a potent class of cyclooxygenase-2 (COX-2) inhibitors

Article abstract of DOI:10.1016/j.bmcl.2004.01.053

The effect of methanesulfonamide (MeSO₂NH) group on COX-2 inhibitory activity of 1,5-diarylpyrazole is described. While this group being at position-4 of the N¹-phenyl ring was found to be ineffective, its installation at position-4

Full text of DOI:10.1016/j.bmcl.2004.01.053

Bioorganic& Medicinal Chemistry Letters 14 (2004) 1683–1688
Methanesulfonamide group at position-4 of the C-5-phenyl ring of
1,5-diarylpyrazole affords a potent class of cyclooxygenase-2
(COX-2) inhibitors§
Sunil Kumar Singh,a,* Saibaba Vobbalareddy,a Samala Shivaramakrishna,a
A. Krishnamraju,a Shaikh Abdul Rajjak,a Seshagiri Rao Casturi,b Vangoori Akhilab and
Yeleswarapu Koteswar Raoa,*
aDiscovery Chemistry, Discovery Research-Dr. Reddy’s Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500 049, India
bDiscovery Biology, Discovery Research-Dr. Reddy’s Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500 049, India
Received 24 December 2003; revised 20 January 2004; accepted 20 January 2004
Abstract—The effect of methanesulfonamide (MeSO2NH) group on COX-2 inhibitory activity of 1,5-diarylpyrazole is described.
While this group being at position-4 of the N1-phenyl ring was found to be ineffective, its installation at position-4 of the C-5 phenyl
ring offered several potent and selective inhibitors of COX-2 with IC50 as low as 30 nM.
# 2004 Elsevier Ltd. All rights reserved.
Two isoforms of prostaglandin synthase (cyclooxygen-
ase) are COX-1 and COX-2.1 These two isozymes have
tissue specific expression and regulation, and entirely
different biochemical roles to play.2 The COX-1, a con-
stitutive enzyme, expressed mainly in gastrointestinal
(GI) tract, is responsible for the biosynthesis of pros-
taglandins (PGs) required for cytoprotection and plate-
let aggregation.3 Therefore, interference with its normal
function for a long time, leads to GI toxicity such as
ulceration, bleeding and perforation.4 In contrast, the
COX-2, induced by pro-inflammatory cytokines such as
tumor necrosis factor-a (TNF-a), interleukines, mito-
gens and endotoxins present in inflammatory cells dur-
ing injury, plays a major role in the biosynthesis of PGs
required for inflammatory cells to cause inflammation,
pain and fever.5 The conventional NSAIDs being effec-
tive inhibitors of both COX-1 and COX-2, down reg-
ulate the biosynthesis of both kinds of PGs
(cytoprotective and inflammatory) in most of the tis-
sues, and exhibit anti-inflammatory activity along with
above described side effects.6 Thus, the selective inhibi-
tion of the inducible COX-2 (the main cause of inflam-
mation), sparing COX-1 (involved in house keeping
function of cells and tissues), emerged as the basis of
inventing new anti-inflammatory agents with greater GI
safety. This new approach has created a new avenue for
inflammation research. Several COX-2 inhibitors were
discovered in this process, but the proof of concept
came into act on humans only with the launch of two
blockbuster drugs celecoxib7 and rofecoxib8 by Pfizer
and Merck for the chronic treatment of rheumatoid and
osteoarthritis. Recently, two more effective drugs viz.
valdecoxib9 and etoricoxib10 have been launched in this
area further validating the new concept of inflammatory
medication. Apart from inflammation, COX-2 has
become a target for other ailments like cancer11 and
Alzheimer’s disease.12 However, a recent report has
appeared as a caution regarding the use of COX-2 inhi-
bitors in cardiac patients.13 But, by and large, this new
concept of treating inflammatory diseases with COX-2
inhibitors has a great clinical advantage over the con-
ventional NSAIDs, and still warrants a search for more
efficacious drugs in this area. Additionally, the recent
discovery of COX-3, is bringing a challenge ahead in
this area.14
Keywords: Methanesulfonamide; 1,5-diarylpyrazoles; Cyclooxygenase-
2 inhibitors.
§DRL Publication No. 385A
* Corresponding authors. Tel.: +91-40-2304-5439; fax: +91-40-2304-
5438/2304-5007; e-mail: sunilkumarsingh@drreddys.com;
koteswarraoy@ddreddys.com
In contrast to the diverse chemical structures of con-
ventional NSAIDs, the selective COX-2 inhibitors
belong to only two major chemical classes: (a) the
0960-894X/$ - see front matter # 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.01.053

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S. K. Singh et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1683–1688
enzyme. Following this principle, many vicinal diaryl
carbocycles17 and heterocycles18 have been successfully
discovered. Lack of this rigid geometry could be the
reason for conventional NSAIDs to be non-selective.
Though several COXIBs (COX-2 inhibitors) have been
introduced in the market, there still remains a need for
the best in class medication in a view to completely
eliminate the use of steroidal and narcotic drugs in
severe to moderate inflammatory pains. Being involved
in the design and synthesis of novel COX-2 inhibitors,
we have recently been successful to introduce a hydro-
xymethyl group adjacent to the sulfonamide group of
celecoxib which fetched many compounds with
improved efficacy.19 Our idea of introducing this
hydrophilicgroup adjaecnt to sulfonamide was based
on the assumption that these groups might preferably
bind to the hydrophilicpokcet of the differentiating
COX-2 enzyme and cause effective inhibition. In further
pursuance in this area, we wished to study the effect of
methanesulfonamide (MeSO2NH) group taken from the
most effective COX-2 inhibitor, nimesulide15 on 1,5-
diarylpyrazole scaffold (Scheme 1). Penning et al.7 also
studied this pharmacophore as replacement of sulfona-
mide at position-4 of the N1-phenyl ring during the dis-
covery of celecoxib. But, the modification was found to
be ineffective for both the enzymes. We took up this
group to study its effect on COX-2 inhibition by instal-
ling at position-4 of the C-5 phenyl ring in combination
with a phenyl ring at N1 and a CF3 group at position-3.
To our surprise, the group demonstrated a dramatic
effect on COX-2 inhibition. Therefore, we wish to
report herein our finding through a brief structure–
activity relationship (SAR) as the preliminary observation.
Figure 1.
Scheme 1.
diphenyl ethers having acidic methanesulfonamide
(MeSO2NH) group as pharmacophore such as nimesu-
lide,15 and (b) the vicinal diarylheterocycles having 4-
sulfamoyl (SO2NH2)/methanesulfonyl (SO2Me)-phenyl
as pharmacophore such as celecoxib,7 valdecoxib,9
rofecoxib8 and etoricoxib10 (Fig. 1).
The syntheticroute for the 1,5-diarylpyrazoles 3–43
reported here is depicted in Scheme 2. The essentially
required 1-[4-(N-acetylaminophenyl)]-1,3-butanediones
(1,3-diketones) 2 were synthesized in 95–98% yield by
the Claisen condensation of 4-(N-acetylamino)aceto-
The latter scaffold has become more acceptable due to
the COX-2 enzyme–ligand co-crystal structure known
for the structure based drug design16 where two vicinal
phenyl rings of the COX-2 inhibitors orient in a rigid
cis-stilbene geometry and the 4-SO2NH2/SO2Me-phenyl
ring extends towards the hydrophilicpocket of COX-2
phenone 1 with ethyl acetate/a-haloacetate using
sodium hydride in dry DMF. This transformation was
identified by the disappearance of the CH3 protons of
acetophenones present at ꢀ2.5 ppm and appearance of
a D2O exchangeable singlet at ꢀ6.5 ppm in the product.
These 1,3-diketones 2 on coupling with appropriate
ꢁ
.
Scheme 2. Reagents and conditions: (a) RCO2Et, NaH, DMF, À5–30 C, 2–3 h. (b) ArNHNH2 HCl, EtOH, reflux, 6–7 h. (c) 2N HCl, EtOH,
reflux, 4–5 h. (d) For R2=4-Me-phenyl, p-toluenesulfonylchloride and for R2=Me, methanesulfonylchloride, TEA, dichloromethane, 0–30 ꢁC, 2–3
h. (e) Acid anhydride, TEA, dichloromethane, 0–5 ꢁC, 1 h followed by reflux, 10–12 h.

S. K. Singh et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1683–1688
1685
aryl/heteroaryl hydrazine hydrochloride afforded a
mixture of 1,5-diarylpyrazoles 3 and 4.19 The 1,3-di-
arylpyrazoles, formed in minor quantities, were easily
eliminated by triturating the products with a mixture of
ethyl acetate–toluene after column chromatography. In
this transformation, the D2O exchangeable singlet of the
diketone became non-D2O exchangeable C-4 proton of
1,5-diarylpyrazoles. The acetanilides 4 were hydrolyzed
back to amines 3 by refluxing with ethanolicHCl which
on treatment with p-toluenesulfonylchloride in presence
of TEA afforded 1,5-diarylpyrazole 5 with a p-toluene-
sulfonamide group. Similarly, the treatment of 3 with
methanesulfonyl chloride under above reaction condi-
tion yielded 1,5-diarylpyrazoles 6–36 having desired
methanesulfonamide pharmacophore. While N,N-di-
methanesulfonamide derivative 37 was obtained as a by-
product during the synthesis of methanesulfonamide 10,
the N-acylated methanesulfonamides 38–43 were syn-
thesized by the acylation of parent methanesulfonamide
compounds 10 and 27 in very good yield (65–70%). All
the compounds reported herein were characterized
spectroscopically and their purity was assessed by
HPLC/microanalyses.
recombinant, expressed in sf-9 cells infected with bacu-
lovirus. The promising compounds were further tested
at lower concentrations, and the IC50’s were calculated
using non-linear regression analysis of the percent inhi-
bitions.20 Celecoxib and indomethacin were used as
reference standards for COX-2 selective and non-
selective inhibitors respectively. Compounds, selected
on the basis of in vitro activity, were screened in the
carrageenan-induced rat paw edema model at 30 mg/kg
to assess their in vivo potency.21
As conceived, the 4-methanesulfonamide pharmaco-
phore at position-4 of C-5 phenyl ring was normally
maintained throughout the study. Diverse substitutions
on the phenyl ring at N1 along with a CF3 group at C-3
were opted for the initial study and the in vitro data is
presented in Table 1. The un-substituted N1 phenyl ring
was found to be less potent whereas 4-OMe-phenyl
analogue 8, though less COX-2 selective, was found to
be highly potent (IC50, 96 nM). Among halogens, 4-Cl-
phenyl analogue 10 demonstrated the highest COX-2
potency (IC50, 30 nM) and selectivity (SI, 520). While 3-
F-phenyl analogue 16 showed reasonable COX-2 selec-
tivity, 2-F-phenyl analogue 15 became non-selective and
3-Cl-phenyl analogue 17 turned out to be COX-1 selec-
tive. The 3,4-Cl2-phenyl analogue 19 was found to be
better than the corresponding 3,4-F2-phenyl analogue
18. Among amines, the 4-N,N-Me2-phenyl 14 exhibited
better potency and selectivity than 4-NHMe analogue
All the 1,5-diarylpyrazoles, reported herein, were
screened for the enzyme activity by TMPD method
initially at 10 mM concentration. While source of COX-
1 enzyme was the microsomal fraction of ram seminal
vesicles, the COX-2 was obtained from the human
Table 1. In vitro activity of 1,5-diarylpyrazoles having methanesulfonamide pharmacophore
Compd
Ar
% Inhibition @ 10 mMa (IC50 in mM)b
COX-1c
COX-2d
6
7
8
9
Phenyl
0 (85.30)
34
100 (2.900)
0
4-NO2-phenyl
4-OMe-phenyl
4-F-phenyl
100 (0.40)
6 (20.30)
25 (15.60)
88 (4.90)
22 (31.60)
14
85 (3.40)
97
49b,e
96
100 (0.096)
65 (0.760)
100 (0.030)
100 (0.230)
69 (2.640)
42
10
11
12
13
14
15
16
17
18
19
4-Cl-phenyl
4-Br-phenyl
4-NH2-phenyl
4-NHMe-phenyl
4-NMe2-phenyl
2-F-phenyl
3-F-phenyl
3-Cl-phenyl
3,4-F2-phenyl
3,4-Cl2-phenyl
100 (0.530)
89
70b,e
3
59
70b,e
32
10b,e
20
21
0
13
12
42
Celecoxib
—
0 (10.7)
100 (0.067)
100 (0.036)
97 (7.810)
Indomethacin
—
a Value from single experiment.
b Mean of three determinations with standard deviation of < Æ10%.
c COX-1 enzyme, obtained from the microsomal fraction of ram seminal vesicles.
d COX-2 enzyme, obtained from the human recombinant, expressed in sf-9 cells infected with baculovirus.
e Not determined.

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S. K. Singh et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1683–1688
13. Electron withdrawing phenyl, multisubstituted
phenyl and heteroaryl rings at N1, for example, 7, 20
and 21 were found to be neither active nor selective. The
effect of CHF2 and CH3 groups at C-3 is depicted in
Table 2. The N1 substituted analogues which were either
inactive, poorly active or non-selective in conjugation
with CF3 (Table 1), did not show much improvement.
However, this change affected the activity of 4-Cl-
phenyl derivative, for example, its CHF2 (IC50, 150 nM)
and CH3 (IC50, 265 nM) analogues 27 and 28, though
slightly less potent, demonstrated very good COX-2
selectivity (SI, 420 and 377, respectively). Similarly, the
4-Br-phenyl analogue showed decrease in potency but
increase in selectivity. Though the optimization of the
Table 2. In vitro activity of 1,5-diarylpyrazoles having methanesulfonamide pharmacophore
Compd
Ar
R
% Inhibition @ 10 mMa (IC50 in mM)b
COX-1c COX-2d
22
23
24
25
26
27
28
29
30
31
32
33
34
Phenyl
Phenyl
CHF2
CH3
CH3
CHF2
CH3
CHF2
CH3
CH3
CHF2
CHF2
CHF2
CHF2
CHF2
22
34
40
22b,e
0
31
7
4-NO2-phenyl
4-F-phenyl
4-F-phenyl
4-Cl-phenyl
4-Cl-phenyl
4-Br-phenyl
2-F-phenyl
3-F-phenyl
2-Cl-phenyl
3,4-F2-phenyl
3,4-Cl2-phenyl
0
62 (8.000)
25
100 (0.150)
88 (0.265)
100 (0.770)
89b,e
0 (63)
0 (100)
10 (63)
90b,e
97
66
11
43b,e
67
22
36
71b,e
35
CH3
0
13
0
36
CHF2
100
aÀe Same as in Table 1.
Table 3. In vitro activity of 1,5-diarylpyrazoles having other than methanesulfonamide pharmacophore
Compd
Ar
R
R1
R2
% Inhibition @ 10 mMa (IC50 in mM)b
COX-1c
COX-2d
3
4-OMe-phenyl
4-OMe-phenyl
4-Br-phenyl
4-Br-phenyl
4-Cl-phenyl
4-Cl-phenyl
4-Cl-phenyl
4-Cl-phenyl
4-Cl-phenyl
4-Cl-phenyl
4-Cl-phenyl
4-Cl-phenyl
CF3
CF3
CF3
CH3
CF3
CF3
CF3
CF3
CF3
CHF2
CHF2
CHF2
H
H
H
H
H
COCH3
COCH3
COCH3
SO2-C6H4-Me
SO2Me
100 (0.072)
51b,e
100 (3.5)
9 (13.3)
0b,e
100 (0.129)
64b,e
87 (0.07)
80 (0.55)
70b,e
4a
4b
4c
5
37
38
39
40
41
42
43
H
SO2Me
COCH3
COC2H5
COC3H7
COCH3
COC2H5
COC3H7
14
13
63b,e
SO2Me
SO2Me
SO2Me
SO2Me
SO2Me
SO2Me
0b,e
18b,e
0b,e
65b,e
62b,e
17
66
100
100
36
42
4d
CF3
H
COCH3
59
0
aÀe Same as in Table 1.

S. K. Singh et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1683–1688
1687
Figure 2. (a) Docking of compound 10 (ball and stick, carbon-violet) in the binding site of COX-2. The hydrogen bonding interactions are shown as
broken lines. (b) Superposition of compound 10 (carbon-violet), SC-558 (carbon-orange) and nimesulide (carbon-gray) in the active site of COX-2.
Ligands are shown in ball and stick rendering. Amino acid residues are not shown for clarity.
series with respect to substitutions at N1 is in progress,
we turned back to search few other similar groups as a
substitute for the methanesulfonamide at position-4 of
C-5 phenyl ring. The results are shown in Table 3. While
the 4-aminophenyl analogue 3 was found to be highly
potent but non-selective, its acetyl derivative 4a–c
(except 4d) and 4-p-toluenesulfonamide derivative 5
were found to be reasonably active and moderately
selective. The N,N-dimethanesulfonamide analogue 37,
in contrast, turned out to be inactive and non-selective.
This could be due to the lack of H-bond donor feature
in this molecule to bind the hydrophilic pocket of the
COX-2 enzyme. While N-acylated methanesulfona-
mides in conjugation with a CF3 at position-3, for
example, 38–40 were found to be COX-2 selective, their
CHF2 analogues 41–43 turned out to be COX-1 selec-
tive. The preliminary in vivo activity of the potent
compounds 10, 27 and 28 in carrageenan-induced rat
paw edema model at 30 mg/kg was found to be in the
range of 45–65% whereas those of 38, 39 and 40 was in
the range of 60–67%. The higher in vivo potency of
compounds 38, 39 and 40 was explained by a pharma-
cokinetic study performed on a model compound 38
which was proved to be the prodrug of compound 10.22
ability to form favorable van der Waals and electro-
static interactions with COX-2 amino acid residues.
In conclusion, the 4-methanesulfonamide group at
position-4 of the C-5 phenyl ring disclosed herein, serves
as a novel pharmacophore to induce COX-2 inhibitory
activity of 1,5-diarylpyrazoles, and has provided a few
potent and selective inhibitors of COX-2 with IC50 up to
30 nM. This pharmacophore which is sensitive to the
variations at different sites of 1,5-diarylpyrazoles, leaves
an excellent opportunity for further studies to fetch
many more potent COX-2 inhibitors. In addition, this
group being amenable to suitable prodrugs, can play an
important role during developmental studies.
Acknowledgements
The authors are thankful to Dr. K. Anji Reddy, Dr. A.
Venkateswarlu, Dr. R. Rajagopalan and Prof. J. Iqbal
for their constant support and encouragement, and to
Analytical Research group, DRL, for spectral analysis.
References and notes
Docking the potent COX-2 inhibitors 10, 27, 28 and
nimesulide15c into COX-2 active site (6COX),16 gener-
ated various structures of different orientations.23 The
orientation and hydrogen bonding interactions of the
most energetically favored conformation of 10 in COX-
2 complex are shown in Figure 2a. The binding mode of
these novel COX-2 inhibitors is similar to that of SC-
55816 and nimesulide15c and is shown in Figure 2b. The
polar methanesulfonamide group of these compounds
binds in a pocket formed by His-90, Arg-513, Gln-192
and Phe-518. The fluorine atoms of CF3 acts as H-bond
acceptor and form hydrogen bond with the side chain of
Arg-120. Similarly, other substituted phenyl ring at N1
of these compounds lie in a hydrophobic cavity lined by
Tyr-385 and Trp-387. Thus, the reason for these com-
pounds to be COX-2 selective, lies with their strong
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22. Unpublished results.
23. All calculations were performed on Sybyl6.9 Octane 2
workstation. Molecules were sketched and minimized
using MMFF94 force field and charges. Docking study
was carried out using SC-558 bound 6COX (monomer)
crystal structure with FlexX module of Sybyl. The active
˚
site was defined as 6.5 A around the ligand. After dock-
ing, the ligands were merged in the binding site of COX-2,
and energy minimization of this complex was performed
using above method.