Identification of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidinyl] amines and ethers as potent and selective cyclooxygenase-2 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2009.02.085

A novel series of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidine-based cyclooxygenase-2 (COX-2) inhibitors, which have a different arrangement of substituents compared to the more common 1,2-diarylheterocycle based molecules, have been dis

Full text of DOI:10.1016/j.bmcl.2009.02.085

Bioorganic & Medicinal Chemistry Letters 19 (2009) 4504–4508
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Identification of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimi-
dinyl] amines and ethers as potent and selective cyclooxygenase-2 inhibitors
Martin E. Swarbrick §§, Paul J. Beswick , Robert J. Gleave , Richard H. Green, Sharon Bingham,
*
Chas Bountra , Malcolm C. Carter à, Laura J. Chambers, Iain P. Chessell §, Nick M. Clayton, Sue D. Collins,
John A. Corfield, C. David Hartley –, Savvas Kleanthous, Paul F. Lambeth, Fiona S. Lucas, Neil Mathews à,
Alan Naylor, Lee W. Page, Jeremy J. Payne, Neil A. Pegg ||, Helen S. Price, John Skidmore, Alexander J. Stevens,
Richard Stocker, Sharon C. Stratton, Alastair J. Stuart , Joanne O. Wiseman
Pain and Neuroexcitability Discovery Performance Unit, Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow,
Essex CM19 5AW, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidine-based cyclooxygen-
ase-2 (COX-2) inhibitors, which have a different arrangement of substituents compared to the more com-
mon 1,2-diarylheterocycle based molecules, have been discovered. For example, 2-(butyloxy)-4-[4-
(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (47), a member of the 2-pyrimidinyl ether series,
has been shown to be a potent and selective inhibitor with a favourable pharmacokinetic profile, high
brain penetration and good efficacy in rat models of hypersensitivity.
Received 28 November 2008
Revised 20 February 2009
Accepted 22 February 2009
Available online 26 February 2009
Keywords:
Cyclooxygenase
COX-2
Ó 2009 Elsevier Ltd. All rights reserved.
Pyrimidine
CNS penetrant
MeO2S
MeO2S
The demonstration that early selective inhibitors of cyclooxy-
genase-2 (COX-2), such as DuP697 (1)1 and SC 58125 (2, Fig. 1),2
could produce analgesic effects in preclinical models that was
not accompanied by the typical gastrointestinal toxicity associated
with nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspi-
rin and indomethacin provoked intense interest in the area, and
several groups have since reported potent and selective COX-2
inhibitors. The clinical promise of this class has been fulfilled by
N
N
Br
CF3
S
F
F
1, DuP697
H2NO2S
2, SC 58125
MeO2S
Cl
N
N
* Corresponding author. Tel.: +44 1279 643079.
CF3
E-mail address: robert.j.gleave@gsk.com (R.J. Gleave).
Present address: Structural Genomics Consortium (SGC), University of Oxford, Old
Road Campus Research Building, Old Road Campus, Roosevelt Drive, Headington,
Oxford OX3 7DQ, UK.
N
Me
Me
N
à
Present address: Arrow Therapeutics, Britannia House, 7 Trinity Street, London
3, Celecoxib
4, Etoricoxib
SE1 1DA, UK.
MeO2S
MeO2S
§
Present address: MedImmune, Milstein Building, Granta Park, Cambridge CB21
6GH, UK.
CF3
–
Present address: BioFocus DPI, Chesterford Research Park, Saffron Walden, Essex
N
N
CB10 1XL, UK.
N
N
N
||
Present address: CellCentric Ltd, Chesterford Research Park, Little Chesterford,
NR1R2
Cambridge CB10 1XL, UK.
EtO
Present address: Takeda Global Research and Development Centre Europe Ltd., 61
Aldwych, London WC2B 4AE, UK.
5, GW406381
6
§§
Discovery Laboratory, Cancer Research Technology Ltd., 12 Rosemary Lane,
Cambridge CB1 3LQ, UK.
Figure 1.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.02.085

M. E. Swarbrick et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4504–4508
4505
CF3
the marketed inhibitors (for example, celecoxib (3) and etoricoxib
CF3
(4), Fig. 1) which demonstrate clinical efficacy equivalent to NSA-
IDs in the treatment of inflammatory and musculoskeletal pain,
but with an improved gastric safety profile. Despite concerns about
the safety of selective COX-2 inhibitors, raised since the with-
drawal of rofecoxib due to evidence of increased cardiovascular
risk, their potential therapeutic utility has now been extended into
the areas of neurodegenerative disorders3 and cancer.4
a
N
N
b
Cl
N
SMe
N
SMe
9
10
MeS
CF3
CF3
At the outset of our work in the area, all of the reported potent
and selective COX-2 inhibitors featured a 1,2-diaryl substituted
heterocyclic ring which represents the typical core template asso-
ciated with this class, and we have recently reported the identifica-
tion of GW406381 (5)5 as well as demonstrating that a series of
4,5-diarylpyrimidines showed good activity against COX-2 with
selectivity over COX-1.6 We report here our discovery and investi-
N
c
N
N
SO2Me
N
NR1R2
MeO2S
MeO2S
11
12
Scheme 1. Reagents: (a) 4(methylthio)phenylboronic acid, Pd(PPh3)4, Na2CO3,
DME, H2O, 82%; (b) oxone, H2O, MeOH, 91%; (c) R1R2NH, MeCN.
gation of
a
novel 4-[4-(methylsulfonyl)phenyl]-6-(trifluoro-
methyl)-2-pyrimidine-based series of COX-2 inhibitors,7
introducing for the first time a 1,3,5-arrangement of substituents
around a 6-membered heterocyclic ring 6. Recently, the identifica-
tion of an isomeric series of pyrimidine COX-2 inhibitors has also
been reported.8
suggested this should bind in a similar area of the enzyme to the
trifluoromethyl group in celecoxib (3) where it has been shown
to be optimal for the small hydrophobic pocket in which it is be-
lieved to bind.10
As part of an exercise to identify novel templates we studied the
structural requirements for potency and selectivity within the 1,2-
diaryl-heterocyclic series and concluded that there were three fun-
damental requirements, illustrated by the pyrimidine 7. A phenyl-
sulfonyl group appears critical for both potency and selectivity,
adjacent to this a lipophilic aryl group often bearing a substituent
R1 is preferred and a small hydrophobic moiety on the heterocycle
R2 commonly confers additional potency. We proposed that a
2,4,6-trisubstituted heterocycle 8 would be capable of adopting a
similar conformation to the 1,2 diaryl template 7 if a linker (X–Y)
were introduced between the core ring and the second aryl group.
This proposal was supported by molecular modelling studies
(Fig. 2) which showed a good overlay of the minimum energy con-
formations of 7 (black) and 8 (magenta).
Preliminary results are shown in Table 1. Encouragingly both
the aniline and benzylamine derived compounds showed high lev-
els of both potency and selectivity. The benzylamine derivatives
demonstrated the greater potency, possibly due to the length of
the linker allowing the aromatic ring to better fit the binding site.
Given the encouraging profiles of the compounds in Table 1 we
were keen to further explore structure activity relationships within
this novel series of COX-2 inhibitors and prepared a number of
analogues in which the nature of the groups (R1 and R2, compound
12) attached to the 2-amino group were varied. Investigation of the
synthetic route used to prepare these molecules identified an opti-
mized procedure for formation of the key intermediate 11 which is
shown in Scheme 2.9 4-(Methylthio)acetophenone 19 is condensed
with ethyl trifluoroacetate in the presence of base, giving the dike-
tone 20 which is condensed with S-methylisothiourea without iso-
lation to give the pyrimidine 10 in quantitative yield for the two
steps. Oxidation using OxoneÒ again efficiently produces 11. Com-
pounds 21–33 were prepared from compound 11 in good yield and
results are shown in Table 2.
To test the hypothesis we initially prepared a series of 2,4,6-tri-
substituted pyrimidines 13–18 as shown in Scheme 1.9 The com-
mercially available chloropyrimidine
9
underwent Suzuki
coupling in good yield to give the sulfinylphenylpyrimidine 10. A
double oxidation using OxoneÒ efficiently converted both sulfide
groups to sulfones and the resulting 2-sulfonyl pyrimidine 11 re-
acted readily with a number of amines to give the desired products
13–18. The amines chosen were aniline, benzylamine and deriva-
tives substituted in the 4-position with either fluorine or methyl,
groups known to confer potency in the 1,2 diaryl series. The
6-trifluoromethyl substituent was chosen as molecular modeling
Table 1
COX-2 inhibition and selectivity data for an initial set of compounds 13–18
CF3
N
(
)
n
N
N
H
R
RO2S
RO2S
R1
MeO2S
R2
13-18
N
Compound
R
n
0
IC50 COX-2a (nM) IC50 COX-1b (nM) Selectivityc
N
Y
N
N
R2
13
14
15
16
17
18
H
5.6
11
7.2
0.25
<10
0.28
68
32
183
347
>1,00,000
>1,00,000
>65,800
>1,00,000
>1,00,000
>1,00,000
1689
>1,00,000
>1,00,000
>1,00,000
>17,857
>9090
>9138
>4,00,000
>10,000
>3,57,142
4
>3125
>546
>288
4-Me
4-F
H
0
0
1
X
R1
7
8
4-Me
4-F
—
1
1
—
—
—
—
Celecoxib (3)
Rofecoxib
Valdecoxib
Etoricoxib (4)
—
—
—
a
IC50 values for inhibition of PGE2 produced by arachidonic acid stimulated COS
cells stably expressing human COX-2 as described in Ref. 14 are an average of two
determinations.
b
IC50 values for inhibition of PGE2 produced by arachidonic acid stimulated COS
cells stably expressing human COX-1 as described in Ref. 14 are an average of two
determinations.
c
IC50 value for COX-1 divided by IC50 value against COX-2.
Figure 2. Overlay of minimal energy conformations of 7 and 8.

4506
M. E. Swarbrick et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4504–4508
Table 3
O
O
O
COX-2 inhibition and selectivity data for compounds 26 and 38–45
Me
a
R5
b
CF3
R4
MeS
N
MeS
19
20
N
N
H
CF3
MeO2S
CF3
Compound R4
R5
IC50 COX-2a (nM) IC50 COX-1b (nM) Selectivityc
N
N
c
26
38
39
40
41
42
43
44
45
H
H
CF3
0.5
>58,400
>11,6800
N
SMe
N
SO2Me
OCH2CF3 16
6321
395
—
>59
—
—
—
MeS
Me CF3
H
Me
H
H
>10,000
1683
>1,00,000
>1,00,000
>1,00,000
>1,00,000
>1,00,000
>1,00,000
>1,00,000
MeO2S
10
11
Me
H
H
NH2
CO2H
CONH2
>10,000
>10,000
>10,000
>10,000
>10,000
Scheme 2. Reagents: (a) Ethyl trifluoroacetate, NaH, DMF; (b) S-methylisothiourea,
CH3CN, ꢀ100% for two steps; (c) oxone, H2O, MeOH, 91%.
H
H
—
—
Interestingly a number of highly potent, selective molecules
were produced, with analogues containing alkyl groups retaining
the potency of the corresponding phenyl and benzyl derivatives.
Potency was optimal when alkyl and cycloakyl groups (22–27)
were present and the primary amino derivative 21 showed some
activity. As reported with other series of COX-2 inhibitors the sul-
fone could be replaced by a sulfonamide group with retention of
activity but accompanied by a drop in selectivity (24, 27). Acyclic
tertiary amines were tolerated (e.g., 31), however cyclic tertiary
amines were not (32). Introduction of any degree of polarity also
resulted in a loss of activity (e.g., 33).
We next investigated SAR around the 5 and 6 positions of the
pyrimidine ring. Results are shown in Table 3 for the N-cyclohexyl
series (R1 = cyclohexyl, R2 = H), and similar trends were observed
for other active R2 groups.
The compounds shown in Table 3 were prepared by the syn-
thetic route illustrated in Scheme 3, a modification of that used
to prepare the initial analogues as shown in Scheme 1. Commercial
2,4-dichloropyrimidines (34) underwent a selective Suzuki cou-
pling, followed by oxidation to introduce the (methylsulfo-
nyl)phenyl group in the 4-position. The 2-amino groups were
then introduced by displacement of chloride. This route was used
a
IC50 values for inhibition of PGE2 produced by arachidonic acid stimulated COS
cells stably expressing human COX-2 as described in Ref. 14 are an average of two
determinations.
b
IC50 values for inhibition of PGE2 produced by arachidonic acid stimulated COS
cells stably expressing human COX-1 as described in Ref. 14 are an average of two
determinations.
c
IC50 value for COX-1 divided by IC50 value against COX-2.
to prepare all of the compounds shown in Table 3 with the excep-
tion of compound 39 which was prepared as shown in Scheme 2.
As discussed earlier, the trifluoromethyl group had been ini-
tially chosen following molecular modeling studies which sug-
gested that this substituent should bind in a similar area of the
enzyme to the trifluoromethyl group in celecoxib (3) where it
has been shown to be optimal for the small hydrophobic pocket
in which it is believed to bind,10 and the data in Table 3 suggests
that our hypothesis was correct. Increasing or reducing the size
and lipophilicity of R5 results in decreased activity (e.g., 38 and
40), and polar functionality does not appear to be tolerated (43–
45). Introduction of a methyl group on the carbon adjacent to the
phenyl group also results in a loss of activity (39 and 41); we
Table 2
COX2 inhibition and selectivity data for compounds 21–33
CF3
N
1R2
N
NR
R3O2S
Compound
R1
R2
R3
IC50 COX-2a (nM)
IC50 COX-1b (nM)
Selectivityc
21
22
23
24
25
26
27
28
29
30
31
32
33
H
nPr
nBu
nBu
iBu
Cyclohexyl
Cyclohexyl
Cyclohexylmethyl
4-Tetrahydropyranyl
4-Tetrahydropyranylmethyl
4-Methylphenyl
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
NH2
Me
Me
NH2
Me
Me
Me
Me
272
5
1.3
<1.4
2
0.5
2.4
29
18
5
3
>10,000
>10,000
>1,00,000
>1,00,000
>1,00,000
700
>66,200
>58,400
167
>1,00,000
>91,629
100,000
>74,175
>1,00,000
>1,00,000
>368
>2000
>76,923
>500
>33,100
>1,16,800
69.5
>3448
>5090
20,000
>24,725
—
–(CH2)5–
4-Piperidinyl
H
Me
—
a
IC50 values for inhibition of PGE2 produced by arachidonic acid stimulated COS cells stably expressing human COX-2 as described in Ref. 14 are an average of two
determinations.
b
IC50 values for inhibition of PGE2 produced by arachidonic acid stimulated COS cells stably expressing human COX-1 as described in Ref. 14 are an average of two
determinations.
c
IC50 value for COX-1 divided by IC50 value against COX-2.

M. E. Swarbrick et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4504–4508
4507
R5
Table 4
R5
Microsomal COX-2 inhibition and selectivity data for [4-[4-(methylsulfonyl)phenyl]-
6-(trifluoromethyl)-2-pyrimidinyl] ethers
R4
R4
Cl
a
N
b
N
CF3
N
Cl
N
Cl
N
MeS
35
34
N
OR
R5
N
R5
N
MeO2S
R4
R4
IC50 COX-2a
(nM)
IC50 COX-1b
(nM)
Selectivityc
>16
N
c
N
Compound
R
Cl
NR1R2
Celecoxib
—
63
>1000
MeO2S
MeO2S
(3)
Rofecoxib
25
47
48
36
37
—
—
nBu
iPr
107
12
21.5
63
ND
—
>1,00,000
>30,000
52,556
52,000
3752
4357
19,000
4038
1860
1921
3000
69,000
>1,00,000
ND
>8333
>1395
834
Scheme 3. Reagents: (a) 4(methylthio)phenyl boronic acid, Pd(PPh3)4, Na2CO3,
DME, H2O, 82%; (b) oxone, H2O, MeOH, 91%; (c) R1R2NH, MeCN.
49
50
tBu
33
1576
>375
>436
>1900
>404
>186
>192
>300
3136
>2222
—
4-Me–C6H4
3-Me–C6H4
Cyclobutyl
Cyclopentyl
Cyclohexyl
Cycloheptyl
Cyclooctyl
Cyclopentylmethyl 22
Cyclohexylmethyl 45
Cycloheptylmethyl 1034
<10
<10
<10
<10
<10
<10
<10
51
52
53
54
55
56
57
58
suspect this loss of activity is due to the adjacent phenyl ring twist-
ing further out of plane into a less favourable conformation.
Encouraged by the good levels of COX-2 potency and selectivity
observed in many examples of the [4-[4-(methylsulfonyl)phenyl]-
6-(trifluoromethyl)-2-pyrimidinyl]amine series, we also sought to
explore alternative linkers such as oxygen in the pyrimidine 2-po-
sition. Ether analogues 47–59 were readily prepared by the treat-
ment of compound 11 with 1 equiv of the sodium anion of the
requisite alcohol, or by treatment with an excess of the alcohol
(as solvent) in the presence of 1.1 equiv of potassium carbonate,
as shown in Scheme 4.11
59
a
IC50 values for inhibition of PGE2 produced by arachidonic acid stimulation of a
COX-2 microsomal preparation from baculovirus-infected SF9 cells as described in
Ref. 11 are an average of two determinations.
b
IC50 values for inhibition of PGE2 produced by arachidonic acid stimulation of a
COX-1 microsomal preparation from baculovirus-infected SF9 cells as described in
Ref. 11 are an average of two determinations.
COX-1 and COX-2 inhibition data for the ether series are sum-
marised in Table 4. It should be noted that, for this series, screening
was carried out using microsomal preparations of the COX en-
zymes, and the analogous data for celecoxib (3), rofecoxib (not
shown) and compound 25 have been included for comparison.
For further comparison, compound 47 gave IC50 values for COX-2
and COX-1 inhibition of 58 nM and >1,00,000 nM respectively
when tested in the cellular assay used for Tables 1–3. It can be seen
that a range of alkoxy, phenoxy and cycloalkoxy substituents (e.g.,
47–56) are well tolerated at the 2-position of the pyrimidine ring.
While cyclopentylmethoxy (57) and cyclohexylmethoxy (58) sub-
stituents are also well tolerated, potency is somewhat eroded with
the larger cycloheptylmethoxy group (59). In general, compounds
from the ether series 47–58 display high levels of selectivity with
respect to COX-1 inhibition, although this is slightly reduced with
phenoxy and larger cycloalkyl substituents.
It has been suggested that COX-2 activity in a human whole
blood assay is representative of clinical efficacy and that relative
selectivity over COX-1 correlates with therapeutic index with re-
spect to gastro-intestinal toxicity.12,13 We tested representatives
of the new 4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-
pyrimidine class of COX-2 inhibitor in a whole blood assay and re-
sults are shown in Table 5.20 The five inhibitors tested were highly
potent COX-2 inhibitors in this assay, at least as potent as mar-
keted drugs and compound 16 was much more potent. High levels
of selectivity over COX-1 were also observed.
c
IC50 value for COX-1 inhibition divided by IC50 for COX-2 inhibition.
To determine their suitability for in vivo testing we investigated
the pharmacokinetic properties of a number of the compounds de-
scribed above, and several demonstrated excellent profiles, as
exemplified by compounds 25 (also known elsewhere as
GW637185X) and 47. Following administration at a dose of
1 mg/kg to male rats as a 1 h intravenous infusion 25 demon-
strated low blood clearance (10 ml/min/kg) with a steady-state
volume of distribution indicative of tissue distribution of 6.0 L/kg
Table 5
COX-2 inhibition and selectivity data for representative compounds in a human
whole blood assay20
CF3
N
N
X
MeO2S
Compound
R
IC50 COX-2a
(nM)
IC50 COX-1b
(nM)
Selectivityc
16
23
25
26
Benzylamino
nButylamino
iButylamino
Cyclohexylamino 62
nButyloxy
8
70
206
39,300
>96,150
62,000
11,600
17,410
10,194
4913
>1374
301
187
110
47
158
336
CF3
CF3
Celecoxib
(3)
—
30
N
N
Rofecoxib
Etoricoxib
(4)
—
—
260
554
15,500
>100,000
60
>180
N
SO2Me
N
OR
a
MeO2S
MeO2S
IC50 values for inhibition of PGE2 produced in lipoplysaccharide-stimulated
human whole blood as described in Ref. 14.
11
46
b
IC50 values for inhibition of TxB2 produced in lipoplysaccharide-stimulated
Scheme 4. Reagents and conditions: ROÀ Na+ (1 equiv), THF, room temperature, or
ROH (excess, as solvent), K2CO3 (1.1 equiv), 50 °C.
human whole blood as described in Ref. 14.
c
IC50 value for COX-1 divided by IC50 value against COX-2.

4508
M. E. Swarbrick et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4504–4508
experimental drugs has been reported.19 Mechanical hypersensi-
120
100
80
tivity was quantified by measuring the reversal of the decrease
in paw withdrawal threshold (in response to a mechanical stimu-
lus) which is present in the ligated animals. Compound 47 was
administered at 5 mg/kg po bid for 10 days and rats were tested
on days 1 (after 1st dose), 3, 7 and 10 after dosing. Compound 47
fully reversed mechanical hypersensitivity to the level present in
sham-operated animals by day 3 of dosing and this effect was
maintained during the dosing period (Fig. 3).
In summary, we have identified a novel series of 4-[4-(methyl-
sulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidines as highly po-
tent and selective COX-2 inhibitors. Several examples, illustrated
by compounds 25 and 47, have favourable pharmacokinetic pro-
files, with high levels of brain penetration in the rat. Compounds
25 and 47 also show good efficacy in a rat model of acute inflam-
matory pain, and 47 has been shown to reverse hypersensitivity in
a rat model of nerve injury-induced hyperalgesia.
↑
↑
Treatment period
60
1
15
20
25 30
Time post-surgery (Days)
35
40
Figure 3. Reversal of the decrease in paw withdrawal threshold to mechanical
stimulus by compound 47 in the CCI model of nerve injury-induced hyperalgesia.
, Vehicle p.o.;
, 47 (5 mg/kg p.o. b.i.d.);
, Vehicle (sham) p.o.
and a terminal half-life of 9.0 h. When administered by oral gavage
at a dose of 5 mg/kg as a suspension in 1% methylcellulose/water in
a separate study, oral bioavailability was estimated to be 107%. Fol-
lowing administration at a dose of 1 mg/kg to male rats as a 1 h
intravenous infusion, compound 47 demonstrated low blood clear-
ance (24 mL/min/kg) with a steady-state volume of distribution
indicative of tissue distribution of 5.7 L/kg and a terminal half-life
of 4.2 h. When administered by oral gavage at a dose of 1 mg/kg as
a suspension in 1% methylcellulose/water, oral bioavailability was
approximately 84%.
Several of the compounds described above were found to be
efficacious in the complete Freund’s adjuvant rat model of acute
inflammatory pain;15 for example, compounds 25 and 47 were
found to have ED50 values (dose that would give 50% reversal of
hypersensitivity) of 0.5 and 2.1 mg/kg, showing a good correlation
between in vitro and in vivo potency.
There is increasing interest in the important roles played by
COX-2 and prostaglandins in the central nervous system (CNS).16
We have determined the extent to which compounds 25, 47, cele-
coxib (3) and rofecoxib, cross the blood-brain barrier in rats. Com-
pounds 25 (3.4:1) and 47 (3.2:1) were found to have relatively high
brain:blood concentration ratios compared to rofecoxib (0.8:1) and
celecoxib (0.1:1), suggesting that the new 4-[4-(methylsulfo-
nyl)phenyl]-6-(trifluoromethyl)-2-pyrimidine class of COX-2
inhibitors may be useful to explore the role of COX-2 in the CNS.
For example, compound 25 has been shown to protect against 1-
methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced in-
jury of nigrostriatal dopaminergic (DA) neurons in the mouse.17
We chose to investigate the potential of compound 47 in the rat
Chronic Constriction Injury (CCI) model18 of nerve injury-induced
hyperalgesia. In this model, hyperalgesia and allodynia are present
for several weeks following loose ligation of the sciatic nerve with
chromic gut suture. Mechanical hyperalgesia develops during the
animals’ post surgery recovery time. Central sensitisation is a com-
ponent of this model, although peripheral mechanisms cannot be
discounted. One group of animals (sham operated), which undergo
an identical surgical procedure with the exception of the ligation,
act as a positive control for reversal of the hypersensitivity.
The sensitivity of this model to various clinically-validated and
References and notes
1. Gans, K. R.; Galbraith, W.; Roman, R. J.; Haber, S. B.; Kerr, J. S.; Schmidt, W. K.;
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6. Manuscript submitted (paper 1, Ms. Ref. No.: BMCL-D-08-01867).
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conversion to the [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-
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11. Full experimental details for the synthesis of compound 47, and
representative procedure for compounds 48–59, can be found in Ref. 7b.
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a
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20. The human biological sample was sourced ethically and its research use was in
accord with the terms of the informed consent.