The discovery of 6-[2-(5-chloro-2-{[(2,4-difluorophenyl)methyl]oxy}phenyl)-1-cyclopenten- 1-yl]-2-pyridinecarboxylic acid, GW848687X, a potent and selective prostaglandin EP1 receptor antagonist for the treatment of inflammatory pain

Article abstract of DOI:10.1016/j.bmcl.2006.10.041

The discovery of a series of selective EP₁ receptor antagonists based on a 1,2-diarylcyclopentene template is described. After defining the structural requirements for EP₁ potency and selectivity, heterocyclic rings were incorporated

Full text of DOI:10.1016/j.bmcl.2006.10.041

Bioorganic & Medicinal Chemistry Letters 17 (2007) 385–389
The discovery of 6-[2-(5-chloro-2-{[(2,4-difluorophenyl)-
methyl]oxy}phenyl)-1-cyclopenten-1-yl]-2-pyridinecarboxylic acid,
GW848687X, a potent and selective prostaglandin EP1 receptor
antagonist for the treatment of inflammatory pain
a
a
a
Gerard M. P. Giblin,a, Rino A. Bit, Susan H. Brown, Helene M. Chaignot,
*
´ `
Anita Chowdhury,b Iain P. Chessell,b Nicholas M. Clayton,b Tanya Coleman,a
Adrian Hall,a Beverley Hammond,a David N. Hurst,a Anton D. Michel,b Alan Naylor,a
Riccardo Novelli,a Tiziana Scoccitti,a David Spalding,a Sac P. Tang,a
Alex W. Wilsonb and Rich Wilsonc
aDepartment of Medicinal Chemistry and DMPK, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
bDepartment of Pain Biology, Neurology and Gastrointestinal Centre of Excellence for Drug Discovery,
New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
cDiscovery Research GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
Received 2 October 2006; revised 13 October 2006; accepted 16 October 2006
Available online 20 October 2006
Abstract—The discovery of a series of selective EP1 receptor antagonists based on a 1,2-diarylcyclopentene template is described.
After defining the structural requirements for EP1 potency and selectivity, heterocyclic rings were incorporated to reduce logD
and improve in vitro pharmacokinetic properties. The 2,6-substituted pyridines and pyridazines gave an appropriate balance of
potency, in vivo pharmacokinetic properties and a low potential for inhibiting a range of CYP450 enzymes. From this series,
GW848687X was shown to have an excellent profile in models of inflammatory pain and was selected as a development candidate.
Ó 2006 Elsevier Ltd. All rights reserved.
Prostaglandin PGE2 is a key mediator of pain and
inflammation.1 Non-steroidal anti-inflammatory drugs
(NSAIDs) and selective COX-2 inhibitors that interrupt
the biosynthesis of PGE2 and other prostaglandins (PGs)
are first-line treatments for inflammatory pain,2 includ-
ing pain associated with osteoarthritis, rheumatoid
arthritis and chronic low back pain.3 Although selective
COX-2 inhibitors have been successful in reducing gas-
trointestinal side effects associated with NSAIDs,4 there
remain significant safety issues as evidenced by the recent
withdrawal from the market of Vioxx.5 PGE2 acts down-
stream on four G-protein coupled 7-transmembrane
receptors, EP1–4.6 Studies with EP1 knock-out mice have
suggested a central role of the EP1 receptor in PGE2-
mediated allodynia7 and inflammatory pain;8 and there
is evidence that PGE2 acts on EP1 receptors located both
peripherally and in the CNS.9 EP1 receptor antagonists
have shown efficacy in preclinical models of postopera-
tive pain,10 neuropathic pain11 and allodynia12 and it is
hypothesised that, by sparing the synthesis of PGs, EP1
receptor antagonists may have an improved safety pro-
file. A number of selective EP1 receptor antagonists have
been reported in the literature (Fig. 1). The Searle group
have described acylhydrazides such as SC5132213 1;
AstraZeneca have highlighted the efficacy of ZD6416 2
in a human model of visceral hyperalgesia,14 Ono have
reported ONO-8713 315 and Merck Frosst have
identified a series of thiophene analogues 4.16 As part
of a long-standing interest in prostaglandin receptors,
we sought to discover EP1 receptor antagonists as
potentially clinically effective analgesics. We focused
our initial approach on exploring 1,2-substituted cyclic
templates17 and this paper describes the optimisation of
the 1,2-diarylcyclopentene series 5 and discovery of
Keywords: EP1; Inflammatory pain; Cyclopentene.
*
Corresponding author. Tel.: +44
ged.m.giblin@gsk.com
0
1279627539; e-mail:
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.10.041

386
G. M. P. Giblin et al. / Bioorg. Med. Chem. Lett. 17 (2007) 385–389
O
O
O
Cl
S
N
H
O
N
Br
N
N
H
O
N
N
S
N
H
O
O
O
1
SC-51322
2
ZD-6416
O
R
OH
F3C
O
O
S
O
O
O
S
O
N
CO2H
CO2H
3
ONO-8713
Cl
4
5
Figure 1. EP1 antagonists (1) Searle, (2) AstraZeneca, (3) Ono, (4) Merck-Frosst and (5) GSK.
GW848687X, a candidate for the treatment of inflamma-
tory pain.
acid 7b is an air stable solid at room temperature
that shows no evidence of self-coupling under Suzuki
reaction conditions.
The synthetic route to the cyclopentene analogues is
shown in Scheme 1.18 We identified commercially avail-
able dibromocyclopentene 7a as a potentially versatile
building block. Appropriately substituted aryl boronic
acids 6a were reacted under carefully controlled Suzuki
conditions with 4 equiv of 1,2-dibromocyclopentene 7a
to furnish the bromocyclopentene 8. A second Suzuki
coupling with the meta substituted boronic acid ester 9
installed the second aromatic ring. Subsequent cleavage
of the methyl ether and ethyl ester with sodium methyl-
thiolate, followed by benzylation and saponification of
the ester, gave the target compound 10. An alternative
first step that utilizes the novel 2-bromo-1-cyclopenten-
eboronic acid 7b was developed. This route allowed
better control of the first Suzuki coupling with
iodo-benzenes such as 6b, requiring just one molar
equivalent of 7b. It is noteworthy that the novel boronic
Evaluation of the aromatic substitution patterns around
the A and B phenyl rings (see structure 10) confirmed
that a meta-acid substituent in the A-ring and an
ortho-benzyloxy substituent in the B ring were optimal
for EP1 potency.19 Detailed exploration of the require-
ments for EP1 activity was initially focused on the role
of the benzyl substitution pattern and the 50-substituent
(Table 1).
The 50-substituent is important for potency. For unsub-
stituted C-ring analogues, the rank order of potency is
X = Cl, H > Br > MeS,MeSO2, CN (analogues 10, 11,
16, 23, 26, and 29). When X = H, the unsubstituted ben-
zyl analogue 11 is most potent. The 2,4-difluorobenzyl
analogue 12 is the next most active. For each of the other
B-ring 50-substituents the 2,4-difluorobenzyl analogue is
B(OH)2
Cl
B(OH)
2
Br
Br
7a
9
OMe
I
MeO
a
d
6a
6b
CO Et
2
Br
Cl
b
7b
(HO)
B
Br
8
2
Cl
OMe
MeO
O
CO2Et
C
CO2H
c
A
B
Cl
10
Cl
Scheme 1. Synthesis of cyclopentene EP1 antagonists. Reagents and conditions: (a) Pd(PPh3)4, DME-H2O, 80 °C; (b) Pd(PPh3)4, DME-H2O, 80 °C;
(c) i—MeSNa; ii—benzyl bromide, K2CO3; iii—NaOH, EtOH; (d) Pd(PPh3)4, 1:1 toluene–ethanol, 90 °C.

G. M. P. Giblin et al. / Bioorg. Med. Chem. Lett. 17 (2007) 385–389
387
Table 1. SAR of phenyl acid analogues
in vivo pharmacokinetic profiles. During the course of
this work we were able to establish that a CF3 group
was an acceptable replacement for halogen substituents
in the B-ring, Table 3 compounds 33 and 35. Compounds
were screened for rate of metabolism (intrinsic clearance,
CLi) in a rat microsomal assay and for CYP450 inhibi-
tion in a human 2C9 CYP450 isozyme assay.
R
O
2'
CO H
2
5'
X
A-ring pyridine analogues gave high EP1 potency with
the exception of the 2,4-isomer 33. The pyridazine ana-
logue 37 showed low EP1 activity but its isomer, com-
pound 38, possessed almost 10-fold higher potency.
Disappointingly pyridazine analogue 38 had high intrin-
sic clearance in rat microsomes and was a potent inhib-
itor of the 2C9 CYP450 isozyme. Pyrimidines 39 and 40
showed low EP1 potency however the pyrazine analogue
41 had high potency with low intrinsic clearance in rat
microsomes and acceptable 2C9 activity. Analogues 35
and 42 had much reduced rat in vivo clearance and im-
proved half-life. Selected compounds were tested in the
Freund’s complete adjuvant rat model of acute inflam-
matory pain.20 Compounds were either assayed in a sin-
gle dose study at 5 mg/kg po or in a 3 point dose
response assay for which an ED50 (dose that would give
50% reversal of hypersensitivity) was calculated (see Ta-
ble 3). Whereas analogues 36 and 41 had modest poten-
cy and failed to show full reversal of hypersensitivity,
analogues 35 and 42 gave a low ED50 and full reversal
of hypersensitivity in this acute model of inflammatory
pain. Subsequent evaluation of pyridine analogues 35
and 42 in a chronic rat model of joint pain21 clearly dif-
ferentiated these compounds. Nicotinic acid analogue 35
showed no significant antihyperalgesic effect (data not
shown) when dosed for 5 days at 30 mg/kg b.i.d. How-
ever, picolinic acid analogue 42 at the same dose showed
complete reversal of the anti-hyperalgesic effect with a
response equivalent to rofecoxib (Fig. 2).
Compound
X
R
hEP1 pIC50
11
12
13
14
15
10
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
H
H
8.2 0.2
7.6 0.1
6.4 0.1
7.3 0.1
7.0 0.0
8.3 0.2
7.9 0.3
7.9 0.2
7.7 0.4
7.0 0.2
8.3 0.3
8.6 0.2
7.4 0.4
7.2 0.1
7.5 0.2
7.8 0.2
7.1 0.1
7.1 0.2
7.8 0.2
7.0 0.2
6.4 0.1
7.4 0.2
6.7 0.2
H
2,4-Difluoro
3,4-Dichloro
H
H
2-Fluoro, 4-chloro
4-Methoxy
H
H
Cl
Br
Br
H
4-Chloro
4-Fluoro
3,4-Dichloro
2,4-Difluoro
2-Fluoro, 4-chloro
4-Methoxy
H
Br
Br
Br
Br
Br
MeS
MeS
MeS
MeSO2
MeSO2
MeSO2
CN
CN
CN
CN
4-Fluoro
2,4-Difluoro
H
4-Fluoro
2,4-Difluoro
H
4-Fluoro
2,4-Difluoro
4-Chloro
Values are means of four experiments SD. All compounds were
inactive (functional pIC50 < 5.5) at the human EP3 receptor.
most potent, suggesting this substitution pattern is
important for high EP1 affinity. In order to characterise
the in vivo pharmacokinetics of this series, selected
analogues were administered intravenously to rats
(Table 2). These compounds had low volumes of distri-
bution, moderate-to-high blood clearance and very short
half-lives. Low volume of distribution and short half-life
are typical properties of lipophilic acids (e.g., NSAIDs)
but we hypothesised that reduction of logD may reduce
clearance and extend half-life. Selected compounds were
assessed in human recombinant CYP450 assays and it
was found that inhibitory activities (IC50) across a panel
of human CYP450 enzymes were generally in excess of
10 lM with the exception of CYP2C9.
On the basis of this profile, compound 42 6-[2-(5-chloro-
2-{[(2,4-difluorophenyl)methyl]oxy}phenyl)-1-cyclopen-
ten-1-yl]-2-pyridinecarboxylic acid, GW848687X, was
selected for further evaluation. GW848687X is a com-
petitive antagonist at the EP1 receptor with a pA2 9.1.
It has >400-fold selectivity relative to the other EP
receptor subtypes, the DP receptor and the IP (prostacy-
clin) receptor. It has 30-fold selectivity over the TP
(thromboxane A2) receptor, acting as a functional
antagonist at this receptor.22 It shows no significant ef-
fect at a range of other receptors and enzymes in the
CEREP screen at 1 lM. GW848687X has an excellent
oral pharmacokinetic profile; oral bioavailability is
54% in the rat and 53% in dog. It has a half-life of 2 h
in both species. These data suggest that GW848687X
may have benefit for treating both acute and chronic
pain conditions.
A-ring heterocyclic replacements were investigated in
an attempt to lower log D and to improve in vitro and
Table 2. Rat iv pharmacokinetics (1 mg/kg) for selected analogues
Compound
CLb (ml/min/kg)
Vd (L/kg)
t1/2 (h)
In conclusion, we have identified a novel series of EP1
receptor antagonists based on
a 1,2-disubstituted
10
16
17
18
20
54
52
33
46
35
0.8
1.0
0.4
0.7
0.6
0.5
0.3
cyclopentene template. Optimising in vitro and in vivo
activities has led to the identification of GW848687X,
a selective EP1 receptor antagonist as a candidate
for the treatment of acute and chronic inflammatory
pain.
NT
0.2
0.2
NT, not tested.

388
G. M. P. Giblin et al. / Bioorg. Med. Chem. Lett. 17 (2007) 385–389
Table 3. A-ring heterocyclic analogues
O
R
Ar
X
Compound
R
X
Ar
hEP1 pIC50 Rat CLi
CYP 2C9 logD Rat CLb
Rat t1/2 Rat FCA
(ml/min/g) IC50 (lM)
(ml/min/kg) (h)
CO2H
33
34
35
36
37
38
39
40
41
42
H
CF3
Br
7.4 0.2
8.5 0.0
8.0 0.1
8.8 0.1
7.4 0.2
8.2 0.2
6.7 0.2
6.8 0.1
8.7 0.1
8.6 0.1
NT
NT
NT
2.7
2.7
2.7
NT
1.2
1.2
0.8
1.6
2.6
NT
NT
NT
N
CO2H
CO2H
4-Fluoro
H
20
5
NT
NT
NT
N
CF3
Cl
2.2
3.8
NT
14
14
22
4.1
ED50 1.3 mg/kg
<30% at 5 mg/kg
NT
N
N
N
N
CO2H
CO2H
CO2H
4-Fluoro
H
9
NT
NT
NT
NT
NT
NT
7
NT
NT
NT
NT
NT
NT
2.2
Cl
NT
5.4
NT
NT
12
N
2,4-Difluoro Cl
NT
N
CO2H
H
H
Cl
Cl
NT
NT
2.6
2.9
NT
N
N
N
N
N
CO2H
CO2H
NT
2,4-Difluoro Cl
2,4-Difluoro Cl
52% at 5 mg/kg
ED50 1.3 mg/kg
N
N
CO2H
14
NT, not tested. For the rat FCA model, data are presented as either an ED50 values corresponding to the dose calculated to show a 50% reduction in
hypersensitivity; or a percentage reversal of hypersensitivity at a given oral dose.
120
Vehicle (1% MC)
100
80
60
40
20
0
GW848687X (30mg/kg)
Rofecoxib (5mg/kg)
F
F
O
N
CO2H
Cl
-1
1
3
5
7
9
11 13 15 17 19
GW848687X
Time (Days post FCA)
Figure 2. Analogue 42, GW848687X, shows anti-hyperalgesic activity (red) in an FCA induced joint pain model of inflammatory pain. GW848687X
was orally dosed at 30 mg/kg per day in a 1% methylcellulose vehicle over 5 days and compared with rofecoxib (Vioxx) 5 mg/kg (green).

G. M. P. Giblin et al. / Bioorg. Med. Chem. Lett. 17 (2007) 385–389
389
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appropriate, an ED50 calculated.
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22. The activity of GW848687X at the prostaglandin FP and
CRTH2 receptors has not been characterised.