Discovery of GSK345931A: An EP1 receptor antagonist with efficacy in preclinical models of inflammatory pain

Article abstract of DOI:10.1016/j.bmcl.2008.11.032

Herein we describe the medicinal chemistry programme to identify a potential back-up compound to the EP₁ receptor antagonist GW848687X. This work started with the lipophilic 1,2-biaryl benzene derivative 4 which displayed molecular weight of 41

Full text of DOI:10.1016/j.bmcl.2008.11.032

Bioorganic & Medicinal Chemistry Letters 19 (2009) 497–501
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of GSK345931A: An EP1 receptor antagonist with efficacy
in preclinical models of inflammatory pain
*
Adrian Hall , Susan H. Brown, Christopher Budd, Nicholas M. Clayton, Gerard M. P. Giblin,
Paul Goldsmith, Thomas G. Hayhow, David N. Hurst, Alan Naylor, D. Anthony Rawlings,
*
Tiziana Scoccitti , Alexander W. Wilson, Wendy J. Winchester
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:
Herein we describe the medicinal chemistry programme to identify a potential back-up compound to the
EP1 receptor antagonist GW848687X. This work started with the lipophilic 1,2-biaryl benzene derivative
4 which displayed molecular weight of 414.9 g/mol and poor in vivo metabolic stability in the rat and
resulted in the identification of compound 7i (GSK345931A) which demonstrated good metabolic stabil-
ity in the rat and lower molecular weight (381.9 g/mol). In addition, 7i (GSK345931A) showed measur-
able CNS penetration in the mouse and rat and potent analgesic efficacy in acute and sub-chronic models
of inflammatory pain.
Received 10 October 2008
Revised 10 November 2008
Accepted 11 November 2008
Available online 14 November 2008
Keywords:
EP1 antagonist
Pain
Ó 2008 Elsevier Ltd. All rights reserved.
Inflammatory pain
CNS penetration
Free concentration
Prostaglandin E2 (PGE2) is a proinflammatory mediator that has
been linked with a causative role in pain and inflammation1 and
this lack of efficacy in a sub-chronic model of inflammatory pain
will be the subject of future publications.
exerts its physiological action by activating four G-protein coupled
As part of an ongoing programme we wished to identify a po-
tential back-up compound to GW848687X which also demon-
strated efficacy in both acute and sub-chronic preclinical models
of inflammatory pain but also offered some form of structural
diversity over GW848687X.
2
receptors, EP1–4
.
Antagonists of the EP1 receptor subtype have
shown efficacy in preclinical models of inflammatory pain.3 Thus
further EP1 antagonists with preclinical efficacy are needed to as-
sess this mechanism of action in a clinical setting.
Following the publication of our initial work to discover novel
EP1 receptor antagonists4 we have subsequently reported the opti-
mization of the pyrrole series,5 which led to the identification of
compounds such as GW855454X (1),5c and the cyclopentene deriv-
ative GW848687X (2)6 which was selected as a development can-
didate (Fig. 1).
Extensive profiling of GW848687X had shown oxidation of the
allylic position of the cyclopentene ring to be one of the metabolic
routes. Thus in order to address the above, we elected to use the
1,2-biarylbenzene lead compound 44 as our starting point (Fig. 2).
Compound 4 showed good in vitro activity in both [3H]-PGE2
binding4 and functional4 (mobilization of intracellular Ca2+ mea-
sured by FLIPR) assays, IC50 50 nM and Ki 32 nM, respectively. De-
spite showing low intrinsic clearance in rat and human liver
microsomes, the rat in vivo pharmacokinetic (PK) profile was not
optimal. Furthermore the compound was highly lipophilic, with a
clogP of 7.0 (measured logD 2.2 at pH 7.4). Thus, our goals were
to investigate the SAR of this template and to optimize EP1 activity
whilst improving the in vivo DMPK profile.
GW848687X was efficacious in acute and sub-chronic preclini-
cal models of inflammatory pain,6 namely the Complete Freund’s
Adjuvant (CFA) model of inflammatory pain5a,6 and
a joint
pain model of inflammatory pain.6,7 However, we previously re-
ported that close structural analogues of GW848687X, such as
GW845706X (3), Figure 1, failed to show efficacy in the joint pain
sub-chronic model of inflammatory pain. Studies to understand
Initial structure–activity relationships (SAR) established that the
Cl-atom on the A-ring (X-group) was not critical for activity, com-
pare 4 to 5a (Table 1) but if moved (Y-position), 5b, was detrimental
to activity (Table 1). Substitution of the central phenyl ring (B-ring)
revealed that only the 4-position was amenable to substitution,
compound 5e, although this did not increase EP1 affinity. This result
* Corresponding authors. Tel.: +44 1279 643464 (A. Hall), +44 1279 643174
(T. Scoccitti).
E-mail addresses: adrian.2.hall@gsk.com (A. Hall), tiziana.2.scoccitti@gsk.com (T.
Scoccitti).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.11.032

498
A. Hall et al. / Bioorg. Med. Chem. Lett. 19 (2009) 497–501
Cl
Cl
F3C
N
CO2H
N
CO2H
CO2H
O
O
F
O
N
F
F
1: GW855454X
2: GW848687X
3: GW845706X
Figure 1. Selected published GSK EP1 receptor antagonists GW855454X (1), GW848687X (2) and GW845706X (3).
As we had found that the C-ring could be replaced by aromatic
EP1 binding pIC50 = 7.3 ± 0.5
EP1 FLIPR pKi = 7.5 ± 0.4
heterocycles in the cyclopentene series, and that this change had re-
sulted in compounds with good oral bioavailability and in vivo effi-
cacy we decided to investigate a similar change in the current series.
Thus, the phenyl ring (C-ring) in compound 4 was replaced with
pyridine to give compound 7a (Table 3) which resulted in a slight
increase in the EP1 affinity.
O
B
Cl
rat CLi < 0.5 mL/min/g liver
human CLi < 0.5 mL/min/g liver
OH
A
C
O
rat pharmacokinetics
CLb = 64 mL/min/kg
Vss = 1.4 L/kg
D
4
t1/2 = 0.3h
Further SAR investigation of the R-group on the A-ring revealed
that benzyl group could be substituted with halogenated benzyl
groups (7b–h). As in the cyclopentene series the 2,4-difluorobenzyl
derivative (7c) was the most preferred benzyl derivative (Table 3).
As we had found that the benzyl group could be replaced by alkyl
groups, and in particular an iso-butyl group, in the pyrrole series5a
we decided to investigate similar modifications in the current series.
Thus compounds 7i–l were prepared. The SAR showed that the iso-
butyl group proved optimal (compound 7i) and was considerably
better than any of the other groups investigated (7j–l) (Table 3).
Based on structural differentiation over GW848687X and its
overall profile, including in vitro activity data, CYP450 inhibition
MW 414.9 g/mol; logD 2.2
Figure 2. Profile of lead compound 4.
is in line with results in the related pyrrole series, where it was found
a methyl group was tolerated in an analogous position.4,5a It was also
found that the acid group could be moved from the meta- to the
ortho-position without affecting activity, whereas translocation to
the para-position drastically reduced activity (Table 1).
We next investigated substitution of the benzoic acid (C-ring).
Substitution in the 2-, 4- or 6-position generally resulted in a de-
crease in EP1 affinity, 6a–c, (Table 2). The effect of substitution at
the 6-position is in contrast to the SAR in the related pyrrole series
where substitution of the 6-position was well tolerated.5c Substitu-
tion at the 5-position was best tolerated. The addition of acylamino
groups generally increased affinity 6e–i; propylacetamide 6g in-
creased the affinity by more than 10-fold.
data (CYP450 IC50 values, 1A2 >100 lM, 2C19 62 lM, 2C9 25 lM,
2D6 >100 lM, 3A4 89 lM) and good in vitro metabolic stability
(Table 4),8 compound 7i (GSK345931A) was selected for further
evaluation.
In terms of solubility, GSK345031A (sodium salt) showed mod-
erate aqueous solubility, low solubility in simulated gastric fluid
(SGF) and good solubility in fasted and fed state simulated intesti-
nal fluid (FaSSIF and FeSSIF), Table 5.9 The compound displays two
pKa values, 4.8 and 1.3, which were attributed to the carboxylic
acid and pyridyl N-atom, respectively.10
Although a good level of affinity was achieved with these sub-
stitutions (Tables 1 and 2), the physicochemical properties of these
compounds were not optimal, as already seen in the related pyr-
role series.5b,c
Table 2
Table 1
In vitro binding data for compounds 6a–i
In vitro binding data for compounds 4 and 5a–h
3
2
O
Z
B
2
C
5
4
X
1
B
o
OH
X
Y
A
m
p
O
6
4
C
A
O
Y
OH
O
a
Compound
X
Y
Binding pIC50
a
Compound
X
Y
Z
Acid
Binding pIC50
4
Cl
H
H
H
H
H
H
2-Me
4-F
6-Cl
5-F
5-NHAc
5-NHCOEt
5-NHCOPr
5-NHCOi-Pr
7.3 0.5
7.7 0.0
6.3 0.3
7.1 0.1
6.9 0.1
7.2 0.1
8.0 0.0
8.2 0.1
8.7 0.1
8.0 0.1
8.4 0.1
5a
6a
6b
6c
6d
6e
6f
6g
6h
6i
4
5a
Cl
H
H
Cl
Cl
Cl
Cl
Cl
Cl
H
H
Cl
H
H
H
H
H
H
H
H
H
2-Me
3-Me
4-Me
3-Cl
H
m
m
m
m
m
m
m
o
7.3 0.5
7.7 0.0
6.5 0.1
<6
<6
7.0 0.0
<6
5b
5cb
5db
5eb
5fb
5g
H
Cl
Cl
Cl
Cl
Cl
7.7 0.1
6.1 0.0
5h
H
p
5-NHCOCH2OMe
a
Values are the means of at least three experiments.
Sodium salt.
a
b
Values are the means of at least three experiments.

A. Hall et al. / Bioorg. Med. Chem. Lett. 19 (2009) 497–501
499
Table 3
GSK345931A also displays good oral bioavailability in the rat
and moderate bioavailability in the cynomolgus monkey (Table 6).
Despite being a carboxylic acid, GSK345931A shows measurable
CNS penetration in both the mouse and the rat with brain-to-blood
(Br:Bl) ratios of 0.24 and 0.33, respectively (Table 7).
In the rat, GSK345931A displayed a low unbound fraction in both
blood and brain tissue (Fu Bl = 0.50 0.14%, Fu Br = 0.53 0.07%,
Kbb = 0.93).11
In vitro binding data for compounds 7a–l
O
B
Cl
N
C
OH
A
O
R
When tested in Complete Freund’s Adjuvant (CFA) model of
inflammatory pain,5,6 GSK345931A produced a dose related rever-
sal of hypersensitivity with calculated ED50 values of 1.6 and
2.4 mg/kg (when dosed at 1, 2 and 3 mg/kg or 1, 3 and 10 mg/kg,
respectively).
Bioanalysis from both studies revealed a dose-proportional in-
crease in exposure (Table 8). The overlapping dose groups (1 and
3 mg/kg) provided comparative exposure. The CNS penetration, as
measured by brain-to-blood ratio (Br:Bl), was similar to that found
in the steady state studies (Table 7). This data shows that despite
being a carboxylic acid, GSK345931A demonstrates reasonable
CNS penetration and good whole brain concentrations (Table 8).
On consideration of free brain concentrations (Table 9), the effi-
cacy in this model appears to be driven by peripheral concentra-
a
Compound
R
Binding pIC50
4
7a
7b
7c
n/a
Bn
7.3 0.5
8.0 0.2
8.3 0.3
8.4 0.2
7.2 0.1
7.3 0.0
7.7 0.1
7.9 0.1
7.4 0.1
7.8 0.1
7.0 0.1
6.6 0.1
6.8 0.2
4-F Bn
2,4-diF Bn
2-Cl, 4-F Bn
2-F, 4-Br Bn
2-F, 4-Cl Bn
2,4,6-triF Bn
2-F Bn
i-Bu
7db
7eb
7fb
7gb
7hb
7ib
7jb
7kb
7lb
Bu
Pr
Cyclopentylmethyl
a
Values are the means of at least three experiments.
Sodium salt.
b
Table 7
In vivo CNS penetration data for 7i (GSK345931A)
Species
Blood conc. (nM)
Brain conc. (nM)
Br:Bl
Table 4
Mousea
Ratb,c
1120 406
1663 20
277 154
550 55
0.24 0.04
0.33 0.05
In vivo pharmacokinetic data for 7i (GSK345931A)
a
3 mg/kg oral dose. Samples taken 0.5 h post-dose.
Steady state penetration study. Compound dosed at a rate of 0.28 mg/kg/h free
O
b
Cl
N
Na+
O
acid over 18 h via femoral vein cannula. Steady state CLb 8 mL/min/kg.
For comparison, GW848687X (2) was found to have a Br:Bl of 0.20 in the rat at
steady state.
c
O
7i: GSK345931A
Table 8
Bioanalysis of blood and brain samples from CFA studies with GSK345931A
Species
Mouse
0.6
Rat
0.7
Dog
60.5
Monkey
8.0
Human
1.9
Dose
1 mg/kg
2 mg/kg
3 mg/kg
1 mg/kg
3 mg/kg
10 mg/kg
Studya
Blood conc.b (nM)
Brain conc.c (nM)
Br:Bld
CLia
A
A
A
B
B
B
1633 518
2139 423
3330 1042
948 118
4274 693
15418 2453
425 61
645 240
1477 184
317 12
1719 214
7261 1073
0.27 0.07
0.22 0.07
0.72 0.64e
0.36 0.05
0.47 0.17
0.48 0.19
a
Intrinsic clearance in liver microsomes (mL/min/g liver), values are the mean of
three experiments.
a
Study A conducted at doses of 1, 2 and 3 mg/kg p.o., study B conducted at doses
of 1, 3 and 10 mg/kg p.o. Samples taken 1 h post-dose.
Table 5
b
Mean of seven values.
Mean of three values.
Solubility data for 7i (GSK345931A)a
c
d
Medium
Water
SGFb
FaSSIFc
FeSSIFd
Mean of three values where the blood and brain samples were taken from the
same three animals.
Solubility at 2 h
Solubility at 24 h
499
612
33
11
1030
1052
1217
1143
e
One rat displayed significantly higher Br:Bl. Individual ratios were 0.30, 0.39
and 1.46.
a
Units = lg/mL.
b
c
Simulated gastric fluid.9
Fasted state simulated intestinal fluid.9
Fed state simulated intestinal fluid.9
d
Table 9
Calculated free concentrations in blood and brain from CFA studies
Dose
1 mg/kg
2 mg/kg
3 mg/kg
1 mg/kg
3 mg/kg
10 mg/kg
Studya
Calc. free Blood conc.b (nM)
Calc. free brain conc.b (nM)
Table 6
In vivo pharmacokinetic data for 7i (GSK345931A)
A
A
A
B
B
B
8.2
10.7
16.7
4.7
21.4
77.1
2.3
3.4
7.8
1.7
9.1
a
Species
CLba (mL/min/kg)
Vssa (L/kg)
t½ (h)
Fpob
Rat
11
26
2
5
1.9 0.6
0.5 0.1
3.5 1.3,
0.8 0.5
95 19%
34 18%
Cynomolgus monkey
38.5
a
a
1 mg/kg intravenous dose. Vehicle = 2% (v/v) DMSO added to saline solution
containing 10% (w/v) Kleptose. Data are the mean from three animals.
Study A conducted at doses of 1, 2 and 3 mg/kg p.o., study B conducted at doses
of 1, 3 and 10 mg/kg p.o. Samples taken 1 h post-dose.
b
b
3 mg/kg oral dose. Vehicle = 1% (w/v) methycellulose aq. Data are the mean
Calculated from data in Table 8 using rat percentage unbound data (0.50% in
from three animals.
blood and 0.54% in brain).

500
A. Hall et al. / Bioorg. Med. Chem. Lett. 19 (2009) 497–501
blood and brain concentrations to free blood and brain concentra-
tions helps to explain the lack of efficacy in the 5 mg/kg group on
thefifthday of dosing (Table10)as boththefree bloodandbraincon-
centrations are below the in vitro IC50 value (rat IC50 12.6 nM). Based
on thebloodconcentration for the5 mg/kgsatellitegrouponday1, it
would be expected that this dose group would have a free blood and
brain concentration in excess of the in vitro IC50 value which may ex-
plain the observed efficacy in the earlier phase of this study. Taken
together these results are consistent with the thesis that the free
drug concentrations drive efficacy in this model, however it is not
possible to conclude the site of action (i.e., peripheral or central)
fromthecurrentdataasboththefree bloodandbrainconcentrations
are below the in vitro IC50 value for the 5 mg/kg dose group on day 5
of dosing. Further work to delineate the site of action for EP1 antag-
onists will be the subject of future publications.
Figure 3. Effect of 5 mg/kg p.o. b.i.d. and 20 mg/kg p.o. b.i.d. GSK345931A (7i) in
the sub-chronic rat joint pain assay versus vehicle (methylcellulose) and positive
control (rofecoxib 5 mg/kg p.o.) and positive control vehicle (DMSO/PEG/water).
Limited selectivity data was collected as related compounds
had not shown any significant activity at related prostanoid recep-
tors, with the exception of the thromboxane A2 (TP) receptor.5,6
Thus, GSK345931A shows good selectivity over the EP3 receptor
in a functional assay, EP1 FLIPR pKi 8.6, EP3 FLIPR pKi 5.7, and
ꢀ100-fold selectivity over the TP receptor, TP FLIPR pIC50 5.8 pKi
tions (binding pIC50 7.8, i.e., IC50 16 nM at the human receptor,
binding pIC50 7.9, i.e., IC50 12.6 nM at the rat receptor) as the free
brain concentrations are below the in vitro IC50 value at doses that
proved efficacious.
6.5, no activity at the PGF2 receptor (FP), FLIPR pIC50 < 5, and no
a
Based on its overall profile GSK345931A (7i) was evaluated in a
sub-chronic rat joint pain model7 at doses of 5 and 20 mg/kg (b.i.d.)
and showed efficacy equivalent to rofecoxib (Fig. 3).
Cl
I
B(OH)2
Cl
Cl
c
a, b
Blood samples were taken 1 h post-dose on day one from a
satellite study group, and terminal blood and brain samples were
taken 1 h post-dose from both satellite and treatment groups (Ta-
ble 10). The data show that the blood concentrations were higher
on day 1 than day 5 for both dose groups. Conversion of the whole
O
O
OH
Bn
Bn
13
14
15
Scheme 2. Reagents and conditions: (a) BnBr, K2CO3, Me2CO, reflux. (b) I2,
SelectfluorTM, CH3CN (c) n-BuLi, THF, À100 °C, B(Oi-Pr)3, À78 °C–rt., 2 M HCl.
Table 10
Bioanalysis data and calculated free brain concentrations from the rat sub-chronic joint pain efficacy study (Fig. 3)
Dose
5 mg/kg
5 mg/kg
5 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
Study groupa
Blood conc.b (nM)
Brain conc.b (nM)
Br:Bl
Calc. free blood conc.c (nM)
Calc. free brain conc.c (nM)
A, day 1
A, day 5
B, day 5
A, day 1
A, day 5
B, day 5
5266 1149
1665 459
1630 462
25900 1916
6771 2467
5526 2409
dn/t
822 181
1074 298
dn/t
3627 996
3213 1483
n/t
26.3
8.3
8.2
129.5
33.9
27.6
n/t
4.4
5.7
n/t
19.2
17.0
0.54
0.57
n/t
0.50
0.45
a
Study group A = satellite animals, values are the mean from five animals. Study group B = treatment group, values are the mean from seven animals.
Samples taken 1 h post-dose.
Calculated using rat percentage unbound data (0.50% in blood and 0.54% in brain).
n/t, not tested.
b
c
d
Cl
Br
O
Cl
Cl
Br
a
b
c
Br
O
OH
8
9
10
O
CO2Et
Cl
N
Cl
Cl
N
+
O
Na
B(OH)2
d
e
O
O
O
11
12
7i
Scheme 1. Reagents and conditions: (a) iso-butyl bromide, K2CO3, DMF, 80 °C, 94%. (b) (2-bromophenyl)boronic acid, Pd(PPh3)4, K2CO3, PhMe-EtOH, 90 °C, 47%. (c) n-BuLi,
THF, À100 °C; B(Oi-Pr)3, À78 °C–rt; 2 M HCl, 83%. (d) Ethyl 6-bromo-2-pyridinecarboxylate, Pd(PPh3)4, K2CO3, PhMe-EtOH, 90 °C, 100%. (e) EtOH, 2 M NaOH, 96%.

A. Hall et al. / Bioorg. Med. Chem. Lett. 19 (2009) 497–501
501
a or b
c
CO2R'
X
Cl
CO2R'
CO2R'
Br
O
16
X=Br or B(OH)2
17
18
Bn
Scheme 3. Reagents and conditions: (a) 1,2-dibromobenzene, Pd(PPh3)4, K2CO3, PhMe-EtOH, 90 °C. (b) (2-bromophenyl)boronic acid, Pd(PPh3)4, K2CO3, PhMe-EtOH, 90 °C.
(c) 15, Pd(PPh3)4, K2CO3, PhMe-EtOH, 90 °C.
activity at hERG cardiac channel (3H-dofetilide binding assay
pIC50 < 4.5). Counter screening against the peroxisome prolifera-
Umland, J. P.; Pandher, K.; Lapointe, J.-M.; Saha, S.; Roach, M. L.; Carter, D.;
Thomas, N. A.; Durtschi, B. A.; McNeish, J. D.; Hambor, J. E.; Jakobsson, P.-J.;
Carty, T. J.; Perez, J. R.; Audoly, L. P. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 9044;
(d) Kamei, D.; Yamakawa, K.; Takegoshi, Y.; Mikami-Nakanishi, M.; Nakatani,
Y.; Oh-ishi, S.; Yasui, H.; Azuma, Y.; Hirasawa, N.; Ohuchi, K.; Kawaguchi, H.;
Ishikawa, Y.; Ishii, T.; Uematsu, S.; Akira, S.; Murakami, M.; Kudo, I. J. Biol. Chem.
2004, 279, 33684.
tor-activated (PPAR) receptors revealed GSK345931 had no activity
at the - or d-isoforms (pEC50 < 5, binding pKi < 4.7 at PPAR- and
receptor (pEC50 5.4,
a
a
PPAR-d) and very weak activity at the PPAR-
c
binding pKi 4.9).
2. (a) Coleman, R. A.; Smith, W. L.; Narumiya, S. Pharmacol. Rev. 1994, 46, 205; (b)
Breyer, R. M.; Bagdassarian, C. K.; Myers, S. A.; Breyer, M. D. Annu. Rev.
Pharmacol. Toxicol. 2001, 41, 661; (c) Narumiya, S.; Sugimoto, Y.; Ushikubi, F.
Physiol. Rev. 1999, 79, 1193.
Overall the data presented support further development of
GSK345931A.
GSK345931A was prepared on a 50 g scale as described in Scheme
1. Alkylation of phenol 8 gave ether 9 which underwent Suzuki reac-
tion12 to give 10. Lithium–halogenexchange, trappingwithtri-isopro-
pyl borate and hydrolysis gave boronic acid 11 which underwent a
second Suzuki reaction12 to give 12. Saponification of 12 yielded 7i
(GSK3435931A)as the sodium salt(Scheme1). Full experimental pro-
cedures and characterising data have been published.13
For the synthesis of analogues, a slightly modified procedure
was employed. 4-Chlorophenol was alkylated then iodinated in
the presence of SelectfluorTM14 to give 14. Iodine–lithium exchange
then reaction with tri-isopropyl borate and hydrolysis gave boronic
acid 15 (Scheme 2).
Derivatives with a benzoic acid derivative on the right hand side
could be prepared by the versatile route outlined in Scheme 3.
In summary we have taken the lipophilic lead compound 4,
logD 2.2, MW 414.9 g/mol and reduced the molecular weight
and lipophilicity to give compound 7i (GSK345931 A), logD 1.9,
MW 381.9 g/mol which shows considerably improved pharmaco-
kinetic parameters in addition to excellent in vivo efficacy in acute
and sub-chronic models of inflammatory pain. The data reported
herein support the further development of GSK345931A.
3. Hall, A.; Billinton, A.; Giblin, G. M. P. Curr. Opin. Drug Discov. Dev. 2007, 105,
597.
4. Hall, A.; Bit, R. A.; Brown, S. H.; Chaignot, H. M.; Chessell, I. P.; Coleman, T.;
Giblin, G. M. P.; Hurst, D. N.; Kilford, I. R.; Lewell, X. Q.; Michel, A. D.; Mohamed,
S.; Naylor, A.; Novelli, R.; Skinner, L.; Spalding, D. J.; Tang, S. P.; Wilson, R.
Bioorg. Med. Chem. Lett. 2006, 16, 2666.
5. (a) Hall, A.; Atkinson, S. A.; Brown, S. H.; Chessell, I. P.; Chowdhury, A.;
Coleman, T.; Giblin, G. M. P.; Gleave, R. J.; Hammond, B.; Healy, M. P.; Johnson,
M. R.; Michel, A. D.; Naylor, A.; Novelli, R.; Spalding, D. J.; Tang, S. P. Bioorg. Med.
Chem. Lett. 2006, 16, 3657; (b) Hall, A.; Brown, S. H.; Chessell, I. P.; Chowdhury,
A.; Clayton, N. M.; Coleman, T.; Giblin, G. M. P.; Hammond, B.; Healy, M. P.;
Johnson, M. R.; Metcalf, A.; Michel, A. D.; Naylor, A.; Novelli, R.; Spalding, D. J.;
Sweeting, J. Bioorg. Med. Chem. Lett. 2007, 17, 732; (c) Hall, A.; Brown, S. H.;
Chessell, I. P.; Chowdhury, A.; Clayton, N. M.; Coleman, T.; Giblin, G. M. P.;
Hammond, B.; Healy, M. P.; Johnson, M. R.; Metcalf, A.; Michel, A. D.; Naylor, A.;
Novelli, R.; Spalding, D. J.; Sweeting, J.; Winyard, L. Bioorg. Med. Chem. Lett.
2007, 17, 916.
6. Giblin, G. M. P.; Bit, R. A.; Brown, S. H.; Chaignot, H. M.; Chowdhury, A.;
Chessell, I. P.; Clayton, N. M.; Coleman, T.; Hall, A.; Hammond, B.; Hurst, D. N.;
Michel, A. D.; Naylor, A.; Novelli, R.; Spalding, D. J.; Tang, S. P.; Wilson, A. W.;
Wilson, R. Bioorg. Med. Chem. Lett. 2007, 17, 385.
7. Wilson, A. W.; Medhurst, S. J.; Dixon, C. I.; Bontoft, N. C.; Winyard, L. A.;
Brackenborough, K. T.; De Alba, J.; Clarke, C. J.; Gunthorpe, M. J.; Hicks,
G. A.; Bountra, C.; McQueen, D. S.; Chessell, I. P. Eur. J. Pain 2006, 10,
537.
8. Clarke, S. E.; Jeffrey, P. Xenobiotica 2001, 31, 591.
9. (a) Kostewicz, E. S.; Wunderlich, M.; Brauns, U.; Becker, R.; Bock, T.; Dressman,
J. B. J. Pharm. Pharmacol. 2005, 56, 43; (b) Galia, E.; Nicolaides, E.; Horter, D.;
Löbenberg, R.; Reppas, C.; Dressman, J. B. Pharm. Res. 1998, 15, 698.
10. (a) Evans, R. F.; Herington, E. F. G.; Kynaston, W. Trans. Faraday Soc. 1953, 49,
1284; (b) Cativiela, C.; Dejardin, J.-L.; Elguero, J.; Garcia, J. I.; Gonzalez, E.;
Mayoral, J. A. Collect. Czech. Chem. Commun. 1990, 50, 72.
11. Summerfield, S. G.; Stevens, A. J.; Cutler, L.; del Carmen Osuna, M.; Hammond,
B.; Tang, S.-P.; Hersey, A.; Spalding, D. J.; Jeffrey, P. J. Pharmacol. Exp. Ther. 2006,
3163, 1282.
Acknowledgments
The authors thank Beverley Hammond, Sac Pham Tang and
Leanne Cutler for in vivo pharmacokinetic data, Philip White for
pKa data and Alan Bristow for solubility data.
12. (a) Suzuki, A. Pure Appl. Chem. 1991, 63, 419; (b) Miyaura, N.; Yamada, K.;
Suzuki, A. Tetrahedron Lett. 1979, 20, 3437.
13. (a) Bit, R. A.; Giblin, G. M. P.; Hall, A.; Hurst, D. N.; Kilford, I. R.; Miller, N. D.;
Scoccitti, T. WO2004039753, 2004.; (b) Bit, R. A.; Giblin, G. M. P.; Hall, A.;
Hayhow, T.; Hurst, D. N.; Kilford, I. R.; Miller, N. D.; Naylor, A.; Novelli, R.;
Scoccitti, T. WO2005108369, 2005.
References and notes
1. (a) Murakami, M.; Nakatani, Y.; Tanioka, T.; Kudo, I. Prostaglandins Other Lipid
Mediat. 2002, 68, 383; (b) Claveau, D.; Sirinyan, M.; Guay, J.; Gordon, R.; Chan,
C.-C.; Bureau, Y.; Riendeau, D.; Mancini, J. A. J. Immunol. 2003, 170, 4738; (c)
Trebino, C. E.; Stock, J. L.; Gibbons, C. P.; Naiman, B. M.; Wachtmann, T. S.;
14. Zupan, M.; Iskra, J.; Stavber, S. Tetrahedron Lett. 1997, 38, 6306.