Discovery of a novel series of nonacidic benzofuran EP1 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2011.05.047

We describe the discovery and optimization of a novel series of benzofuran EP₁ antagonists, leading to the identification of 26d, a novel nonacidic EP₁ antagonist which demonstrated efficacy in preclinical models of chronic inflammat

Full text of DOI:10.1016/j.bmcl.2011.05.047

Bioorganic & Medicinal Chemistry Letters 21 (2011) 4343–4348
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of a novel series of nonacidic benzofuran EP1 receptor antagonists
Amanda C. Allan, Andy Billinton, Susan H. Brown, Anita Chowdhury, Andrew J. Eatherton,
⇑
Charlotte Fieldhouse, Gerard M. P. Giblin, Paul Goldsmith, Adrian Hall , David N. Hurst, Alan Naylor,
⇑
D. Anthony Rawlings, Mairi Sime , Tiziana Scoccitti, Pamela J. Theobald
Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe the discovery and optimization of a novel series of benzofuran EP1 antagonists, leading to the
identification of 26d, a novel nonacidic EP1 antagonist which demonstrated efficacy in preclinical models
of chronic inflammatory pain.
Received 5 April 2011
Revised 13 May 2011
Accepted 16 May 2011
Available online 23 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
EP1 antagonist
Pain
CNS penetration
Scaffold hopping
There is significant interest in the identification of EP1 receptor
antagonists for the treatment of inflammatory pain.1 Toward
this end we have previously reported several classes of EP1
receptor antagonists, for example, the development compound
GW848687X (1)2 and the related phenyl derivative GSK345931A
(2)3 We have also described the pyrrole series, exemplified by 3
and 4,4 and the methylene-linked pyrazole series, represented by
5 and 6.5 The latter examples demonstrated the utility of the iso-
butyl group (R = iPr) as a replacement for the benzyl group
(R = Ph), Figure 1. We have also described analogues of 5 and 6
where the carboxylic acid moiety was replaced by nonacidic
groups such as amides, reversed amides and heterocycles.6
As part of an ongoing medicinal chemistry programme we were
interested in identifying new lead series which may offer potential
improvements over the compounds described in Figure 1, for
example, increased affinity for the EP1 receptor, increased meta-
bolic stability or increased oral exposure.
could be mimicked by conformational constraint as outlined in
Figure 2. In addition, the resultant benzofurans also have less rotat-
able bonds than the corresponding alkoxy analogues, a property
which has been shown to have
a beneficial effect on oral
bioavailability.7
Initially, we targeted benzofuran derivatives where R = iPr. The
synthesis is outlined in Scheme 1. 2-Methyl-3-butyn-2-ol (8) was
O
O
N
Cl
N
Cl
OH
OH
O
F
O
F
2: GSK345931A
1: GW848687X
EP1 binding pIC50 8.0
EP1 binding pIC50 8.6
During the course of our research activities we conducted small
molecule X-ray crystallographic studies with several compounds.
Analysis of these structures revealed that the alkoxy group of the
left hand phenyl ring adopted a co-planar conformation with the
phenyl ring as represented in Figure 2. As the solid state conforma-
tion may be a low energy conformation, we hypothesized that it
O
O
N
Na+
O
N
Cl
OH
Cl
N
R
O
R
O
⇑
Corresponding authors at present address: Eisai Ltd., Neuroscience Product
Creation Unit, European Knowledge Centre, Mosquito Way, Hatfield AL10 9SN, UK
(A.H.); Drug Discovery Programme, Beatson Institute For Cancer Research, Garscube
Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK (M.S.).
E-mail addresses: adrian_hall@eisai.net, adrianh26@yahoo.co.uk (A. Hall),
m.sime@beatson.gla.ac.uk (M. Sime).
3: R = Ph, EP1 binding pIC50 8.1
4: R = i-Pr, EP1 binding pIC50 8.3
5: R = Ph, EP1 binding pIC50 8.0
6: R = i-Pr, EP1 binding pIC50 8.0
Figure 1. Selected GSK EP1 receptor antagonists.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.05.047

4344
A. C. Allan et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4343–4348
Cl
R'
O
Cl
R'
O
Cl
R'
O
H
R
R
R
H
observed conformation
of analogues in X-ray
crystallographic studies
could this be mimicked
target benzofurans to mimic
X-ray conformation
by conformational constraint?
Figure 2. Selected GSK EP1 receptor antagonists.
CO2Me
OH
CO2Me
O
CO2Me
O
CO2Me
O
Cl
Cl
Cl
Cl
b
c
+
7
10
11
12
d
O
a
Cl
OH
X
O
CF3
13: X = OH
14: X = Br
15: X = Cl
e
f
8
O
9
N
CO2Et
HN
g
16
O
O
N
Cl
N
N
OEt
Cl
N
OH
h
O
O
17
18a
Scheme 1. Reagents and conditions: (a) TFAA, DBU, MeCN, À10 to 0 °C; (b) 9, DBU, MeCN, CuCl2, À10 to 0 °C; (c) PhNEt2, CsF, 180 °C, 50%; (d) 1 M LiAlH4 in THF, THF, rt; (e)
PBr3, hexane/CH2Cl2 (1:1), rt; (f) SOCl2, CH2Cl2, rt; (g) 16, 14, DMF, K2CO3, rt, 59%; (h) NaOH, EtOH, rt.
Table 1
converted to the corresponding trifluoroacetate derivative 9 and
treated in situ with phenol 7 in the presence of copper(II) chloride
SAR of C-2 alkyl benzofuransa
to give derivative 10. Acetylene 10 underwent thermal rearrange-
N
ment in N,N-diethylaniline to give a separable mixture of 11 and
12, the former being the major product.8 Ester reduction gave
the corresponding alcohol 13 which was converted to a suitable
leaving group and displaced with pyrazole derivative 16 to give
two regioisomers (approximately 2:1 when X = Br), of which 17
was the major product (59%). The yield of the undesired regioisom-
er was 32% and the isomers where easily separated by column
chromatography. Ester hydrolysis of 17 thus furnished 18a
(Scheme 1).9
CO2H
Cl
N
O
A
b
Compd.
A
EP1 binding pIC50
We were pleased to find that compound 18a showed good affin-
ity for the EP1 receptor in our [3H]-PGE2 binding assay, Table 1.9
Testing in a functional assay (FLIPR)9 confirmed that compound
18a was a potent EP1 antagonist, FLIPR pKi 9.4 0.1 (n = 3) with
good selectivity over the EP3 receptor subtype, EP3 FLIPR pKi 6.0
(n = 1).
Investigation of the SAR at the 2-position of the benzofurans,
Table 1, revealed that a range of alkyl groups could be introduced,
with iso-propyl and cyclohexyl resulting in the highest affinity.
We next sought to investigate benzofuran replacements with
the goal of lowering the lipophilicity of the series. Results from this
18a
18b
18c
18d
18e
iPr
cPr
Pr
Cyhex
t-Bu
8.3c
7.3
7.6
8.4
7.2
Data from [3H]-GW875240X binding assay.
Values are means of at least three experiments.
Data from [3H]-PGE2 binding assay.
a
b
c
investigation are summarized in Table 2. Disappointingly, all deriv-
atives showed a significant decrease in affinity. Surprisingly, the

A. C. Allan et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4343–4348
4345
Table 2
Table 3
SAR of bicyclic benzofurans replacementsa
SAR of various novel carboxylic acid replacementsa
Compd.
Structure
EP1 binding pIC50
N
R
Cl
N
N
N
N
N
N
CO2H
CO2H
CO2H
CO2H
CO2H
Cl
N
N
N
N
N
O
19a
6.6b
O
Cl
b
Compd.
R
EP1 binding pIC50
6.9c
6.3c
<6c
N
19b
19c
19d
19e
N
O
O
20a
7.3
N
Cl
H
N
H
20b
20c
7.2
7.2
N
N
N
H
O
N
H
Cl
O
N
O
20d
c6.5
N
H
N
O
O
O
NH
20e
20f
20g
6.1
7.0
7.3
Cl
N
H
<6b
N
N
N
N
N
H
O
a
b
c
Values are means of at least three experiments.
Data from [3H]-GW875240X binding assay.
Data from [3H]-PGE2 binding assay.
N
H
a
b
c
Values are means of at least three experiments.
Data from [3H]-PGE2 binding assay.
Data from [3H]-GW875240X binding assay.
regioisomeric benzofuran 19a also displayed a 50-fold decrease in
activity. More polar heterocycles (19c–e) showed very weak
affinity.
Retaining the iso-propyl group in the 2-postion of the benzofu-
ran ring, we investigated several replacements for the carboxylic
acid, Table 3.
CNS penetration was also good (as measured from the 30 mg/kg
dose group); brain concn 11.315 M (n = 3) with a blood concn
of 10.818 M (n = 3) for the corresponding rats, giving a Br:Bl of
l
Results in Table 3 indicated that it was possible to incorporate a
weakly basic centre to the compounds, compound 20g retained
reasonable affinity whilst displaying modest solubility. Compound
20g was profiled further, a summary of the data generated is listed
in Table 4. The compound was found to have good in vitro meta-
bolic stability, poor aqueous solubility, but moderate solubility in
fed state simulated intestinal fluid. Compound 20g was also found
to be highly permeable in MDCK cells and was not a Pgp substrate
(efflux ratio 0.9). Based on this data, compound 20g was profiled in
the rat CFA model of inflammatory pain10 where it demonstrated
an oral ED50 of 14.7 mg/kg, with a dose of 30 mg/kg showing com-
parable reversal of hypersensitivity to the standard (celecoxib at a
dose of 10 mg/kg po). Disappointingly, compound 20g was found
to have low oral bioavailability in the rat, which we attributed to
its high blood clearance, Table 4. The intrinsic clearance in rat liver
microsomes predicts low to moderate metabolic stability for 20g,
however in vivo the clearance is high, equal to or in excess of liver
blood flow. The high in vivo clearance may be suggestive of
non-cytochrome P450 metabolism also occurring. Despite the high
in vivo clearance, bioanalysis from the CFA study revealed that
compound 20g exhibited high blood concentrations 1 h post-dose;
l
1.05. Free fractions in blood and brain tissue were not determined
for this compound but are likely to be low in line with that of close
analogues such as 26a and 26d, vide infra. The high blood concen-
trations do not exclude the fact that the efficacy is mediated by a
metabolite, however in a separate study compound 20g was dosed
orally in the rat CFA model at 5 mg/kg (in 1% methylcellulose, as
before) and efficacy was assessed at 1 and 3 h post-dose. At this
dose, there was a small but significant reversal of hypersensitivity
at the 1 h time point but no effect at the 3 hour time point support-
ing the fact that the efficacy is mediated by the parent compound,
but not excluding a contribution from the 2-isopropenyl metabo-
lite, vide infra, which is likely to have EP1 activity. The blood and
brain concentrations of 20g 3 h post-dose were 0.694 and
0.804 lM giving a Br:Bl of 1.15.
To further optimize this series and improve the in vivo meta-
bolic stability, a study was conducted to assess the sites of metab-
olism and the vulnerability of this compound to form reactive
metabolites. One of the major sites of metabolism was found to
be the iso-propyl group in the 2-position of the benzofuran which
appeared to undergo oxidation and elimination. In order to address
this liability we sought to replace the iso-propyl group with a phe-
nyl group.
3 mg/kg blood concn 1.945
lM (n = 7), 10 mg/kg blood concn
5.614 M (n = 7), 30 mg/kg blood concn 10.166
l
lM (n = 7). The

4346
A. C. Allan et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4343–4348
Table 4
Table 5
Summary of data for compound 20g
Summary of data for compound 26a
O
O
O
O
N
N
Cl
Cl
N
N
N
N
N
H
N
H
O
O
Metabolic stabilitya
Solubilityb (1 h)
Human CLi (mL/min/g liver)
Rat CLi (mL/min/g liver)
1.1
2.8
EP1 binding affinity
Metabolic stabilitya
pIC50
8.0
Water (lg/mL)
0
1
5
71
Human CLi (mL/min/g liver)
Rat CLi (mL/min/g liver)
1.1
1.3
SGF ( g/mL)
l
FaSSIF (
l
g/mL)
g/mL)
Solubilityb (1 h)
Water (
SGF ( g/mL)
FaSSIF (
FeSSIF (
l
g/mL)
171
227
382
0
FeSSIF (
l
l
Lipophilicityc
Permeabilityd
Log D (pH 7.4)
2.6
l
l
g/mL)
g/mL)
Pexact
Efflux ratio
Doses 3,10 and 30 mg/kg
671 nm/sec
0.9
ED50 14.7 mg/kg
Lipophilicityc
In vivo activityd (CFA)
Log D (pH 7.4)
Dose 10 mg/kg
3.0
In vivo activitye (CFA)
Rat pharmacokinetics
49% reversal
f
CLb (mL/min/kg)
85
3.0 0.3
0.5
19 6%
1.7 0.2
8
e
f
Rat pharmacokinetics
CLb (mL/min/kg)
22
3.5
2.1
Vss (L/kg)
e
f
Vss (L/kg)
t
(h)
1
½
e
g
t
½
(h)
Fpo
g
t
(h)
a
½
See Ref. 11 for details.
Solubility of solid material in each fluid determined at several time points, only
1 h time point quoted. See Ref. 12 for details, SGF (simulated gastric fluid), FaSSIF
(fasted state simulated intestinal fluid), FeSSIF (fed state simulated intestinal fluid).
b
a
See Ref. 11 for details.
Solubility of solid material in each fluid determined at several time points, only
1 h time point quoted. See Ref. 12 for details, SGF (simulated gastric fluid), FaSSIF
(fasted state simulated intestinal fluid), FeSSIF (fed state simulated intestinal fluid).
b
c
Shake flask method.
Efficacy at 1 h post-dose (oral).
1 mg/kg intravenous dose, compound dissolved in 2% (v/v) DMSO then added to
d
c
Shake flask method.
MDCK cells.
Efficacy at 1 h post-dose (oral).
1 mg/kg intravenous dose, compound dissolved in 2% (v/v) DMSO then added to
e
d
e
0.9% (w/v) saline containing 10% (w/v) kleptose.
f
0.9% (w/v) saline containing 10% (w/v) Kleptose.
g
3 mg/kg oral dose, vehicle = 1% (w/v) methylcelluose aq.
with commercially available pyrazole 16 to give 24 as a mixture
of regiosiomers which were easily separated using column chro-
matography. Finally, ester hydrolysis of 24 gave carboxylic acid
25.14
Gratifyingly, this structural change, to give 26a, Table 5, re-
sulted in increased affinity, EP1 binding pIC50 8.0, maintained
in vitro metabolic stability and improved in vivo metabolic stabil-
ity (rat CLb 22 mL/min/kg), supporting the hypothesis that the iso-
propyl group of 20g was a major site of metabolism. Surprisingly,
Our initial route to prepare the 2-alkyl benzofurans, Scheme 1,
was clearly unsuitable for the preparation of 2-aryl benzofurans. As
a result, a new route was devised, Scheme 2. Starting from phenol
7, bromination using N-bromosuccinimide afforded 21. Bromide 21
was subjected to a modified Castro reaction13 to provide the ben-
zofuran intermediate 22 in one step. Subsequent reduction of ester
22, and coversion of the intermediate alcohol to a suitable leaving
group gave mesylate 23 in good yield. The mesylate was reacted
CO2Me
CO2Me
OH
Cl
CO2Me
OH
Cl
Cl
Cl
c,d
OMs
a
b
O
O
Br
21
7
Ph
Ph
22
23
e
N
Cl
N
Cl
N
CO2Et
N
CO2H
f
O
O
Ph
Ph
24
25
Scheme 2. Reagents and conditions: (a) NBS, DMF, rt; (b) phenylacetylene, CuI, PdCl2(PPh3)2, Et3N, DMF, 75 °C; (c) 1 M LiAlH4 in THF, THF 0 °C; (d) MsCl, Et3N, DCM, 0 °C; (e)
16, DMF, K2CO3, rt; (h) NaOH, EtOH, 50 °C.

A. C. Allan et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4343–4348
4347
Table 6
Table 7
SAR of various novel carboxylic acid replacementsa
Summary of data for compound 26d
N
O
R
Cl
N
N
Cl
N
N
H
O
O
Compd.
R
EP1 bindingb pIC50
EP1 binding affinity
Lipophilicitya
pIC50
Log D (pH 7.4)
8.0
2.9
25
CO2H
8.7
O
In vivo activityb (CFA)
Rat pharmacokinetics
Doses 1, 3, 10 mg/kg
ED50 5 mg/kg
28
4.3
4.2
c
26b
26c
26d
8.0
CLb (mL/min/kg)
N
H
c
Vss (L/kg)
c
O
t
½
(h)
8.3
8.0
a
b
c
NH2
Shake flask method.
Efficacy at 1 h post-dose (oral).
1 mg/kg intravenous dose, compound dissolved in 2% (v/v) DMSO then added to
O
N
H
0.9% (w/v) saline containing 10% (w/v) kleptose.
O
and brain tissue binding assays16 26a exhibits high binding with
0.662% free in blood and 0.170% free in brain, that is, Bl Fu
0.0066, Br Fu 0.0017, which results in a calculated free blood concn
of 15 nM and free brain concn of 7 nM, which are in line with the
binding IC50 (10 nM). Following this encouraging data, compound
26a was profiled in the joint pain model of chronic inflammatory
pain17 at doses of 1, 3, 10 and 30 mg/kg po b.i.d.. Disappointingly,
a statistically significant reversal (p <0.001) was only observed in
the 30 mg/kg dose group. Thus, although we had made a significant
improvement of optimizing the pharmacokinetic parameters of the
series, the in vivo efficacy required improvement.
Toward this end, we opted to make further amide analogues,
data summarized in Table 6. A selection of neutral amides (26b–
e) showed good affinity. Various groups were assessed in the
amide or reversed amide series to try to lower the lipophilicity of
the series either via the introduction of a basic amine (26f–j) or
polarity (26k–m). It was found that basic amines were relatively
well tolerated in this region of the molecule, however it appeared
that affinity could be increased by decreasing the amine pKa, com-
pare 26h with 26i and 26j.
A range of compounds were assessed in the rat CFA model of
inflammatory pain10 (oral dose of 10 mg/kg in 1% methylcellulose,
efficacy reading 1 h postdose, when blood and brain samples were
also collected) to screen for efficacy and exposure in both blood
and brain. Disappointingly, most compounds displayed low effi-
cacy, which could generally be attributed to low exposure. How-
ever, compound 26d, displayed promising efficacy in this screen
(95% reversal of hypersensitivity, as measured by weight bearing,
at 10 mg/kg po) and good CNS penetration (blood concn = 381 nM,
brain concn = 112 nM, Br:Bl 0.3). Based on this data, the compound
was progressed to a dose–response study in CFA-treated rats
(doses 1, 3 and 10 mg/kg po) where it gave an ED50 of 5 mg/kg. Bio-
analysis of the 10 mg/kg dose group showed similar blood expo-
sure to the previous study (blood concn = 493 nM) but higher
brain exposure (brain concn = 407nM) which resulted in a Br:Bl
of 0.8. The slightly higher Br:Bl in the second experiment is within
the range of variability of these assays (<3-fold variation), the same
strain and sex of rat and administration vehicle were used in both
studies. In blood and brain tissue binding assays16 26d exhibits
high binding with 0.028% free in blood and 0.017% free in brain,
which results in calculated free blood and free brain concentra-
tions considerably lower than the in vitro binding IC50 value of this
26e
26f
8.3
7.7
N
H
O
N
H
NH
H
N
26g
26h
7.2
7.0
O
O
O
O
NH
NH
H
N
NH
N
H
N
26i
26j
7.4
7.6
F
CF3
H
N
OH
O
26k
26l
8.1
8.2
7.6
N
H
O
O
O
N
H
CF3
OH
26m
N
H
Data from [3H]-GW875240X binding assay.
Values are means of at least three experiments.
a
b
despite the increased lipophilicity (log D 3.0 @ pH 7.4) this ana-
logue displayed higher solubility in all media tested apart from
FaSSIF. When tested in the rat CFA model of inflammatory pain,10
compound 26a showed moderate reversal of hypersensitivity
(using a weight bearing readout) following an oral dose of
10 mg/kg. Bioanalysis indicated good exposure in both blood and
brain (blood concn 2.340
lM, n = 6, brain concn 3.969 lM, n = 3,
1 h post-dose, which equates to a Br:Bl of 1.70, n = 3).15 In blood

4348
A. C. Allan et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4343–4348
4. Hall, A.; Atkinson, S.; Brown, S. H.; Chessell, I. P.; Chowdhury, A.; Clayton, N. M.;
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.; Wilson, R.
J. Bioorg. Med. Chem. Lett. 2006, 16, 3657.
5. McKeown, S. C.; Hall, A.; Giblin, G. M. P.; Lorthioir, O.; Blunt, R.; Lewell, X. Q.;
Wilson, R. J.; Brown, S. H.; Chowdhury, A.; Coleman, T.; Watson, S. P.; Chessell,
I. P.; Pipe, A.; Clayton, N.; Goldsmith, P. Bioorg. Med. Chem. Lett. 2006, 16, 4767.
6. (a) Hall, A.; Billinton, A.; Brown, S. H.; Clayton, N. M.; Chowdhury, A.; Giblin, G.
M. P.; Goldsmith, P.; Hayhow, T. G.; Hurst, D. N.; Kilford, I. R.; Naylor, A.;
Passingham, B.; Winyard, L. Bioorg. Med. Chem. Lett. 2008, 18, 3392; (b) Hall, A.;
Billinton, A.; Bristow, A. K.; Brown, S. H.; Chowdhury, A.; Cutler, L.; Giblin, G. M.
P.; Goldsmith, P.; Hayhow, T. G.; Kilford, I. R.; Naylor, A.; Passingham, B.;
Rawlings, D. A. Bioorg. Med. Chem. Lett. 2008, 18, 4027.
compound. The reason for this is unknown, however, there are
likely to be errors in the measurements of the free fractions in both
tissues with such lipophilic compounds. It is also feasible that the
affinity at the rat receptor is higher than that at the human recep-
tor. However without an assessment of in vivo/ex vivo receptor
binding it is not possible to say whether the concentrations
achieved in these studies were sufficient to block the receptor or
whether the effect is on-target. Assessment in the joint pain model
of chronic inflammatory pain17 (at doses of 0.3, 1, 3 and 10 mg/kg
po b.i.d.) produced a dose-related reversal of hypersensitivity with
a calculated ED50 of ꢀ0.6 mg/kg and a corresponding calculated
7. Veber, D. F.; Johnson, S. R.; Cheng, H.-Y.; Smith, B. R.; Ward, K. W.; Kopple, K. D.
J. Med. Chem. 2002, 45, 2615.
8. Attwood, M. R.; Churcher, I.; Dunsdon, R. M.; Hurst, D. N.; Jones, P. S.
Tetrahedron Lett. 1991, 32, 811.
blood concentration of 0.06 lM. Full reversal of hypersensitivity
was achieved at 10 mg/kg. Profiling of the compound in a rat PK
study demonstrated good metabolic stability with satisfactory
half-life, Table 7.
In conclusion we have described the identification of a new ser-
ies of EP1 antagonists which enriches the chemical tools available
for the investigation of EP1 pharmacology. We have also described
the use of metabolite identification in lead optimisation which re-
sulted in compounds such as 26a and 26d, which, to the best of our
knowledge, are the first nonacidic EP1 antagonists to demonstrate
efficacy in preclinical models of chronic inflammatory pain.
9. Gibson, M.; Hall, A.; Hurst, D.N.; Rawlings, D.A. WO2007113289A1.
10. (a) Iadarola, M. J.; Douglass, J.; Civelli, O.; Naranjo, J. R. Brain Res. 1988, 455,
205; (b) Hay, C. H.; Trevethick, M. A.; Wheeldon, A.; Browers, J. S.; De
Belleroche, J. S. Neuroscience 1997, 7, 843.
11. Clarke, S. E.; Jeffrey, P. Xenobiotica 2001, 31, 591. In this assay CLi of 5 mL/min/g
liver corresponds to approximately 60% turnover after 30 min incubation.
12. (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.
13. (a) Castro, C. E.; Gaughan, E. J.; Owsley, D. C. J. Org. Chem. 1966, 31, 4071; (b)
Castro, C. E.; Havlin, R.; Honwad, V. K.; Malte, A.; Mojé, S. J. Am. Chem. Soc. 1969,
91, 6464.
14. Eatherton, A. J.; Giblin, G. M. P.; Gibson, M.; Hurst, D. N. WO2008098978A2/A3.
15. Note the brain concentrations were measured in only three rats, mean brain
References and notes
concentration = 3.969
three rats was 2.339
l
M. The average blood concentration from the same
lM. Thus, this equates to a Br:Bl of 1.70, n = 3.
1. Hall, A.; Billinton, A.; Giblin, G. M. P. Curr. Opin. Drug Discovery Dev. 2007, 10,
597. and references cited therein.
2. 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.; Scoccitti, T.; Spalding, D.; Tang, S. P.;
Wilson, A. W.; Wilson, R. Bioorg. Med. Chem. Lett. 2007, 17, 385.
3. Hall, A.; Brown, S. H.; Budd, C.; Clayton, N. M.; Giblin, G. M. P.; Goldsmith, P.;
Hayhow, T. G.; Hurst, D. N.; Naylor, A.; Rawlings, D. A.; Scoccitti, T.; Wilson, A.
W.; Winchester, W. J. Bioorg. Med. Chem. Lett. 2009, 19, 497.
16. 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,
316, 1282.
17. 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.