Discovery of novel biaryl heterocyclic EP1 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2006.02.014

We describe the generation of novel EP₁ receptor antagonists by investigation of thiophene isosteres. In addition, we disclose preliminary in vitro and in vivo DMPK for selected compounds.

Full text of DOI:10.1016/j.bmcl.2006.02.014

Bioorganic & Medicinal Chemistry Letters 16 (2006) 2666–2671
Discovery of novel biaryl heterocyclic EP1 receptor antagonists
Adrian Hall,a,* Rino A. Bit,a Susan H. Brown,a Helene M. Chaignot,a Iain P. Chessell,a
Tanya Coleman,a, Gerard M. P. Giblin,a David N. Hurst,a Ian R. Kilford,a
Xiao Q. Lewell,b Anton D. Michel,a Shiyam Mohamed,a Alan Naylor,a Riccardo Novelli,a
Lee Skinner,a David J. Spalding,a Sac P. Tanga and Richard J. Wilsonc
aNeurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline,
New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
bDepartment of Structural and Computational Sciences, GlaxoSmithKline, New Frontiers Science Park,
Third Avenue, Harlow, Essex CM19 5AW, UK
cDepartment of Screening and Compound Profiling, GlaxoSmithKline, New Frontiers Science Park,
Third Avenue, Harlow, Essex CM19 5AW, UK
Received 19 January 2006; revised 8 February 2006; accepted 9 February 2006
Available online 28 February 2006
Abstract—We describe the generation of novel EP1 receptor antagonists by investigation of thiophene isosteres. In addition, we
disclose preliminary in vitro and in vivo DMPK for selected compounds.
Ó 2006 Elsevier Ltd. All rights reserved.
Non-steroidal anti-inflammatory drugs (NSAIDs),
which inhibit both cyclooxygenase-1 (COX-1) and -2
(COX-2) and, more recently, selective inhibitors of
(COX-2) have demonstrated efficacy in the treatment
of inflammatory pain.1 Although NSAIDs are effective
analgesic agents, as a class they suffer from gastrointes-
tinal (GI) toxicity as a common side-effect liability upon
chronic dosing, which hampers their use in the treatment
of chronic pain conditions such as rheumatoid arthritis
(RA) and osteoarthritis (OA).2 Whilst selective COX-2
inhibitors have been shown to have an improved GI
side-effect profile relative to NSAIDs,3 there has recently
been concern over the cardiovascular safety of one of
these agents which has resulted in the recent withdrawal
from the market of Vioxx (Rofecoxib).4 Prostaglandin
E2 (PGE2) has been shown to be the major pro-inflam-
matory mediator from the arachidonic acid cascade.5
Studies with mice lacking prostaglandin E synthase
(PGES) have shown that PGE2 plays an important role
in pain.5 The physiological actions of PGE2 are attribut-
ed to agonism at four 7-transmembrane (7-TM) receptor
6
subtypes, EP1–4. Studies with knock-out (KO) mice
have implicated the EP1 receptor in the generation of
PGE2-mediated allodynia7 and inflammatory pain.8
EP1 receptor antagonists have shown efficacy in preclin-
ical models of postoperative pain,9 neuropathic pain10
and allodynia.11 There is also evidence to suggest that
PGE2-mediated pyrexia is controlled by the EP1 recep-
tor.12 Furthermore, a recent report described the efficacy
of the AstraZeneca compound ZD6416 in a human
model of visceral hypersensitivity.13 Thus, an EP1 recep-
tor antagonist has the potential to deliver efficacy in var-
ious pain states. Hence, we sought to identify potent
selective, bioavailable EP1 receptor antagonists as po-
tential analgesics.
A survey of the literature revealed several reports of
known EP1 antagonists (Fig. 1).
Published compounds include ZD6416 (1)14 from Astra-
Zeneca, ONO-8713 (2)15 and ONO-871116 (not shown),
SC-51322 (3)17 and analogues18 from Searle and thio-
phene 4 from Merck Frosst.19
Keywords: EP1 antagonist; Pain; Heterocycles; Cyclopentene; Isostere.
*
Corresponding author. Tel.: +44 1279 643464; e-mail:
adrian.2.hall@gsk.com
The replacement of ring systems and functional groups
by isosteric groups is known.20–22 Therefore, we sought
Present address: AstraZeneca, Mereside, Alderley Park, Macclesfield,
Cheshire SK11 4TG, UK.
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.02.014

A. Hall et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2666–2671
2667
O
Addition of a third N-atom to give the triazoles 14 and
15 resulted in complete loss of activity.
O
O
O
OH
S
N
F3C
O
O
H
N
Br
O
N
N
S
As it had been found that the thiophene ring in the
COX-2 inhibitor DuP-697 could be replaced by a bute-
nolide to give rofecoxib,20e we investigated a similar
modification. We found that lactone 16 was well tolerat-
ed, whereas the regioisomer 17 was inactive, again dem-
onstrating that polarity can be tolerated on the right-
hand side of the central ring, but not the left-hand side.
O
N
O
1
ZD-6416
2
ONO-8713
O
Cl
N
Cl
O
O
H
O
N
N
S
S
O
H
Taken together these results show that the central ring
needs to be lipophilic as the more hydrophilic rings such
as triazole showed weaker activity whereas the most
lipophilic rings, such as cyclopentene and pyrrole,
showed the highest activity. Polarity can be tolerated
in this central ring on the right-hand side but not the
left-hand side, as shown by comparing pyrazole 10 with
11 and butenolide 16 with 17.
HO
O
4
3
SC-51322
Figure 1. Literature EP1 antagonists disclosed by AstraZeneca (1),
Ono (2), Searle (3) and Merck Frosst (4).
to replace the thiophene of 4 with isosteric ring systems
and investigate the effect of these changes on EP1 activ-
ity and physicochemical properties.
We also sought to replace the thiophene with a six-mem-
bered ring and were encouraged to find that the phenyl
derivative 18 displayed good activity. Its slightly dimin-
ished activity relative to the cyclopentene 5 and thio-
phene 4 could possibly be attributed to its narrower
bond vector angle: 60° for the phenyl ring versus 69°
for the cyclopentene and 2,3-disubstituted thiophene.
Hence, we initiated an early stage programme to estab-
lish the role of the thiophene in these ligands, and to
determine if this heterocycle could be replaced to gener-
ate potent EP1 antagonists with good pharmacokinetic
properties.
Replacement of the phenyl ring with a pyridine to give
compounds 19–22 revealed an interesting trend. Com-
pounds 19 and 21 showed good activity in both binding
and functional assays. Compound 22 displayed some-
what weaker activity in the binding assay but good
activity in the functional assay. Isomer 20 was essential-
ly inactive in the binding assay but displayed high activ-
ity in the functional assay. The reasons for the
discrepancy in assay results are not clear but could be
due to an allosteric mode of action or modulation of
other cellular pathways which affect intracellular calci-
um concentration. Replacement of the phenyl ring to
give the pyrazine 23 led to a marked decrease in activity,
again highlighting the preference for lipophilicity in this
region, although a detrimental interaction with the polar
nitrogen atoms cannot be ruled out.
Various analogues were synthesized and tested in a [3H]-
PGE2 binding assay.23 Selected compounds were also
tested in a functional assay (FLIPR).24 Results are sum-
marized in Table 1.
Thiophene 4 was found to be a potent EP1 antagonist
with a binding IC50 of approximately 5 nM and a func-
tional Ki of approximately 0.3 nM, which is in good
agreement with data published by Merck Frosst (bind-
ing Ki = 4 nM, functional Kb = 7 nM).19
We were pleased to find that the thiophene could be re-
placed by a cyclopentene or pyrrole ring with no de-
crease in activity, as shown by compounds 5–7.
Although the initial pyrrole derivatives had an addition-
al Me-group on the pyrrole ring, this substitution was
found to be unnecessary for activity, as demonstrated
by the activity of compound 8. Addition of a second
N-atom to 8 gave the pyrazole 10, which was approxi-
mately 10-fold less active. The regioisomeric pyrazole
11 showed no measurable affinity up to a concentration
of 1 lM. These results show that lipophilic ring systems
are preferred, however, some polarity can be tolerated
on the right-hand side of the central ring, but not on
the left-hand side.
The results shown in Table 1 show a similar trend to
that observed for the phenyl acetic acid analogues of
compound 4, as described by Merck Frosst.19
Since several analogues displayed good affinity for the
EP1 receptor, selected compounds were profiled in vitro
and in vivo to assess their pharmacokinetic parameters.
Compounds were first screened for CYP450 interactions
and metabolic stability (intrinsic clearance).
With the exception of pyrrole 9, all compounds showed
good metabolic stability in rat microsomes and dis-
played good CYP450 profiles, although all interacted
with CYP2C9 to some degree (Table 2). To investigate
how the in vitro metabolic stability results would trans-
late into the in vivo situation, selected compounds were
administered via intravenous injection to male Sprague–
The pyrrole derivative 9 was considerably less active
than its regioisomer 6, indicating electronic or steric
considerations are important as compounds 6 and 9
are of similar lipophilicity. Of the imidazole isomers pre-
pared, compound 12 showed moderate activity, whereas
analogue 13 was inactive.

2668
A. Hall et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2666–2671
Table 1. SAR for compound 4 and synthesized analogues 5–23
Table 1. (continued)
a
Compound Ring
X
Binding pIC50 Functional pKib,c
O
ring
X
OH
O
N
19
Cl 7.0 0.2 (8)
Cl <6 0.1 (8)
Cl 7.1 0.1 (4)
Cl 6.5 0.2 (8)
Cl 6.4 0.2 (4)
8.18 0.01 (2)
7.28 0.50 (2)
6.86 0.01 (2)
7.55 0.16 (2)
n/t
a
Compound Ring
X
Binding pIC50 Functional pKib,c
N
20
S
4
Cl 8.2 0.2 (12)
Cl 7.9 0.4 (12)
Cl 8.1 0.4 (16)
Br 8.1 0.2 (7)
Cl 8.0 0.1 (12)
Cl 6.7 0.2 (8)
Cl 7.1 0.2 (4)
9.51 0.15 (4)
8.37 0.14 (2)
9.15 0.01 (2)
n/t
N
21
5
6
7
8
9
N
22
N
N
N
23
N
a See Ref. 23.
b See Ref. 24.
c n/t, not tested.
9.23 0.89 (4)
7.81 0.18 (2)
n/t
N
Table 2. In vitro pharmacokinetic data for compounds 5–9 and 12, 18,
19, and 21
N
Compound
Rat CLia
Human CLia
CYP450b,c
(IC50 at isozyme)
N
10
5
6
4.1
1.4
2.1
2.6
5.9
1.7
8.4
1.6
1.8
1.5
7.9
0.96
5.7 lM (2C9)
6.5 lM (2C9)
6.8 lM (2C9)
7.3 lM (2C9)
n/t
N
7
8
N
9
12
11
12
13
14
Cl <6 0 (4)
Cl 6.9 0.4 (8)
Cl <6 0 (8)
Cl <6 0 (7)
n/t
N
1.9 lM (2C9),
<1 lM (3A4)
3.9 lM (2C9)
All >50 lM
4.3 lM (2C9),
1.4 lM (3A4)
N
18
19
21
<0.5
1.3
<0.5
<0.5
1.4
8.45 0.33 (2)
N
3.6
a Intrinsic clearance values measured in microsomes (mL/min/g liver).
b In vitro CYP450 assay results using Gentest protocol for isozymes
1A2, 2C9, 2C19, 2D6 and 3A4. Data quoted only for isozymes with
IC50 < 10 lM.
N
N
<6 (2)
N
N
c n/t, = not tested.
<6 (2)
N
Dawley rats at a target dose of 1 mg/kg to assess blood
clearance, volume of distribution and half-life (Table 3).
N
N
15
16
Cl <6 0 (8)
<6 (2)
n/t
N
Most compounds displayed a relatively short half-life,
due to a combination of a low volume of distribution
and moderate to high blood clearance. Although phenyl
derivative 18 appeared much more stable in vitro than
the cyclopentene 5 and pyrrole 6 analogues, their in vivo
O
O
Cl 7.1 0.2 (3)
O
O
17
18
Cl <6 0.1 (8)
n/t
Table 3. In vivo pharmacokinetic data for compounds 5–7 and 18
Compound
CLb (mL/min/kg)
Vss (L/kg)
t1/2 (h)
5
6
54
67
41
64
0.8
3.0
0.6
1.4
0.5
0.5
0.3
0.3
Cl 7.3 0.5 (16)
7.54 0.42 (4)
7
18

A. Hall et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2666–2671
2669
blood clearance values are high. This may be indicative
that the major metabolic route is phase 2 metabolism
(possibly glucuronidation) of the carboxylic acid. It is
also interesting to note that it was possible to reduce
the blood clearance in the pyrrole series by simple mod-
ification, changing a chlorine atom to a bromine atom, 6
versus 7 (Table 3). On the basis of these results and
excellent EP1 activity, the cyclopentene 5, pyrroles 6
and 7 and benzene 18 were selected for further optimiza-
tion. The results of these studies will be reported in fu-
ture publications.
mental details and characterizing data for key com-
pounds have been described.25
Scheme 1 depicts the synthesis of 2-benzyloxy-5-chloroi-
odobenzene 25 and 2-benzyloxy-5-chlorophenylboronic
acid 26 which proved useful intermediates in the synthe-
sis of several analogues.
Cyclopentene 5, butenolide 17 and benzene 18 were pre-
pared by sequential Suzuki reactions26 with either 3-eth-
oxycarbonylphenylboronic acid or 3-tert-butoxycar
bonylphenylboronic acid followed by 26 as described
for related compounds.20a,20c,27 Butenolide 16 and pyra-
zine 23 were prepared in a similar fashion by sequential
Suzuki reactions26,27 with 26 and 3-ethoxycarbonylphen
ylboronic acid.
Compounds were synthesized according to literature
procedures or as outlined in Schemes 1–4. Full experi-
Cl
I
Cl
I
Cl
B(OH)2
OBn
The methyl-pyrrole derivatives 6, 7 and 9 were pre-
pared via sequential Stetter reaction28 with methylvi-
nylketone (MVK) and Paal–Knorr condensation29 in
an analogous manner to published analogues.20d The
des-methyl pyrrole 8 was prepared via literature proce-
dures.30 The pyrazoles 10 and 11 were prepared by
known procedures.20f Imidazoles 12 and 13 were pre-
pared via reaction of the requisite Schiff base with
van Leusen’s reagent (TosMIC)20h,31 followed by ester
hydrolysis. Imidazole 23 was prepared in two steps by
condensation of aldehyde 27 with aniline 28 and glyox-
al in the presence of ammonium acetate, followed by
ester hydrolysis (Scheme 2).
a, b
c, d, e
OMe
OBn
24
25
26
Scheme 1. Reagents and conditions: (a) BBr3, DCM, À78 °C to rt,
91%; (b) BnBr, K2CO3, Me2CO, 60 °C, 86%; (c) n-BuLi, THF,
À100 °C; (d) B(Oi-Pr)3, À78 °C to rt; (e) 2 M HCl, 53% for three steps.
O
CO2Et
Cl
H2N
a, b
23
+
OBn
27
28
Scheme 2. Reagents and conditions: (a) glyoxal, AcOH, NH4OAc,
100 °C, 2 h, 17%; (b) 2 M NaOH, EtOH, reflux.
Triazoles 14 and 15 were synthesized by standard
methods.32
Synthesis of the four pyridine isomers employed the
chemistry developed by Gallagher and co-workers.33
ortho-Lithiation of 2-bromopyridine or 3-bromopyri-
dine and trapping with ZnCl2 followed by Negishi cou-
pling34 with 25 and ethyl-3-iodobenzoate gave 29 and
30, respectively. Suzuki coupling25 with 3-eth-
oxycarbonylphenylboronic acid and 26 followed by ba-
sic hydrolysis gave 19 and 20, respectively (Scheme 3).
a
d
N
N
N
Cl
CO2Et
Br
Br
Br
OBn
30
20
29
19
b, c
e, f
Scheme 3. Reagents and conditions: (a) LDA, THF, ZnCl2, À95 °C to
rt, then 25, Pd(PPh3)4, reflux, 83%; (b) 3-ethoxycarbonylphenylboronic
acid, Pd(PPh3)4, K2CO3, PhMe–EtOH 90 °C, 84%; (c) 2 M NaOH,
EtOH, 60 °C, 78%; (d) LDA, THF, ZnCl2, À95 °C to rt, then ethyl-3-
iodoacetate, Pd(PPh3)4, reflux, 76%; (e) 26, Pd(PPh3)4, K2CO3, PhMe–
EtOH 90 °C, 75%; (f) 2 M NaOH, EtOH, rt, 78%.
Pyridines 21 and 22 were prepared in a similar fashion,
but starting from 3-bromopyridine (Scheme 4).
In summary, we have discovered several novel, potent,
EP1 antagonists by replacing the thiophene ring of 4
with alternative isosteric ring systems. The most promis-
ing analogues were profiled in vivo and the data gener-
ated support their use as lead compounds. Details of
the optimization of these templates will be the subject
of future publications.
N
N
N
a
d
Cl
CO Et
Br
2
Br
Br
OBn
31
21
32
e,f
b, c
References and notes
22
1. (a) Camu, F.; Shi, L.; Vanlersberghe, C. Drugs 2003,
63(suppl. 1), 1; (b) Bianchi, M.; Broggini, M. Drugs 2003,
63(suppl. 1), 37; (c) Jeger, R. V.; Greenberg, J. D.;
Ramanathan, K.; Farkouh, M. E. Exp. Rev. Clin. Immu-
nol. 2005, 1, 37; (d) Lee, Y.; Rodriguez, C.; Dionne, R. A.
Curr. Pharm. Des. 2005, 11, 1737.
Scheme 4. Reagents and conditions: (a) LDA, THF, ZnCl2, À95 °C to
rt, then ethyl-3-iodoacetate, Pd(PPh3)4, reflux, 44%; (b) 26, Pd(PPh3)4,
K2CO3, PhMe–EtOH 90 °C, 79%; (c) 2 M NaOH, EtOH, rt, 83%; (d)
LDA, THF, ZnCl2, À95 °C to rt, then 25, Pd(PPh3)4, reflux, 32%; (e)
3-(ethoxycarbonylphenyl)boronic acid, Pd(PPh3)4, K2CO3, PhMe–
EtOH 90 °C, 75%; (f) 2 M NaOH, EtOH, rt, 77%.

2670
A. Hall et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2666–2671
2. (a) Akarca, U. S. Curr. Pharm. Des. 2005, 11, 1779; (b)
Sheen, C. L.; MacDonald, T. M. Expert Opin. Pharmac-
other. 2002, 3, 265.
14. (a) Anon Expert Opin. Ther. Patents 2004, 14, 435(b)
Breault, G. A. WO9700863A1, 1997.
15. Watanabe, K.; Kawamori, T.; Nakatsugi, S.; Ohta, T.;
Ohuchida, S.; Yamamoto, H.; Maruyama, T.; Kondo, K.;
Narumiya, S.; Sugimura, T.; Wakabayashi, K. Cancer
Lett. 2000, 156, 57.
16. Kawamori, T.; Uchiya, N.; Nakatsugi, S.; Watanabe, K.;
Ohuchida, S.; Yamamoto, H.; Maruyama, T.; Kondo, K.;
Sugimura, T.; Wakabayashi, K. Carcinogenisis 2001, 22,
2001.
17. Hallinan, E. A.; Stapelfeld, A.; Savage, M. A.; Reichman,
M. Bioorg. Med. Chem. Lett. 1994, 4, 509.
3. (a) Hawkey, C. J.; Jackson, L.; Harper, S. E.; Simon, T. J.;
Mortensen, E.; Lines, C. R. Aliment. Pharmacol. Ther.
2001, 15, 1; (b) Bombardier, C.; Laine, L.; Reicin, A.;
Shapiro, D.; Burgos-Vargas, R.; Davis, B.; Day, R.; Bosi
Ferraz, M.; Hawkey, C. J.; Hochberg, M. C.; Kvien, T.
K.; Schnitzer, T. J. N. Eng. J. Med. 2000, 343, 1520; (c)
Silverstein, F. E.; Faich, G.; Goldstein, J. L.; Simon, L. S.;
Pincus, T.; Whelton, A.; Makuch, R.; Eisen, G.; Agrawal,
N. M.; Stenson, W. F.; Burr, A. M.; Zhao, W. W.; Kent, J.
D.; Lefkowith, J. B.; Verburg, K. M.; Geis, G. S. J. Am.
Med. Assoc. (JAMA) 2000, 284, 1247.
18. Hallinan, E. A.; Hagen, T. J.; Tsymbalov, S.; Husa, R. K.;
Lee, A. C.; Stapelfeld, A.; Savage, M. A. J. Med. Chem.
1996, 39, 609.
4. Meagher, E. A. Curr. Pharm. Des. 2004, 10, 603.
5. (a) Murakami, M.; Nakatani, Y.; Tanioka, T.; Kudo, I.
Prostaglandins Other Lipid Mediat. 2002, 68–69, 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.;
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.; Takego-
shi, Y.; Mikami-Nakanishi, M.; Nakatani, Y.; Oh-ishi, S.;
Yasui, H.; Azuma, Y.; Hirasawa, N.; Ohuchi, K.; Kaw-
aguchi, H.; Ishikawa, Y.; Ishii, T.; Uematsu, S.; Akira, S.;
Murakami, M.; Kudo, I. J. Biol. Chem. 2004, 279, 33684;
(e) Mabuchi, T.; Kojima, H.; Abe, T.; Takagi, K.;
Sakurai, M.; Ohmiya, Y.; Uematsu, S.; Akira, S.; Watan-
abe, K.; Ito, S. NeuroReport 2004, 15, 1395.
6. (a) Coleman, R. A.; Smith, W. L.; Narumiya, S. Pharma-
col. 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; (d) Coleman, R.
A.; Kennedy, I.; Humphrey, P. P. A.; Bunce, K.; Lumley,
P.. In Comprehensive Medicinal Chemistry; Pergamon:
Oxford, UK, 1990; Vol. 3, pp 643–714.
7. (a) Minami, T.; Nakano, H.; Kobayashi, T.; Sugimoto,
Y.; Ushikubi, F.; Ichikawa, A.; Narumiya, S.; Ito, S.
Br. J. Pharmacol. 2001, 133, 438; (b) Mebane, H.;
Turnbach, M. E.; Randich, A. J. Pain 2003, 4, 392.
8. Stock, J. L.; Shinjo, K.; Burkhardt, J.; Roach, M.;
Taniguchi, K.; Ishikawa, T.; Kim, H.-S.; Flannery, P. J.;
Coffman, T. M.; McNeish, J. D.; Audoly, L. P. J. Clin.
Invest. 2001, 107, 325.
9. (a) Omote, K.; Kawamata, T.; Nakayama, Y.; Kawa-
mata, M.; Hazama, K.; Namiki, A. Anesth. Analg.
2001, 92, 233; (b) Omote, K.; Yamamoto, H.; Kawa-
mata, T.; Nakayama, Y.; Namiki, A. Anesth. Analg.
2002, 95, 1708.
`
19. Ducharme, Y.; Blouin, M.; Carriere, M.-C.; Chateauneuf,
A.; Cote, B.; Denis, D.; Frenette, R.; Greig, G.; Kargman,
ˆ ´
S.; Lamontagne, S.; Martins, E.; Nantel, F.; O’Neill, G.;
Sawyer, N.; Metters, K. M.; Friesen, R. W. Bioorg. Med.
Chem. Lett. 2005, 15, 1155.
20. (a) Pinto, D. J. P.; Copeland, R. A.; Covington, M. B.;
Pitts, W. J.; Batt, D. G.; Orwat, M. J.; Lam, G. N.;
Joshi, A.; Chan, Y.-C.; Wang, S.; Trzaskos, J. M.;
Magolda, R. L.; Kornhauser, D. M. Bioorg. Med. Chem.
Lett. 1996, 6, 2907; (b) Gauthier, J. Y.; Leblanc, Y.;
Black, W. C.; Chan, C.-C.; Cromlish, W. A.; Gordon,
´
R.; Kennedey, B. P.; Lau, C. K.; Leger, S.; Wang, Z.;
Ethier, D.; Guay, J.; Mancini, J.; Riendeau, D.; Tagari,
P.; Vickers, P.; Wong, E.; Xu, L.; Prasit, P. Bioorg. Med.
Chem. Lett. 1996, 6, 87; (c) Li, J. J.; Anderson, G. D.;
Burton, E. G.; Gogburn, J. N.; Collins, J. T.; Garland,
D. J.; Gregory, S. A.; Huang, H.-C.; Isakson, P. C.;
Koboldt, C. M.; Logusch, E. W.; Norton, M. B.;
Perkins, W. E.; Reinhard, E. J.; Seibert, K.; Veenhuizen,
A. W.; Zhang, Y.; Reitz, D. B. J. Med. Chem. 1995, 38,
4570; (d) Khanna, I. K.; Weier, R. M.; Yu, Y.; Collins,
P. W.; Miyashiro, J. M.; Koboldt, C. M.; Veenhuizen, A.
W.; Currie, J. L.; Seibert, K.; Isakson, P. C. J. Med.
Chem. 1997, 40, 1619; (e) Prasit, P.; Wang, Z.; Brideau,
C.; Chan, C.-C.; Charleson, S.; Cromlish, W.; Ethier, D.;
Evans, J. F.; Ford-Hutchinson, A. W.; Gauthier, J. Y.;
Gordon, R.; Guay, J.; Gresser, M.; Kargman, S.;
´
Kennedy, B.; Leblanc, Y.; Leger, S.; Mancini, J.; O’Neill,
G. P.; Ouellet, M.; Percival, M. D.; Perrier, H.;
´
Riendeau, D.; Rodger, I.; Tagari, P.; Therien, M.;
Vickers, P.; Wong, E.; Xu, L.-J.; Young, R. N.;
Zamboni, R. Bioorg. Med. Chem. Lett. 1999, 9, 1773;
(f) Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.;
Carter, J. S.; Collins, P. W.; Docter, S.; Graneto, M. J.;
Lee, L. F.; Malecha, J. W.; Miyashiro, J. M.; Rogers, R.
S.; Rogier, D. J.; Yu, S. S.; Anderson, G. D.; Burton, E.
G.; Cogburn, J. N.; Gregory, S. A.; Koboldt, C. M.;
Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang,
Y. Y.; Isakson, P. C. J. Med. Chem. 1997, 40, 1347; (g)
Talley, J. J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.;
Koboldt, C. M.; Masferrer, J. L.; Perkins, W. E.; Rogers,
R. S.; Shaffer, A. F.; Zhang, Y. Y.; Zweifel, B. S.;
Seibert, K. J. Med. Chem. 2000, 43, 775; (h) Almansa,
10. Kawahara, H.; Sakamoto, T.; Takeda, S.; Onodera, H.;
Imaki, J.; Ogawa, R. Anesth. Analg. 2001, 93, 1012.
11. Maruyama, T.; Koketsu, M.; Yamamoto, H.; Yamamoto,
K.; Yamamoto, L. T.; Hayashida, K.-i.; Ohuchida, S.;
Kondo, K. Prostaglandins Other Lipid Mediat. 1999, 59,
217.
´
C.; Alfon, J.; de Arriba, A. F.; Cavalcanti, F. L.;
Escamilla, I.; Gomez, L. A.; Miralles, A.; Soliva, R.;
´
´
Bartolı, J.; Carceller, E.; Merlos, M.; Garcıa-Rafanell, J.
J. Med. Chem. 2003, 46, 3463.
´
12. (a) Oka, T.; Oka, K.; Saper, C. B. Brain Res. 2003, 968,
256; (b) Oka, T. Front. Biosci. 2004, 9, 3046; (c) Oka, K.;
Oka, T.; Hori, T. Brain Res. 1997, 767, 92; (d) Oka, T.;
Hori, T. Am. J. Physiol. 1994, 267, R289; (e) Oka, T.; Oka,
K.; Kobayashi, T.; Sugimoto, Y.; Ichikawa, A.; Ushikubi,
F.; Narumiya, S.; Saper, C. B. J. Physiol. 2003, 551, 945.
13. Sarkar, S.; Hobson, A. R.; Hughes, A.; Growcott, J.;
Woolf, C. J.; Thompson, D. G.; Aziz, Q. Gastroenterology
2003, 124, 18.
´
21. (a) Rinaldi-Carmona, M.; Barth, F.; Heaulme, M.;
´
`
Alonso, R.; Shire, D.; Congy, C.; Soubrie, P.; Breliere,
J.-C.; Le Fur, G. Life Sci. 1995, 56, 1941; (b) Lange, J.
H. M.; Kruse, C. G. Drug Discovery Today 2005, 10,
693.
22. (a) King, F. D. In Medicinal Chemistry Principles and
Practice, 2nd ed.; RSC: Cambridge, UK, 2002; p 327;

A. Hall et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2666–2671
2671
(b) Thornber, C. W. Chem. Soc. Rev. 1979, 8, 563; (c)
Wermuth, C. G. In The Practice of Medicinal Chemistry,
2nd ed.; Elsevier: London, UK, 2003.
M. P.; Hall, A.; Healy, M. P.; Lewell, X. Q.; Miller, N. D.;
Novelli, R.; King, F. D.; Naylor, A. WO2005054191A1.;
(c) Giblin, G. M. P.; Hall, A.; Kilford, I. R.; Lewell, X. Q.;
Miller, N. D.; Naylor, A WO2005037786A1.; (d) Giblin,
G. M. P.; Hall, A.; Lewell, X. Q.; Miller, N. D.
WO2004083185A2.; (e) Bit, R. A.; Giblin, G. M. P.; Hall,
A.; Hurst, D. N.; Kilford, I. R.; Miller, N. D.; Scoccitti, T.
WO2004039753A2.
23. Compound potencies were determined using a radioli-
gand binding assay where the ability of compounds to
compete with tritiated prostaglandin E2 ([3H]-PGE2)
binding to the human EP1 receptor was measured in
Chinese hamster ovary-K1 (CHO-K1) cells into which a
stable vector containing the EP1 cDNA had previously
been transfected. Cell membranes, competing com-
pounds and [3H]-PGE2 (3 nM final assay concentration)
were incubated in a final volume of 100 lL for 30 min
at 30 °C. The radioactivity retained was measured by
liquid scintillation counting in Packard TopCount
scintillation counter.
24. The antagonist properties of compounds were assessed by
their ability to inhibit the mobilisation of intracellular
calcium ([Ca2+]i) in response to activation of the EP1
receptor by prostaglandin E2 (PGE2). The amount of
calcium produced was assessed using a calcium-sensitive
fluorescent dye such as Fluo-3, AM and a suitable
instrument such as a Fluorimetric Imaging Plate Reader
(FLIPR).
26. Suzuki, A. Pure Appl. Chem. 1991, 63, 419; Miyaura, N.;
Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 20,
3437.
27. Bellina, F.; Anselmi, C.; Rossi, R. Tetrahedron Lett. 2001,
42, 3851.
28. Stetter, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 639.
29. Paal, C. Ber. 1885, 18, 367; Knorr, L. Ber. 1885, 299.
30. Mach, R. H.; Huang, Y.; Freeman, R. A.; Wu, L.; Blair,
S.; Luedtke, R. Bioorg. Med. Chem. 2003, 11, 225.
31. van Leusen, D.; van Leusen, A. M.. In Organic Reactions;
Overman, L. E., Ed.; John Wiley and Sons, 2001; Vol. 57,
p 417.
32. Stocks, M. J.; Cheshire, D. R.; Reynolds, R. Org. Lett.
2004, 6, 2969.
33. Karig, G.; Spencer, J. A.; Gallagher, T. Org. Lett. 2001, 3,
835.
34. Negishi, E. i.; King, A. O.; Okukado, N. J. Org. Chem.
1977, 42, 1821; Knochel, P.; Singer, R. D. Chem. Rev.
1993, 93, 2117.
25. (a) Giblin, G. M. P.; Hall, A.; Hurst, D. N.; Kilford, I. R.;
Lewell, X. Q.; Naylor, A.; Novelli, R. WO2003084917A1.;
(b) Giblin, G. M. P.; Hall, A.; Healy, M. P.; Lewell, X. Q.;
Miller, N. D.; Novelli, R. WO2003101959A1; Giblin, G.