Structure-activity relationships and pharmacokinetic parameters of quinoline acylsulfonamides as potent and selective antagonists of the EP4 receptor

Article abstract of DOI:10.1016/j.bmcl.2008.01.103

A new series of EP₄ antagonists based on a quinoline acylsulfonamide scaffold have been identified as part of our on-going efforts to develop treatments for chronic inflammation. These compounds show subnanomolar intrinsic binding potency towar

Full text of DOI:10.1016/j.bmcl.2008.01.103

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 2048–2054
Structure–activity relationships and pharmacokinetic parameters
of quinoline acylsulfonamides as potent and selective
antagonists of the EP4 receptor
*
´
ˆ
Jason D. Burch, Michel Belley, Rejean Fortin, Denis Deschenes, Mario Girard,
John Colucci, Julie Farand, Alex G. Therien, Marie-Claude Mathieu, Danielle Denis,
´
´
´
Erika Vigneault, Jean-Franc¸ois Levesque, Sebastien Gagne, Mark Wrona, Daigen Xu,
Patsy Clark, Steve Rowland and Yongxin Han*
Merck Frosst Centre for Therapeutic Research, 16711 Trans-Canada Highway, Kirkland, Que., Canada H9H 3L1
Received 19 December 2007; revised 24 January 2008; accepted 25 January 2008
Available online 31 January 2008
Abstract—A new series of EP4 antagonists based on a quinoline acylsulfonamide scaffold have been identified as part of our on-
going efforts to develop treatments for chronic inflammation. These compounds show subnanomolar intrinsic binding potency
towards the EP4 receptor, and excellent selectivity towards other prostanoid receptors. Acceptable pharmacokinetic profiles have
also been demonstrated across a series of preclinical species.
ꢀ 2008 Elsevier Ltd. All rights reserved.
À=À
mice showed
Prostanoids (prostaglandins and thromboxanes) are
important lipid hormones formed from arachidonic acid
metabolism. Prostaglandin E2 (PGE2), in particular, is
the principal proinflammatory prostanoid and is impli-
cated in the pathogenesis of a number of diseases such
as pain, fever, arthritis and cancer. Inhibition of PGE2
production by NSAIDs and COX-2 inhibitors (Coxibs)
relieves arthritis symptoms, and thus is the basis of
widespread uses of these drugs as analgesics.1 Unfortu-
nately, the therapeutic utilities of these drugs are limited
by their potential to cause either gastro-intestinal toxic-
ity (by NSAIDs)2 or cardiovascular (CV) side effects (by
both NSAIDs and Coxibs).3 The CV adverse events
associated with these drugs are not clearly understood
although it is speculated that inhibition of prostacyclin
biosynthesis may cause the prothrombotic and hyper-
tensive effects.4 Therefore, there is a vast unmet medical
need to discover alternatives for treating chronic ail-
ments such as arthritis.
body induced arthritis (CAIA), the EP4
a remarkable resistance to both the incidences and
symptom scores (paw swelling/redness, ankylosis) of
arthritis compared to the wild type controls while the
EP1–3À=À mice showed no effect, suggesting that the effect
of PGE2 in chronic inflammation was mediated predom-
inantly by the EP4 receptor.5 Lin et al. demonstrated
that EP4, not EP1–3, contributed to inflammatory pain
hypersensitivity in rats, providing further evidence that
EP4 antagonism is a valid strategy for treating inflam-
matory pain.6 It is plausible that a selective EP4 antago-
nist may ameliorate symptoms of chronic inflammation
without the potential CV side effects observed with
NSAIDs and COX-2 inhibitors since it does not inter-
fere with biosynthesis of any prostanoids including pros-
tacyclin and thromboxanes. In addition to its role in
inflammation, the EP4 receptor has also been implicated
in destabilizing atherosclerotic plaques in human7 and in
developing tumour metastasis.8 Therefore, EP4 antago-
nists represent potential promising new therapeutic
agents for treating inflammatory pain, atherosclerosis
and cancer. In this paper, we describe the discovery of
a highly potent EP4 antagonist with excellent pharmaco-
kinetic properties and in vivo potency.
PGE2 exerts its biological effects through four subtype
EP receptors, EP1–4. In a mouse model of collagen-anti-
Keywords: Anti-inflammatories; Prostanoid receptor antagonists;
Quinoline acylsulfonamides.
At the outset of our investigations, acylsulfonamide 1
was a known EP4 antagonist from the literature
*
Corresponding authors. Tel.: +1 514 428 3839; e-mail:
jason_burch@merck.com
0960-894X/$ - see front matter ꢀ 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.01.103

J. D. Burch et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2048–2054
2049
(Fig. 1).9 While this compound showed low nanomolar
intrinsic potency for binding with the EP4 receptor,10
it suffered from extensive shift in the presence of human
serum. Further, in vivo hydrolysis of the acylsulfona-
mide moiety resulted in the formation of a circulating
carboxylic acid which was shown to be a partial agonist
for EP4.11 We sought to alleviate this issue by reversal of
the orientation of the acylsulfonamide, with an eye to
increasing potency through a combination of increasing
rigidity through steric constraints, and by changing the
polarity by the introduction of heterocyclic frameworks
(Fig. 1).
the diesters under basic conditions followed by treat-
ment of the resulting dicarboxylates with refluxing acetic
anhydride. Bromides D were converted to protected sul-
fonamides E via oxidation of the intermediate thioimi-
date with chlorine gas.13 Reduction to anilines F, then
treatment with anhydride C under acidic conditions
provided the phthalimides G. Sequential reductions pro-
vided lactams H, which in the case of the quinoline series
were a readily separable mixture of regioisomers. Final-
ly, formation of the acylsulfonamides I was accom-
plished by either treatment with the desired acid
chloride, or from the acid using peptide coupling
conditions.14
The acylsulfonamide targets were prepared as shown in
Scheme 1. Claisen condensation12 of dimethyl succinate
with dimethyl phthalate or dimethyl pyridine dicarbox-
ylate A, then bis-alkylation of the resulting diphenol
provided the alkylated dihydroquinones B. Conversion
to the anhydrides C was accomplished by hydrolysis of
The first phase of our SAR investigation involved paral-
lel synthesis of a ꢀ50-member library of acylsulfona-
mides based on a naphthalene scaffold, differing in the
acyl substituent. Selected results from this library are
summarized in Table 1 below.
In terms of intrinsic binding affinity, good potency
(Ki < 10 nM) is maintained for a wide range of acyl sub-
stituents: methylene aryl (entries 1, 4–8 and 10), methy-
lene heteroaryl (entry 2), methylene phenoxy (entry 3)
and bis-methylene heteroaryl (entry 9). The extent of
protein shift, however, is drastically affected by the con-
stitution of this position. While a simple benzyl substitu-
ent leads to extensive protein shift (entry 1), substitution
of the ortho-position of the aryl or heteroaryl ring
significantly improves the potency in the presence of
10% human serum (entries 1, 5, 6 and 10). In particular,
2,5-dimethoxyphenyl (entry 6, 100-fold shifted) and
naphthalene (entry 10, 10-fold shifted) provide the best
results. For simplicity, moving forward, ortho-methoxy-
Figure 1. Planned SAR evolution.
Scheme 1. Reagents: (a) (MeO2CCH2)2, NaH, MeOH; (b) R1I or R1OTf K2CO3; (c) NaOH; (d) Ac2O; (e) H2NCSNH2; (f) Cl2, tBuNH2; (g) H2, Pd/
C; (h) AcOH; (i) NaBH4; (j) TFA, Et3SiH; (k) R3COCl, Et3N or R3COOH, EDC, DMAP.

2050
J. D. Burch et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2048–2054
Table 2. Effect of ortho-substitution on the central ringa
Table 1. Library of naphthalene acylsulfonamidesa
Entry
R
Compound
EP4 Ki (nM)
0% HS 10% HS
Entry
R
Compound
EP4 Ki (nM)
0% HS
10% HS
1
2
H
Me
(2)
(12)
0.31 0.01
0.25 0.10
>4000
29 11
1
2
3
(2)
(3)
(4)
0.31 0.01 >4000
a Values are means from at least three experiments; HS, human serum;
for details of the EP4 binding assay see Ref. 10.
2.0 0.4
600 130
0.38 0.08 1200 500
gards to crystal packing and solubility. As can be seen
in Table 2, this modification has a much more beneficial
effect: introduction of an ortho-methyl substituent
diminished the protein shift from >10,000-fold to
ꢀ100-fold (entry 2 vs entry 1). We postulate that this
is due to a disruption in albumin binding by deviation
from planarity.
4
5
(5)
(6)
1.0 0.1
940 470
380 60
0.43 0.07
For the western ring, we sought to replace the naphtha-
lene ring with a quinoline. The benefits of this replace-
ment were twofold: (a) synthetic access to the
quinoline precursors was more favourable; and (b)
introduction of a basic nitrogen would allow for the pos-
sibility of formation of a wider variety of salt forms for
formulation. Further, we had hoped that altering the
polarity of this region might have a positive effect on
the extent of protein shift. As can be seen in Table 3,
binding potency and shift are greatly affected by the reg-
iochemistry of the quinoline ring: while the 6-carboxy-
quinoline (entry 2) exhibits similar potency and shift
to the naphthalene (entry 1), the 7-carboxyquinoline
(entry 3) is ꢀ10-fold less potent and significantly more
shifted. Although no benefit was observed in terms of
potency and shift for the 6-carboxyquinoline, this scaf-
fold was selected for further explorations due to the
aforementioned practical benefits.
6
(7)
0.37 0.07
38 12
7
8
(8)
(9)
2.4 0.5
1600 400
7.9 6.0
>4000
9
(10)
(11)
4.2 0.6
>4000
With an optimal scaffold selected, further SAR studies
were performed on the phenylacetate (eastern) frag-
ment through the synthesis of a second targeted library
10
0.43 0.20
4.8 2.2
a Values are means from at least three experiments; HS, human serum;
for details of the EP4 binding assay see Ref. 10.
Table 3. Western fragment SARa
phenylacetate was selected since we postulated that the
5-methoxy substituent did little to diminish protein shift
(entry 7), and compounds possessing naphthalene sub-
stitution exhibited poor bioavailability.
Entry
A
B
Compound
EP4 Ki (nM)
0% HS
10% HS
Concurrent with these explorations, optimization stud-
ies on the central and western ring were undertaken.
In the case of the central ring, we were interested in
the effect of introduction of ortho-substitution. Origi-
nally the aim of this substitution was to investigate the
effect of changing the orientation of this ring with re-
1
2
3
CH
CH
N
CH
N
(12)
(13)
(14)
0.25 0.10
0.76 0.16
3.3 1.3
29 11
31 28
660 430
CH
a Values are means from at least three experiments; HS, human serum;
for details of the EP4 binding assay see Ref. 10.

J. D. Burch et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2048–2054
Table 4. Eastern SAR in the 6-carboxyquinoline seriesa
2051
Entry
A
B
C
X
Compound
EP4 Ki (nM)
0% HS
10% HS
1
CH
CH
CH
CH
CH
CH
CH
CH
N
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
H
(13)
(15)
(16)
(17)
(18)
(19)
(20)
(21)
(22)
(23)
(24)
(25)
(26)
0.76 0.16
0.74 0.46
0.43 0.11
0.48 0.14
0.27 0.07
0.21 0.06
0.27 0.03
0.32 0.08
2.4 1.0
31 28
3.6 1.0
350 60
34 16
2
OMe
CF3
F
3
4
5
Cl
37
7
6
OCF3
OEt
OCHF2
H
56 44
8.9 5.4
13 11
7
8
9
13
7
10
11
12
13
CH
CH
CCl
COMe
H
2.8 0.9
9.8 4.1
48 11
160 30
4.8 2.8
2.3 0.6
CH
CH
CH
H
Cl
CH
CH
0.28 0.05
0.12 0.09
OMe
a Values are means from at least three experiments; HS, human serum; for details of the EP4 binding assay see Ref. 10.
Table 5. Pharmacokinetic parameters for compound 15a
(Table 4). As expected from our initial library screen,
introduction of an ortho-methoxy substituent resulted
in a dramatic reduction in protein shift (entry 2 vs entry
1). While electron withdrawing substituents were toler-
ated at the ortho-position in terms of intrinsic potency
(entries 2–5), this substitution did not provide any ben-
efit in terms of protein shift. Replacement of the hydro-
gen atoms of the methoxy substituent with two or three
fluorine atoms (entries 6 and 8) or an additional methyl
group (entry 7) also resulted in an increase in protein
shift. We investigated the replacement of the phenylace-
tate with the various isomers of pyridylacetates (entries
9–11). In all cases this resulted in a significant reduction
in intrinsic binding potency, but interestingly the pyri-
din-2-yl isomer (entry 9) was only moderately shifted.
Finally, we were interested in exploring the effect of
substituting both ortho positions (entries 12 and 13).
In the case of chloro and methoxy substitution, this
addition further increased the intrinsic binding potency
and, in the case of chlorine (entry 12), dramatically re-
duces the extent of protein shift.
Species
Dose
(mg/kg)
F
T1/2
Cl
(mL/min/kg)
Vdss
(%)
(h)
(L/kg)
po
iv
Rat
Guinea pig
Dog
20
20
10
5
5
2
>99
18
2.7
8.6
4.1
7.8
3.6
0.4
1.6
0.6
0.1
49
a The corresponding sodium salt was used for pharmacokinetic studies.
F denotes bioavailability; T1/2 is the half-life in plasma, and is
determined from the intravenous (iv) data; Cl is plasma clearance;
Vdss is the volume of distribution; po vehicle is 0.5% methocel; iv
vehicle is 60% PEG 200.
nol 27 or 28 and deacylated sulfonamide (29). Unlike
the acid metabolite of 1, sulfonamide 29 showed no
functional activity towards the EP4 receptor. The dee-
thylation product was troubling, due to the possibility
of further metabolic degradation to a quinone (not ob-
served) which could act as a reactive intermediate lead-
ing to covalent protein labelling. Further, in vitro
microsomal incubations across a variety of species indi-
cated that acylsulfonamide hydrolysis leading to 29 was
likely to be exacerbated in higher species, especially hu-
mans. For these reasons, further SAR explorations were
undertaken with the goal of limiting these metabolic
liabilities.
Compound 15, alternatively referred to as MF498 in
other publications,15 was selected for further profiling
due to its excellent intrinsic potency and moderate
protein shift. This compound was found to be potent
(IC50 = 1.1 0.2 nM) and moderately shifted (ꢀ10-
fold in the presence of 10% human serum) in an
EP4 functional assay16 and was shown to be a full
antagonist. A full prostanoid receptor screen was
performed (Table 9, vide supra) and 15 was found
to be nearly 1000-fold selective against all other
receptors.
In order to limit in vivo oxidative deethylation, the ethyl
groups were replaced by the oxidatively more stable tri-
fluoroethyl and isopropyl substituents (Table 6). While
intrinsic binding potency was maintained, both com-
pounds were more shifted in the presence of human ser-
um. Nonetheless, it was hoped that by further tuning of
the acylsulfonamide (eastern) terminus, acceptable levels
of protein shift could be obtained with the trifluoroethyl
replacement.
Analysis of the pharmacokinetic parameters of 15
showed that it exhibited acceptable absorption, half-life
and clearance in a variety of species (Table 5). Two main
circulating metabolites were observed (Scheme 2): phe-

2052
J. D. Burch et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2048–2054
In an effort to reduce the extent of in vivo acylsulfona-
mide hydrolysis, the steric hindrance near the carbonyl
group was increased (Table 7). Replacement of the
methylene bridge with a cyclopropyl substituent resulted
in the retention of binding potency and shift (entry 2 vs
entry 1). Unfortunately, replacement of the ethyl moie-
ties with trifluoroethyl groups resulted in the same in-
crease in protein shift observed above (entry 3).
Fortuitously, while an additional ortho-methoxy substi-
tuent had minimal effect in the diethyl case (entry 4 vs
entry 1), the same replacement in the bis-trifluoroethyl
series had a marked effect (entry 5 vs entry 3). Acylsulf-
onamide 35 exhibits similar intrinsic potency to our pre-
vious lead (15), but has improved protein shift, and
possesses the oxidatively more stable trifluoroethyl sub-
stituents on the dihydroquinone moiety, and also has in-
creased steric hindrance about the acylsulfonamide
carbonyl. Compound 35 was thus selected for further
in vitro and in vivo profiling.
Analysis of the pharmacokinetic parameters of com-
pound 35 indicated a good overall profile across several
species (Table 8). Further, in vitro metabolism in hepa-
tocytes showed good correlation with the in vivo results,
and demonstrated that human pharmacokinetics would
be expected to be intermediate between dog and rhesus
monkey. Acylsulfonamide hydrolysis was observed
in vitro and in vivo (see Scheme 3), but to a lesser extent
than was observed for compound 15. No dealkylation of
the western dihydroquinone was observed in any
species.
Scheme 2. Observed circulating metabolites of compound 15.
Table 6. Diphenol diether SARa
Compound
35
was
found
to
be
potent
(IC50 = 3.2 1.6 nM) and was only moderately shifted
in the presence of 10% human serum (ꢀ4-fold) in an as-
say for functional EP4 antagonism,15 and was shown to
be a full antagonist. A full prostanoid receptor screen
was performed (Table 9), and 35 was found to be signif-
icantly less selective than 15, but still showed a >50-fold
selectivity against the other receptors.
Entry
R
Compound
EP4 Ki (nM)
0% HS
10% HS
1
2
3
CH2CH3
CH2CF3
CH(CH3)2
(15)
(30)
(31)
0.74 0.46
0.38 0.10
0.36 0.15
3.6 1.0
17 10
26 10
Compound 35 was then submitted to an in vivo preclin-
ical model for chronic inflammation: the rat adjuvent-in-
duced arthritis (AIA) model.17 This compound was
found to be extremely potent in this model, with an
a Values are means from at least three experiments; HS, human serum;
for details of the EP4 binding assay see Ref. 10.
Table 7. Final SAR optimizationa
Entry
R
A
B
X
Compound
EP4 Ki (nM)
0% HS
10% HS
1
2
3
4
5
CH2CH3
CH2CH3
CH2CF3
CH2CH3
CH2CF3
H
H
H
(15)
(32)
(33)
(34)
(35)
0.74 0.46
0.55 0.29
0.95 0.58
0.54 0.24
0.79 0.48
3.6 1.0
4.2 1.2
–CH2 CH2–
–CH2 CH2–
–CH2 CH2–
–CH2 CH2–
H
H
12
7
OMe
OMe
2.3 1.0
1.6 0.7
a Values are means from at least three experiments; HS, human serum; for details of the EP4 binding assay see Ref. 10.

J. D. Burch et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2048–2054
Table 8. Pharmacokinetic parameters for compound 35a
2053
Species
Dose (mg/kg)
F (%)
T1/2 (h)
Cl (mL/min/kg)
Vdss (L/kg)
Metab.b (%)
po
iv
Mouse
Rat
Dog
100
20
4
10
10
5
44
73
69
40
—
3.5
14.8
13.2
3.8
2.6
0.6
0.2
2.0
—
0.7
0.7
0.2
0.3
—
—
6
20
39
36
Rhesus
Human
4
2
—
—
—
a The corresponding sodium salt was used for pharmacokinetic studies. F denotes bioavailability; T1/2 is the half-life in plasma, and is determined
from the intravenous (iv) data; Cl is plasma clearance; Vdss is the volume of distribution; po vehicle is 0.5% methocel; iv vehicle is 60% PEG 200.
b In vitro metabolism in standard hepatocytes (20 lM 35, 1 · 106 cells/0.5 mL, 2 h).
Table 9. Prostanoid receptor binding affinities (Ki, nM) for lead compounds 15 and 35a
Compound
EP1
EP2
EP3
EP4
DP
TP
FP
IP
15
35
>7000
>9000
1900 800
300 200
4000 1000
2700 1500
0.74 0.46
0.79 0.48
1200 300
53 16
630 120
39 26
2000 1000
340 240
>7000
2000 1000
a Values are means from at least three experiments; for details of the prostanoid binding assays see Ref. 10.
Acad. Sci. U.S.A. 1999, 96, 272; (b) FitzGerald, G. A.;
Patrono, C. N. Eng. J. Med. 2001, 345, 433; For a recent
review see: (c) Funk, C. D.; FitzGerald, G. A.
J. Cardiovasc. Pharm. 2007, 50, 470.
ED50 of approximately 0.005 mg/kg ([35]trough = 30 nM)
with once-daily dosing, making compound 35 one of the
most potent compounds reported in the rat-AIA model.
For comparison, the COX-2 inhibitor rofecoxib exhib-
ited an ED50 of 0.74 mg/kg/day in this model.16
5. McCoy, J. M.; Wicks, J. R.; Audoly, L. P. J. Clin. Invest.
2002, 110, 651.
6. Lin, C.-R.; Amaya, F.; Barrett, L.; Wang, H.; Takada, J.;
Samad, T. A.; Woolf, C. J. J. Pharmacol. Exp. Ther. 2006,
319, 1096.
7. Cipollone, F.; Fazia, M. L.; Iezzi, A.; Cuccurollo, C.; De
Cesare, D.; Ucchino, S.; Spigonardo, F.; Marchetti, A.;
Buttitta, F.; Paloscia, L.; Mascellanti, M.; Cuccurollo, F.;
Mezzetti, A. Arterioscler. Thromb. Vasc. Biol. 2005, 25,
1925.
In summary, we have presented a potent and selective
EP4 receptor antagonist (compound 35). This com-
pound exhibits subnanomolar binding potency for the
EP4 receptor and >50-fold selectivity against other pro-
stanoid receptors. Compound 35 is also potent in a func-
tional assay for EP4 antagonism, and exhibits good
pharmacokinetic properties across several preclinical
species. Potency was optimized and protein shift was
minimized by the introduction of ortho-substituents on
the central and eastern aromatic rings, and metabolic
liabilities were minimized by reducing the oxidative
instability of the dihydroquinone ether groups, and by
increasing the steric hindrance around the acylsulfona-
mide moiety. This compound has shown excellent effi-
cacy in an in vivo preclinical model of inflammation,
and further details of these discoveries will be reported
in due course.
8. (a) Ma, X.; Kundu, N.; Rifat, S.; Walser, R.; Fulton, A.
M. Cancer Res. 2006, 66, 2923; (b) Chell, S. D.; Wither-
den, I. R.; Dobson, R. R.; Moorghen, M.; Herman, A. A.;
Qualtrough, D.; Williams, A. C.; Paraskeva, C. Cancer
Res. 2006, 66, 3106; (c) Yang, L.; Huang, Y.; Porta, R.;
Yanagisawa, K.; Gonzalez, A.; Segi, E.; Johnson, D. J.;
Narumiya, S.; Carbone, D. P. Cancer Res. 2006, 66, 9665.
9. (a) Wilson, R. J.; Giblin, G. M. P.; Roomans, S.; Rhodes,
S. A.; Cartwright, K.; Shield, V. J.; Brown, J.; Wise, A.;
Chowdhury, J.; Pritchard, S.; Coote, J.; Noel, L. S.;
Kenakin, T.; Burns-Kurtis, C. L.; Morrison, V.; Gray, D.
W.; Giles, H. Br. J. Pharmacol. 2006, 148, 326; For other
examples of EP4 antagonists from the literature see: (b)
Brittain, R. T.; Boutal, L.; Carter, M. C.; Coleman, R. A.;
Collington, E. W.; Geisow, H. P.; Hallett, P.; Hornby, E.
J.; Humphrey, P. P.; Jack, D.; Kennedy, I.; Lumley, P.;
McCabe, P. J.; Skidmore, I. F.; Thomas, M.; Wallis, C. J.
Circulation 1985, 72, 1208; (c) Machwate, M.; Harada, S.;
Leu, C. T.; Seedor, G.; Labelle, M.; Gallant, M.;
Hutchins, S.; Lachance, N.; Sawyer, N.; Slipetz, D.;
Metters, K. M.; Rodan, S. B.; Young, R.; Rodan, G. A.
Mol. Pharmacol. 2001, 60, 36; (d) Mutoh, M.; Watanabe,
K.; Kitamura, T.; Shoji, Y.; Takahashi, M.; Kawamori,
T.; Tani, K.; Kobayashi, M.; Maruyama, T.; Kobayashi,
K.; Ohuchida, S.; Sugimoto, Y.; Narumiya, S.; Sugimura,
T.; Wakabayashi, K. Cancer Res. 2002, 62, 28; (e) Hattori,
K.; Tanaka, A.; Fuji, N.; Takasugi, H.; Tenda, Y.;
Tomita, M.; Nakazato, K.; Kato, Y.; Kono, Y.; Murai,
H.; Sakane, K. J. Med. Chem. 2005, 48, 3103; (f) Nakao,
K.; Murase, A.; Ohshiro, H.; Okumura, T.; Taniguchi, K.;
Murata, Y.; Masuda, M.; Kato, T.; Okumura, Y.;
Takada, J. J. Pharmacol. Exp. Ther. 2007, 322, 686.
References and notes
1. Flower, R. J. Nat. Rev. Drug Disc. 2003, 2, 179.
2. Bombardier, C.; Laine, L.; Reicin, A.; Shapiro, D.;
Burgos-Vargas, R.; Davis, B.; Day, R.; Bosi Ferraz, R.;
Hawkey, C. J.; Hochberg, M. C.; Kvien, T. K.; Schnitzer,
T. J. N. Eng. J. Med. 2000, 343, 1520.
3. (a) Solomon, S. D.; McMurray, J. J. V.; Pfeiffer, M. A.;
Wittes, J.; Fowler, R.; Finn, P.; Anderson, W. F.; Zauber,
A.; Hawk, E.; Bertagnolli, M. N. Eng. J. Med. 2005, 352,
1071; (b) Nussmeier, N. A.; Whelton, A. A.; Brown, M.
T.; Langford, R. M.; Hoeft, A.; Parlow, J. L.; Boyce, S.
W.; Verbug, K. M. N. Eng. J. Med. 2005, 352, 1081; (c)
Bresalier, R. S.; Sandler, R. S.; Quan, H.; Bolognese, J. A.;
Oxenius, B.; Horgan, K.; Lines, C.; Ridell, R.; Morton,
D.; Lanas, A.; Konstam, M. A.; Baron, J. A. N. Eng. J.
Med. 2005, 352, 1092.
4. (a) McAdam, B. F.; Catella-Lawson, F.; Mardini, I. A.;
Kapoor, S.; Lawson, J. A.; FitzGerald, G. A. Proc. Natl.

2054
J. D. Burch et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2048–2054
10. Abramovitz, M.; Adam, M.; Boie, Y.; Carriere, M.; Denis,
D.; Godbout, C.; Lamontagne, S.; Rochette, C.; Sawyer,
N.; Tremblay, N. M.; Belley, M.; Gallant, M.; Dufresne,
C.; Gareau, Y.; Ruel, R.; Juteau, H.; Labelle, M.; Ouimet,
N.; Metters, K. M. Biochem. Biophys. Acta 2000, 1483,
285.
11. Data not shown; for functional assay details see Ref. 15.
12. Homeyer, W. J. Am. Chem. Soc. 1942, 64, 798.
13. Johnson, T. B.; Sprague, J. M. J. Am. Chem. Soc. 1936,
58, 1348.
15. Mathieu, M.-C. et al. and Clark, P. et al. (in preparation).
16. Slipetz, D.; Buchanan, S.; Mackereth, C.; Brewer, N.;
Pellow, V.; Hao, C.-M.; Adam, M.; Abramovitz, M.;
Metters, K. M. Biochem. Pharmacol. 2001, 62, 997.
17. Chan, C.-C.; Boyce, S.; Brideau, C.; Charleson, S.;
Cromlish, W.; Ethier, D.; Evans, J.; Ford-Hutchinson,
A. W.; Forrest, M. J.; Gauthier, J. Y.; Gordon, R.;
Gresser, M.; Guay, J.; Kargman, S.; Kennedy, B.;
´
Leblanc, Y.; Leger, S.; Mancini, J.; O’Neill, G. P.; Ouellet,
M.; Patrick, D.; Percival, M. D.; Perrier, H.; Prasit, P.;
Rodger, I.; Tagari, P.; Therien, M.; Vickers, P.; Visco, D.;
Wang, Z.; Webb, J.; Wong, E.; Xu, L.-J.; Young, R. N.;
Zamboni, R.; Riendeau, D. J. Pharmacol. Exp. Ther.
1999, 290, 551.
14. More detailed experimental procedures can be found in:
Belley, M.; Burch, J.; Colucci, J.; Farand, J.; Girard, M.;
Han, Y. WO Patent 2006122403; Chem. Abstr. 2006, 145,
505342.