Naphthalene/quinoline amides and sulfonylureas as potent and selective antagonists of the EP4 receptor

Article abstract of DOI:10.1016/j.bmcl.2010.12.014

Two new series of EP₄ antagonists based on naphthalene/quinoline scaffolds have been identified as part of our on-going efforts to develop treatments for inflammatory pain. One series contains an acidic sulfonylurea pharmacophore, whereas the other is a neutral amide. Both series show subnanomolar intrinsic binding potency towards the EP₄ receptor, and excellent selectivity towards other prostanoid receptors. While the amide series generally displays poor pharmacokinetic parameters, the sulfonylureas exhibit greatly improved profile. MF-592, the optimal compound from the sulfonylurea series, has a desirable overall preclinical profile that suggests it is suitable for further development.

Full text of DOI:10.1016/j.bmcl.2010.12.014

Bioorganic & Medicinal Chemistry Letters 21 (2011) 1041–1046
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Naphthalene/quinoline amides and sulfonylureas as potent and selective
antagonists of the EP4 receptor
Jason D. Burch a, Julie Farand a, John Colucci a, Claudio Sturino a, Yves Ducharme a, Richard W. Friesen a,
Jean-François Lévesque b, Sébastien Gagné b, Mark Wrona b, Alex G. Therien c, Marie-Claude Mathieu c,
Danielle Denis c, Erika Vigneault c, Daigen Xu d, Patsy Clark d, Steve Rowland d, Yongxin Han a,
⇑
a Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, Merck Frosst Canada Ltd, 16711 Trans-Canada Hwy. Kirkland, Québec, Canada H9H 3L1
b Department of DMPK, Merck Frosst Centre for Therapeutic Research, Merck Frosst Canada Ltd, 16711 Trans-Canada Hwy. Kirkland, Québec, Canada H9H 3L1
c Department of In vitro Sciences, Merck Frosst Centre for Therapeutic Research, Merck Frosst Canada Ltd, 16711 Trans-Canada Hwy. Kirkland, Québec, Canada H9H 3L1
d Department of In vivo Sciences, Merck Frosst Centre for Therapeutic Research, Merck Frosst Canada Ltd, 16711 Trans-Canada Hwy. Kirkland, Québec, Canada H9H 3L1
a r t i c l e i n f o
a b s t r a c t
Article history:
Two new series of EP4 antagonists based on naphthalene/quinoline scaffolds have been identified as part
of our on-going efforts to develop treatments for inflammatory pain. One series contains an acidic sulfo-
nylurea pharmacophore, whereas the other is a neutral amide. Both series show subnanomolar intrinsic
binding potency towards the EP4 receptor, and excellent selectivity towards other prostanoid receptors.
While the amide series generally displays poor pharmacokinetic parameters, the sulfonylureas exhibit
greatly improved profile. MF-592, the optimal compound from the sulfonylurea series, has a desirable
overall preclinical profile that suggests it is suitable for further development.
Received 4 November 2010
Revised 30 November 2010
Accepted 2 December 2010
Available online 8 December 2010
Keywords:
Naphthalene/quinoline amides and
sulfonylureas
Ó 2010 Elsevier Ltd. All rights reserved.
EP4 receptor antagonist
Inflammatory pain
Prostanoids (prostaglandins and thromboxanes) are important
lipid hormones formed from arachidonic acid metabolism. Prosta-
glandin E2 (PGE2), in particular, is the principal proinflammatory
prostanoid and is implicated in the pathogenesis of a number of
diseases such as pain, fever, arthritis and cancer. Inhibition of
PGE2 biosynthesis by NSAIDs and COX-2 inhibitors (Coxibs) consti-
tutes an effective therapy to relieve inflammatory symptoms, lead-
ing to the widespread uses of these drugs as analgesics.1
Unfortunately, their therapeutic utility is limited by their potential
to cause either gastro-intestinal toxicity (by NSAIDs)2 or cardiovas-
cular (CV) side effects (by both NSAIDs and Coxibs).3 Therefore,
there is a vast unmet medical need to discover alternatives for
treating chronic inflammatory conditions such as osteoarthritis
(OA) and rheumatoid arthritis (RA).
to inflammatory pain hypersensitivity in rats, providing further
evidence that EP4 antagonism is a valid strategy for treating
inflammatory pain.5 Using highly selective EP1, EP3 and EP4 antag-
onists, we and others demonstrated pharmacologically that EP4,
not EP1 or EP3, was the primary receptor involved in joint inflam-
mation and pain in rodent models of rheumatoid and osteoarthri-
tis,6,7 further supporting EP4 antagonism as a valid strategy for
treating inflammatory pain. Furthermore, EP4 was also shown to
mediate TH1 cell differentiation and TH17 cell expansion, and a
selective EP4 antagonist was effective in mouse models of immune
inflammatory conditions such as multiple sclerosis (MS) and skin
allergy.8
The CV adverse events associated with NSAIDs and Coxibs are
not clearly understood although it is speculated that the prothrom-
botic and hypertensive effects are caused by inhibition of prostacy-
clin biosynthesis.9 It is plausible that a selective EP4 antagonist
may ameliorate symptoms of chronic inflammation without the
potential CV side effects observed with NSAIDs and COX-2 inhibi-
tors since they should not interfere with the biosynthesis of any of
the prostanoids including prostacyclin and thromboxanes. In addi-
tion to its role in inflammation, the EP4 receptor has also been
implicated in migraine headaches,10 in destabilizing atheroscle-
rotic plaques in human,11 and in angiogenesis and tumor metasta-
sis.12 Therefore, EP4 antagonists represent potential promising new
therapeutic agents for treating pain, atherosclerosis and cancer.
PGE2 exerts its biological effects through four subtype EP recep-
tors, EP1–4. In a mouse model of collagen–antibody induced arthri-
À/À
tis (CAIA), McCoy et al. demonstrated that the EP4
mice are
resistant to both the incidences and symptom scoresÀo/Àf arthritis
compared to the wild type controls. Conversely, EP1–3 mice re-
sponded as wild type controls, suggesting that the effect of PGE2
in chronic inflammation was mediated predominantly by the EP4
receptor.4 Lin et al. demonstrated that EP4, not EP1–3, contributed
⇑
Corresponding author.
E-mail address: yongxin_han@merck.com (Y. Han).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.12.014

1042
J. D. Burch et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1041–1046
Table 1
We have previously disclosed our progress in this area which
Scaffold SAR for the amide series of EP4 antagonists
led to the discovery of the quinoline acylsulfonamide series of
EP4 antagonists, typified by MF-310 ( Fig. 1).13 This compound
was a highly potent antagonist of the EP4 receptor (Ki = 0.74 nM)
and was only moderately protein-shifted (ꢀfive-fold in the pres-
ence of 10% human serum). A major drawback of this acylsulfona-
mide was its species dependent, CYP 3A mediated acylsufonamide
hydrolysis, leading to variable drug levels of the parent and high
levels of the corresponding sulfonamide M1 as a circulating metab-
olite. We reported previously one of our successful strategies to
alleviate this problem by replacing the acylsulfonamide pharmaco-
phore with a carboxylic acid bioisostere.14,15 We report herein an-
other successful strategy to alleviate these problems by modifying
the acylsulfonamide moiety with an alternative acidic (sulfonyl-
urea) or non-acidic (amide) moiety and the discovery of a sulfonyl-
urea analog MF-592 ( Fig. 1), a highly potent and selective EP4
antagonist with vastly improved metabolic stability.
OR1
O
O
N
O
α
R2
NH
X
R3
OR1
Entry
X
R1
R2
R3
Compd
EP4 Kia (nM)
0% HS 10% HS
0.32
0.71
4.4
0.87
0.67
0.20
1
2
3
4
5
6
CH
CH
CH
N
N
CH
CH2CH3
CHF2
CH2CF3
CH2CH3
CH2CH3
CH2CH3
H
H
H
H
H
H
H
H
1a
1b
1c
1d
1e
1f
2.7
8.4
104
2.6
1.3
H
Me
–CH2CH2–
0.68
a
Values are means from at least three experiments; HS = human serum; For
details of the EP4 binding assay see Refs. 6 and 16.
We initially focused on replacement with the amide pharmaco-
phore. We have previously shown that ortho-methoxy phenyl ace-
tate was a privileged substitution for the eastern portion of the
acylsulfonamide class of EP4 antagonists,13 thus this moiety was
selected as a starting point for optimization (Table 1). For the initial
lead, diethoxy naphthalene substitution was selected for the scaf-
of the western aromatic framework was optimal, as difluorome-
thoxy (1b, Table 1) and trifluoroethoxy (1c, Table 1) replacements
led to a reduction in potency and an increase in protein shift. Fur-
ther, analogs with the quinoline template (1d, Table 1) were equi-
potent to the one containing a naphthalene (1a, Table 1), which
was also observed for the acylsulfonamide series. Taken together,
these observations indicated preferred structural features were
common to the amides and acylsulfonamides, suggesting that the
fold, and the amide was unsubstituted at the a-position (1a, Table
1). Gratifyingly, it was found that this amide retained the excellent
binding affinity and acceptable protein shift profile, indicating the
acidic nature of the acylsulfonamide was not crucial for EP4 affin-
ity. As was shown for the acylsulfonamides, diethoxy substitution
F3C
O
O
O
F3C
O
O
O
O
N
O
CYP
N
S
O
NH
O
N
F3C
S
O
NH2
N
F3C
O
O
MF-310
M1
OR1
OR1
O
O
N
O
O
Cl
O
NH
S
O
N
Y
NH
NH Ar
X
R2
O
R3
O
Cl
1: X = CH or N, Y = CH2
2: X = CH or N, Y = NHSO2
MF-592
Figure 1. Metabolic liability of MF-310 and structural-activity optimization to MF-592.
O
O
O
O
O
O
O
N
[O]
N
O
N
O
NH
N
N
O
O
1d
hydrolysis
O
O
O
[O]
N
N
OH
H
N
N
O
O
O
O
3
Figure 2. Proposed metabolic pathway for formation of acid 3 from dosing compound 1d in rat.

J. D. Burch et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1041–1046
1043
Table 2
from a-hydroxylation of the CH2NH moiety and subsequent hydro-
lysis (to form the corresponding aldehyde) and further oxidation to
Phenacetyl SAR for the amide series of EP4 antagonists
acid 3 (Fig. 2).
O
O
With an optimal scaffold selected, further optimization of the
phenacetyl moiety was investigated (Table 2). We were interested
in modulation of the polarity of this region, and it was found that
basic (1g, Table 2) and acidic (1h, Table 2) substitution were toler-
ated in terms of inherent binding potency, although the extent of
protein shift was significantly increased when an acidic residue
was present. Similar to the acylsulfonamide series, it was also
found that chlorine was an adequate replacement for the methoxy
substituent (1i and 1j, Table 2). These compounds were also shown
to exhibit excellent selectivity against other prostanoid (PG) recep-
tors. For example, 1f was found to be >2000-fold selective for EP4
versus other receptors, namely EP1–4, DP1, DP2, FP, IP and TP.
While the amide series of EP4 antagonists generally showed
excellent affinity and selectivity profile, these compounds suffered
from poor pharmacokinetics in rat, with short elimination half-
lives (t1/2 <1 h) and high clearance rates. Further in vitro and
in vivo metabolism studies indicated that extensive and complex
oxidative metabolism were the likely culprit for the observed short
t1/2. As a result, we shifted our attention to the corresponding sul-
fonylurea analogs. Once again, the general SAR in this series
tracked with that observed for the acylsulfonamide and the amide
series so only a few representatives are shown in Table 3.
As shown, compounds incorporating the bis-trifluroethoxy-
quinoline template seen in MF-310 (2c and 2k, Table 3) generally
gave compounds with significantly higher serum protein shift.
para-Substitution on the phenylsulfonamide moiety (2a, 2l and
2m, Table 3) also generally gave compounds with more significant
protein shift. Other arylsulfonamides such as naphthalenesulfona-
mide (2g and 2k, Table 3) were tolerated but had no advantage.
ortho-Substitution on the phenylsulfonamide moiety was generally
preferred (2b–2e, 2h and 2j, Table 3) and 2,6-bis-substitution (2f,
2i and 2o, Table 3) was optimal for potency in the human whole
blood (HWB) assay.15 The 2,6-di-Cl analog 2f (MF-592), in particu-
lar, exhibited good EP4 affinity (Ki = 0.3 nM, shifted to 3.1 nM in
O
N
NH
Ar
O
b
Entry Ar
Compd
EP4 Kia (nM)
EP4 IC50 (nM)
0% HS 10% HS 0% HS 10% HS
1
1f
0.20
0.16
0.68
1.44
4.6
4.9
16.0
23.6
MeO
N
2
1g
MeO
COOH
3
4
5
1h
1i
0.18
0.32
0.34
6.2
3.8
6.0
2.1
60.6
35.1
10.2
MeO
Cl
1.3
1j
0.53
Cl
Cl
a
Values are means from at least three experiments.
Values are means from two to four experiments; HS = human serum; for details
of the EP4 binding and functional assays, see Refs. 6 and 16.
b
two series likely had a conserved binding mode. Substitution of the
-position of the amide was also tolerated (1e and 1f, Table 1). The
a
cyclopropyl substitution (1f), in particular, resulted in a significant
reduction in protein shift. In addition, this substitution improved
the metabolic stability of these molecules by preventing formation
of the corresponding carboxylic acid 3 (observed as one of the
major circulating metabolites after oral dosing of compound 1d
in rat), presumably by shutting down the formation of the imine
Table 3
SAR of sulfonylurea series of EP4 antagonist
OR1
O
O
N
NH
NH
S Ar
X
O
OR1
O
b
c
Entry
Ar
R1
X
Compd
EP4 Kia (nM)
0% HS 10% HS
EP4 IC50 (nM)
0% HS 10% HS
HWB IC50 (nM)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
p-MePh
o-ClPh
o-ClPh
o-MePh
Et
Et
CH2CF3
Et
Et
Et
Et
Et
Et
Et
CH2CF3
Et
Et
Et
CH
CH
N
2a
2b
2c
2d
0.11
0.16
0.48
0.23
0.17
0.30
0.52
0.39
0.34
0.49
1.2
10
2.3
14
1.5
2.4
3.0
3.3
3.8
3.0
2.5
3.3
3.3
2.2
8.9
8.3
4.6
2.0
3.2
17
33
48
14
23
14
37
28
21
22
103
370
80
613
423
NDd
ND
162
78
ND
ND
102
ND
ND
ND
ND
ND
77
CH
CH
CH
CH
CH
CH
CH
N
CH
CH
CH
CH
3.0
3.0
3.1
6.3
8.9
1.6
7.5
21
57
21
64
1.6
o-MeOPh
2,6-Di-ClPh
2-Naphthyl
o-CF3Ph
2,6-Di(MeO)Ph
o-BrPh
2-Naphthyl
p-CF3OPh
p-FPh
2,3-Di-ClPh
2,6-Di-MePh
2e
2f (MF-592)
2g
2h
2i
2j
2k
2l
2m
2n
2o
0.66
0.48
0.40
0.40
28
19
Et
a
b
c
Values are means from at least three experiments.
Values are means from one to eight experiments; HS = human serum; for details of the EP4 binding and functional assays, see Refs. 6 and 16.
Average of 2–4 experiments, for details of the human whole blood assay, see Ref. 15.
ND = not done.
d

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J. D. Burch et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1041–1046
Table 4
To ascertain that MF-592 did not have the same liability as
Pharmacokinetic parameters of MF-592
observed with MF-310, its metabolic profile was evaluated exten-
sively in vitro and in vivo. When the 14C-labeled MF-592 (Fig. 3,
prepared according to Scheme 1 using commercially available
14C-labeled ethyl chloroformate) was incubated in NADPH fortified
rat and human liver microsomes at 37 °C for 1 h, 97% and 90% of
the parent was recovered, respectively. Acceptable levels of cova-
lent protein labeling (31 and 23 pmol-equiv/mg-protein@1 h in
rat and human liver microsomes, respectively) were observed in
the same experiments. Similarly, when incubated in cryopreserved
or freshly isolated rat and human hepatocytes for 2 h at 37 °C, 91%
and 96% of the parent was recovered, respectively. Several very
minor oxidative metabolites were also detected. The potential for
covalent protein binding in vivo was evaluated in SD rats after oral
Species
SD rat
Beagle dog
Dosea (iv/po, mg/kg)
CL (mL/kg/min)
t1/2 (h)
F (%)
po AUC0–24
5/20
11
6.6
84
37.4
1/4
1.2
4.3
100
101.1
(lMÁh)
a
Both iv and po doses were administered as aqueous solutions of the sodium salt
in 60% PEG-200.
14C-label
O
O
O
O
Cl
NH
S
dosing (20 mg/kg, 150 lCi/kg in 60% PEG-200). Very low levels of
N
residual radioactivity (<10 pmol-equiv/mg-protein) was observed
at 24 h in both the plasma and the liver, reflecting the observed ro-
bust metabolic stability and minimal potential for bioactivation
observed in vitro. Furthermore, no sulfonylurea hydrolysis was de-
tected from all these experiments. This is in direct contrast to the
acylsulfonamide series which is plagued with species dependent,
CYP mediated acylsulfonamide hydrolysis.
The in vivo potency and efficacy of MF-592 was evaluated in
the chronic rat adjuvant-induced-arthritis (AIA) model. The ED50
was established at 0.1 mg/kg/day, which was significantly more
potent than has been reported for potent COX-2 inhibitors (0.5–
0.7 mg/kg/day).15
NH
O
O
Cl
Figure 3. Structure of 14C-labeled MF-592.
presence of 10% HS) and functional potency (IC50 = 3 nM, shifted to
14 nM in presence of 10% HS), and good potency in the whole
blood assay with an IC50 of 78 nM. It also showed excellent selec-
tivity (>1300-fold) against other PG receptors. This compound
was profiled further and the results are discussed in the following
sections.
The synthesis of these compounds can be accomplished
according to Scheme 1 and Scheme 2. Starting with anhydride
4,13 condensation with methyl 4-amino-3-methylbenzoate (5) in
refluxing acetic acid gave imide 6 in high yield. Deoxygenation
was accomplished in two-steps, reduction with NaBH4 to give
the hemiaminal which was subsequently reduced to lactam 7 with
triethylsilane in the presence of trifluoacetic acid. The methyl ester
First, the pharmacokinetic profile of MF-592 was evaluated in
SD rats and Beagle dogs, and the results are summarized in
Table 4. As shown, this compound exhibited excellent oral
bioavailability in both rats (F = 84%) and dogs (100%), along with
moderate to low clearance rates (1.2–11 mL/kg/min) and good
elimination t1/2 (4.6–6.6 h). All these contributed to the observed
high oral exposures, especially in dogs.
OR1
O
OR1
O
H2N
a
O
+
N
CO2Me
CO2Me
X
X
X
O
O
OR1
b,c
OR1
5
6
4
OR1
OR1
OR1
O
O
d,e
N
N
CO2Me
OH
X
8
OR1
7
f,g
OR1
O
N
OR1
O
CN
X
O
OR1
9
Y
N
h (R2,R3 = CH2CH2)
i (R2,R3 = H)
Ar
NH
X
R2
R3
OR1
OR1
1: Y = CH2
2: Y = NHSO2
O
j (Y = CH2)
k (Y = NHSO2)
N
NH2
X
R2
R3
OR1
10
Scheme 1. Reagents and conditions: (a) reflux AcOH; (b) NaBH4, THF/MeOH; (c) Et3SiH, TFA/CH2Cl2; (d) LiOH, THF/MeOH/H2O; (e) BH3–DMS, THF; (f) MsCl, triethylamine,
CH2Cl2; (g) NaCN, DMF; (h) EtMgBr, Ti(OiPr)4, THF then BF3–OEt2; (i) BH3–DMS, THF then MeOH and HCl; (j) ArCH2CO2H, EDC, DMAP, CH2Cl2; (k) ArSO2NHC(O)OEt, Hünig’s
base, THF.

J. D. Burch et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1041–1046
1045
OR1
OR1
OR1
O
O
H2N
a,b,c
O
+
N
Br
Br
X
X
O
OR1
d
O
12
11
4
OR1
OR1
OR1
O
O
e,f
N
N
O
X
X
OR1
O
14
13
g,h,i
OR1
OR1
O
j
N
N
NH2
N3
X
X
OR1
OR1
15
16
Scheme 2. Reagents and conditions: (a) reflux AcOH; (b) NaBH4, THF/MeOH; (c) Et3SiH, TFA/CH2Cl2; (d) 2-tri-n-butylstannylpropene, Pd(PPh3)4, tol.; (e) OsO4, NMO, acetone/
water; (f) NaIO4, acetone; (g) NaBH4, ethanol; (h) MsCl, triethylamine, CH2Cl2; (i) NaN3, DMF; (j) H2, Pd/C, ethanol.
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. Engl. J. Med. 2005, 352,
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Horgan, K.; Lines, C.; Ridell, R.; Morton, D.; Lanas, A.; Konstam, M. A.; Baron, J.
A. N. Engl. J. Med. 2005, 352, 1092.
was hydrolyzed to the acid which was reduced to alcohol 8 using
BH3–DMS. Conversion of the alcohol to the mesylate followed by
treating with NaCN gave benzylic nitrile 9. Nitrile 9 could be
reduced directly with BH3–DMS to amine 10 (R2 = R3 = H). Alterna-
tively,
9
could be converted to the cyclopropylamine (R2,
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R3 = CH2CH2) according to the Szymoniak variation17 of the Kulin-
kovich reaction. Standard amide coupling of amine 10 and an
appropriate acid furnished the amide derivatives 1. Alternatively,
amine 10 was reacted with an appropriate ethyl (arylsulfonyl)car-
bamate (commercially available or easily prepared from arylsulf-
onamide and ethyl chloroformate in the presence of a suitable
base18) to give the corresponding sulfonylurea analogs 2.
Compounds bearing an
a-Me substitution (e.g., 1e) were pre-
pared according to Scheme 2. Condensation of anhydride 4 with
4-bromo-2-methylaniline (11) followed by a similar deoxygen-
ation sequence gave lactam 12. Stille coupling of the bromide with
2-tri-n-butylstannylpropene using Pd(PPh3)4 as the catalyst gave
alkene 13 which was converted to ketone 14 in two-steps: dihydr-
oxylation with OsO4 to give the diol; and oxidative diol cleavage
with NaIO4. Ketone 14 was then transformed to azide 15 in
three-steps: reduction with NaBH4, formation of mesylate and
SN2 reaction of the mesylate with sodium azide. Reduction of azide
15 under the standard hydrogenation conditions gave amine 16
which was converted to the amide or sulfonylurea analogs under
the aforementioned conditions.
In conclusion, we have described the identification and SAR
optimization of two new series of EP4 antagonists, the amides
and sulfonylureas. While the neutral amide analogs suffered from
poor pharmacokinetics due to extensive oxidative metabolism,
the sulfonylureas exhibited a greatly improved metabolic stability
and pharmacokinetic profile. MF-592, the optimal compound from
these efforts, exhibited the desired potency, selectivity, metabolic
stability and pharmacokinetic profiles that suggest that it is suit-
able for further development.
References and notes
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