Structure-activity relationship studies on ortho-substituted cinnamic acids, a new class of selective EP3 antagonists

Article abstract of DOI:10.1016/j.bmcl.2004.11.051

A series of novel ortho-substituted cinnamic acids have been synthesized, and their binding activity and selectivity on the four prostaglandin E ₂ receptors evaluated. Many of them are very potent and selective EP₃ antagonists (K_i 3-10 nM), while compound 9 is a very good and selective EP₂ agonist (K_i 8 nM). The biological profile of the EP₂ agonist 9 in vivo and the metabolic profile of selected EP₃ antagonists are also reported.

Full text of DOI:10.1016/j.bmcl.2004.11.051

Bioorganic & Medicinal Chemistry Letters 15 (2005) 527–530
Structure–activity relationship studies on ortho-substituted
cinnamic acids, a new class of selective EP3 antagonists
Michel Belley,* Michel Gallant, Bruno Roy, Karine Houde, Nicolas Lachance,
Marc Labelle, Laird A. Trimble, Nathalie Chauret, Chun Li, Nicole Sawyer,
`
Nathalie Tremblay, Sonia Lamontagne, Marie-Claude Carriere, Danielle Denis,
Gillian M. Greig, Deborah Slipetz, Kathleen M. Metters, Robert Gordon,
Chi Chung Chan and Robert J. Zamboni
´
Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval, Quebec, Canada H9R 4P8
Received 3 November 2004; revised 16 November 2004; accepted 19 November 2004
Available online 15 December 2004
Abstract—A series of novel ortho-substituted cinnamic acids have been synthesized, and their binding activity and selectivity on the
four prostaglandin E2 receptors evaluated. Many of them are very potent and selective EP3 antagonists (Ki 3–10 nM), while com-
pound 9 is a very good and selective EP2 agonist (Ki 8 nM). The biological profile of the EP2 agonist 9 in vivo and the metabolic
profile of selected EP3 antagonists are also reported.
Ó 2004 Elsevier Ltd. All rights reserved.
Prostaglandins (PGs) are generated from arachidonic
acid in response to extracellular stimuli and are pre-
sumed to play an important role in a variety of physio-
logical and pathophysiological processes in the body.
The eight known human prostanoid receptors have been
cloned, their sequences determined and the affinities and
selectivities of many agonists and antagonists to these
receptors have been measured.1
nists would be required. Herein, we wish to disclose the
discovery of potent and selective EP3 antagonists.
We have previously observed that minor modification of
substituents or variation of the substitution pattern
around the aromatic cores of ligands for the PG recep-
tors can dramatically alter their EP selectivity profile.4
Using this strategy, we hoped to obtain selective EP3
antagonists by modifying the structure of known EP1
antagonists of general structure 1, where X and Y are
linkers containing 2–3 and 0–2 atoms, respectively
(Fig. 1).5 A small number of compounds were synthe-
sized and we rapidly found that a mixture of the two iso-
mers 2a and 3a (Fig. 1 and Table 1) provided very good
Prostaglandin E2 (PGE2) binds preferentially to the four
receptors EP1, EP2, EP3, and EP4. Studies on EP3
knockout mice and experiments with EP3 agonists sug-
gest that activation of the EP3 receptor might play a
key role in fever generation, hyperalgesia (exaggerated
response to a normally painful stimulus), uterine con-
traction, gastric acid secretion, smooth muscle contrac-
tion of the GI tract, neurotransmitter release, and
sodium/water reabsorption in kidney tubules.2 Prior to
our work, no EP3 antagonists had been identified.3 In
order to fully characterize the biological role of this
receptor, pharmacologically active and selective antago-
O
Ar2
Y
Ar1
CO2H
V
OBn
W
X
2a W = CH2CH=CH
3a W = CH=CHCH2
EP1 antagonists 1
examples: V = NHPr, X = CH2S, Y = OCH2
5a
5b
V = OH, X = (CH2)3, Y = OCH2
V = OH, X = CH=CH, Y = bond5c
Keywords: PGE2; EP3 receptor antagonist.
*
Corresponding author. Tel.: +1 514 428 3075; fax: +1 514 428
4900; e-mail: belley@merck.com
Figure 1.
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.11.051

528
M. Belley et al. / Bioorg. Med. Chem. Lett. 15 (2005) 527–530
Table 1. Affinities (Ki lM)a of a series of cinnamic acids and their analogs for the different human prostanoid E2 receptor subtypes and their
stimulation/inhibition of c-AMP production (Kb lM) in HEK (EBNA) cells
Ar1
Ar2
W
X
OH
R'
R
O
Compd
R
R0
W
Ar1 Substitution
X
EP1
19
EP2
EP3-III EP4 c-AMP assay
b
2a/3a
2a
3a
2-BnO
2-BnO
2-BnO
2-BnO
2-BnO
H
3-Me
3-Me
3-Me
3-MeO
H
CH@CHCH2
CH2CH@CH
CH@CHCH2
CH@CHCH2
CH@CHCH2
CH@CHCH2
CH@CHCH2
CH@CHCH2
CH@CHCH2
CH@CHCH2
CH@CHCH2
CH@CHCH2
CH@CHCH2
CH@CHCH2
CH@CHCH2
CH@CHCH2
CH@CHCH2
CH@CHCH2
(CH2)3
ortho
ortho
ortho
ortho
ortho
ortho
ortho
ortho
ortho
ortho
meta
para
CH@CH
CH@CH
CH@CH
CH@CH
CH@CH
0.86
0.55
8.1
0.009
0.013
0.007
0.011
0.025
0.10
2.0
1.2
1.9
1.8
1.0
4.4
6.2
0.032
0.023
0.017
0.020
0.050
>15
12
b
b
b
b
b
b
2b/3b
2c/3c
2d/3d
2e/3e
2f/3f12
2g/3g
3h
16
24
5.3
0.68
1.4
H
CH@CH >100
CH@CH >100
4-MeO
3-BnO
4-BnO
2-HO
2-BnO
2-BnO
H
2.5
0.018 0.050
0.068
H
CH@CH
CH@CH
CH@CH
CH@CH
CH@CH
––
14
>20
68
0.45 0.062
0.61 0.006
3-MeO
3-Me
3-Me
3-Me
3-Me
3-Me
5-Ac
H
0.75
7.3
0.008
0.010
2.0
1.6
3.1
5.5
5.7
4.3
0.83
0.59
2.4
0.028
b
b
b
b
b
b
2i/3i
2j/3j
21
0.63
1.7
>30
16
2.9
2.7
2k/3k14 2-BnO
ortho
ortho
ortho
ortho
ortho
ortho
ortho
ortho
ortho
ortho
ortho
ortho
7.1
2.9
2l/3l
2m/3m
2n/3n13 3-PhO
2-BnO
2-BnO
CH2
21
3.4
0.26
CH@CH
CH@CH
CH@CH
CH@CH
CH@CH
CH@CH
(CH2)2
2.8 8.7
>18
17
0.11
4.1
0.060
0.007
0.003
0.013
0.019
0.065
0.041
3o
3p
2-(4-FBn)O 3-Me
2-(2,6-Cl2Bn)O 3-Me
0.004
6.7 5.4
0.62 0.006
0.038
0.029
6a
6b
2-BnO
2-BnO
2-BnO
2-BnO
2-BnO
3-Me
3-MeO
3-Me
3-Me
H
>10
>9
23
0.38
1.1
2.9
4.3
(CH2)3
(CH2)3
6c
0.94
0.99
0.44
1.7
c
7, 8
9
(1,2-c-Pr)CH2
CH@CH
CH@CH
CH@CH
CH@CH
CH@CH
CH@CH
>9
45
0.059
0.003d
0.008 1.4
2.8
0.74
e
10/11
12
13
2-(2,6-Cl2Bn)O 3-(HOCH2) CH@CHCH2
2-(2,6-Cl2Bn)O 3-Me
2-(2,6-Cl2Bn)O 3-Me
7.1 2.5
3.0 2.1
13 3.9
0.013
0.010
0.009
CH@CHCHOH ortho
CHOHCH@CH ortho
0.93 0.030
1.0 0.030
a Ki determinations are averages based on at least two experiments.
b Mixture of regioisomers where W is also CH2CH@CH.
c Mixture of regioisomers where W is also CH2-(1,2-c-Pr); c-Pr is a cyclopropyl group.
d Stimulation of c-AMP production.
e Mixture of regioisomers where W is CH@CHCH2 for 10 and CH2CH@CH for 11.
and selective antagonism (9 nM) on the EP3 receptor
subtype. With this lead in hand, additional analogs were
prepared and their in vitro activity assessed.
ylacetic, phenylpropanoic, or cinnamic acid 5 gave a
mixture of allylic isomers 2 and 3, which could easily
be purified by a simple trituration in ether/hexane
(Scheme 1). We were able to separate the two regioiso-
mers 2a and 3a using HPLC techniques only to find that
their difference of activity on the EP3 receptor was only
2-fold (vide infra). We thus decided to test the remaining
analogs as mixtures in order to obtain a rapid estimate
of the structure–activity relationship (SAR).8 Later, it
Most of the compounds in this study were synthesized6
starting from the allylbenzenes 4, which can be prepared
in >80% yield by benzylation of the known phenols with
NaH and benzyl bromide in DMF at room temperature.
A Heck reaction7 between 4 and a bromobenzoic, phen-
a
X
X
+
OH
OH
R'
R'
R'
X
OH
R
R
R'
O
R
O
Br
5
O
4a R = 2-BnO, R' = 3-Me
4b R = 2-BnO, R' = 3-MeO
4c R = 2-BnO, R' = H
4d R = R' = H
2a-n
3a-n
X = 0-2 carbon linker
CO2H
4e R = 4-MeO, R' = H
4f R = 3-BnO, R' = H12
4g R = 4-BnO, R' = 3-MeO
4h R = 2-HO, R' = 3-Me
CHO
OBn
OBn
R'
b, c
d, e
4a-b
4i R = 2-(2,6-Cl2Bn)O, R' = 3-Me
4j R = 2-BnO, R' = 5-Ac
4k R = 3-PhO, R' = H13
6a-b
Scheme 1. Reagents and conditions: (a) Pd(OAc)2, LiCl, LiOAc, Bu4NCl, DMF, 100 °C, 16 h,7 50–85% yield; (b) 9-BBN; (c) PdCl2 (dppf), 2-
bromobenzaldehyde, K3PO4, DMF, 50 °C, 9–16 h,9 50–72% yield; (d) Ph3P@CHCO2Me, toluene, 80 °C, 10 h, 82–91% yield; (e) NaOH, MeOH/
THF/H2O, 60–98% yield.

M. Belley et al. / Bioorg. Med. Chem. Lett. 15 (2005) 527–530
529
CO2H
CO2H
CH@CHCO2H substituent to the meta or para position
(mixtures 2i/3i and 2j/3j), as well as diminishing its chain
length to give benzoic or phenylacetic acids (mixtures
2k/3k and 2l/3l), reduced the Ki on the EP3 receptor
by at least 200-fold. Reduction of the cinnamic acid to
the phenylpropanoic acid also decreased the activity 5-
fold (6c vs 6a).
R
a-c
OH
O
3h
3a R = Bn
3o R = 4-FBn
3p R = 2,6-Cl2Bn
Scheme 2. Reagents and conditions: (a) NaH, MeI, DMF, rt, 2 h, 94%
yield; (b) NaH, BnBr, DMF, 0 °C, then rt, 1 h, >75% yield; (c) NaOH,
MeOH/THF/water, >75% yield.
The length and the nature of the linker W between the
benzene rings Ar1 and Ar2 are also very important.
Reducing it by one carbon unit dramatically changed
the selectivity pattern to give the very potent and selec-
tive EP2 agonist 9. The two isomers 2a and 3a were also
separated by HPLC and the isomer 3a was found to be
twofold more active on the EP3 receptor and more selec-
tive against the EP2 receptor than 2a. Finally, reduction
or cyclopropanation of the double bond afforded deriv-
atives that were twofold or fivefold less potent on the
EP3 receptor, respectively. These compounds were also
less selective toward EP2 (6a vs 3a and 7/8 vs 2a/3a).
was found that the major isomer 3h could be obtained in
48% yield after purification by crystallization. Benzyl-
ation of its phenol group afforded the more active
isomer 3 (Scheme 2).
Compounds 6a and 6b were prepared using a slightly
different approach. Addition of 9-BBN to the allylben-
zene 4 gave a B-alkyl-9-BBN derivative, which could
not be cross-coupled9 with 2-bromocinnamic acid in
good yield. It was thus reacted with o-bromobenzalde-
hyde to produce an intermediate aldehyde, which was
then subjected to a Wittig–Horner reaction followed
by hydrolysis of the ester (Scheme 1). Compound 6c
was prepared via the catalytic hydrogenation of the mix-
ture of compounds 2a and 3a over (Ph3P)3RhCl in
MeOH–EtOAc 1:1. The mixture of compounds 7 and
8, which contains a cyclopropane unit replacing the dou-
ble bond in analogs 2a and 3a, was prepared in six steps
with an overall yield of 71% as follows: (1) Heck reac-
tion between the allylbenzene 4a and ethyl 2-bro-
mobenzoate (as in Scheme 1, reaction (a)), (2)
cyclopropanation of the double bond by sequential
treatments with diazomethane and Pd(OAc)2,10 (3)
reduction of the ester to the alcohol with DIBAL-H
(THF, ꢀ72 °C, then ꢀ40 °C for 5 min), (4) oxidation
of the alcohol with MnO2 (EtOAc, rt, 6 h), and (5) Wit-
tig–Horner reaction on the aldehyde followed by hydro-
lysis of the ester (as in Scheme 1, reactions (d and e)).
The substitution pattern around the second benzene ring
Ar2 does not have a pronounced effect on the selectivity
or the activity of the compounds. For example, while re-
moval of the benzyl ether gave a less active mixture
(compounds 2d/3d vs 2c/3c, 4-fold decrease), changing
its position around the ring did not significantly alter
the activity on the EP3 receptor (compounds 2g/3g vs
2b/3b and 2f/3f vs 2c/3c), even though 2f/3f binds to
the EP2 receptor. Replacement of the benzyloxy by a
methoxy or phenoxy group gave slightly less potent
compounds (2e/3e and 2n/3n vs 2f/3f), while the smaller
hydroxy substituent was found to be equipotent (com-
pounds 2h/3h vs 2a/3a). Addition of a methyl or a meth-
oxy group in position 3 provided a slight increase in
activity (compounds 2a/3a and 2b/3b vs 2c/3c), while
addition of an electron withdrawing group such as an
acetyl in position 5 (compounds 2m/3m vs 2c/3c) affor-
ded a mixture of isomers with 10-fold loss in potency.
Finally, halogen substituents on the benzyl ether are well
tolerated (compound 3o vs 3a), with the 2,6-dichloro
substitution giving the best EP3 analog in the series
(compound 3p).
The EP2 selective agonist 9 was prepared via a Heck
coupling between 1-(benzyloxy)-2-vinylbenzene11 and
2-bromocinnamic acid in 67% yield (as in Scheme 1,
reaction (a)). The mixture containing the metabolite 10
(W is CH@CHCH2) and its isomer 11 was prepared in
42% overall yield in four steps as follows: (1) Claisen
rearrangement of 2-allyloxybenzaldehyde to 3-allyl-2-
In our functional assays measuring stimulation (for EP2)
or inhibition (for EP3) of c-AMP production in HEK
(EBNA) cells,16 the compounds of Table 1 behave as full
EP3 antagonists, except for 9, which behaves as a full
EP2 agonist. The EP3 antagonistic activity is propor-
tional to the affinity on the receptor. The selected EP3
antagonists described in Table 2 are also selective
against the other prostanoid receptors (Ki for the IP,
TP, FP, and DP receptors >0.5 lM) and they displayed
excellent pharmacokinetics in rats. Metabolism studies
on the EP3 selective antagonist 3a, carried out with rat
liver microsomes supplemented with NADPH, indicated
that the compound was 65% metabolized after a typical
1 h incubation.17 The major metabolites were isolated
and characterized by HPLC/MS and NMR.17 The
major metabolic pathways are, in order of decreasing
importance: (1) oxidation at the allylic position to give
an allylic alcohol, (2) oxidation of the methyl group to
produce an hydroxymethyl substituent, (3) oxidation
hydroxybenzaldehyde
(1,2-dichlorobenzene,
reflux
16 h), (2) benzylation of the phenol (as in Scheme 2),
(3) reduction of the aldehyde with DIBAL-H (THF,
ꢀ10 °C, 15 min), and (4) palladium catalyzed cross-cou-
pling with 2-bromocinnamic acid (as in Scheme 1).
Finally, compounds 12 and 13 were prepared from
acetoxylation of the mixture 2p/3p using SeO2 (AcOH,
reflux, 20 min, 92% yield),15 followed by hydrolysis of
the acetate (AcOH–water 1:1, reflux, 45 min, 31% yield)
and HPLC separation.
Table 1 shows the affinity of several analogs of the lead
mixture 2a/3a on the different EP receptors. The ortho-
substituted cinnamic acid portion of the molecule is crit-
ical for antagonism at the EP3 receptor. Moving the

530
M. Belley et al. / Bioorg. Med. Chem. Lett. 15 (2005) 527–530
Table 2. Pharmacokinetics of the EP2 agonist
antagonists 2a/3a and 3p in rats
9
and the EP3
Y.; Okamoto, S.; Sato, F.; Ichikawa, A. Bioorg. Med.
Chem. 2000, 8, 353; (d) Kobayashi, T.; Narumiya, S.
Prostaglandins Other Lipid Mediat. 2002, 68–69, 557.
3. Concurrently to this work, we pursued two other series of
EP3 receptor antagonists (a) Juteau, H.; Gareau, Y.;
Labelle, M.; Sturino, C. F.; Sawyer, N.; Tremblay, N.;
2a/3aa
3p
9
Bioavailability (%)b
Clearance (mL/min/Kg) 10
97
74
5.8
17
16
Cmax (lM)
t1/2
22 (30 min) 25 (30 min) 1.7 (15 min)
2 h 2 h 2 h
`
Lamontagne, S.; Carriere, M.-C.; Denis, D.; Metters, K.
M. Bioorg. Med. Chem. 2001, 9, 1977; (b) Gallant, M.;
a Ratio 2a:3a 1:1.3.
`
Belley, M.; Carriere, M.-C.; Chateauneuf, A.; Denis, D.;
b Compounds dosed as their sodium salts at 10 mg/kg PO in 0.5%
methocel and 5 mg/kg IV in 5% dextrose, except for 9 where 25% b-
cyclodextrin was used as vehicle IV and PO, in male Sprague–Dawley
rats weighing 300–400 g.
Lachance, N.; Lamontagne, S.; Metters, K. M.; Sawyer,
N.; Slipetz, D.; Truchon, J. F.; Labelle, M. Bioorg. Med.
Chem. Lett. 2003, 13, 3813.
`
4. Gallant, M.; Carriere, M. C.; Chateauneuf, A.; Denis, D.;
Gareau, Y.; Godbout, C.; Greig, G.; Juteau, H.;
Lachance, N.; Lacombe, P.; Lamontagne, S.; Metters,
K. M.; Rochette, C.; Ruel, R.; Slipetz, D.; Sawyer, N.;
Tremblay, N.; Labelle, M. Bioorg. Med. Chem. Lett. 2002,
12, 2583.
of both the methyl group and the allylic position, and (4)
cleavage of the benzyl group to yield the phenol 3h. The
structures of the major metabolites were also confirmed
by synthesizing compounds 10–13, from which 10 and
12 were found to be metabolites of 3p, and their affinities
to the PGE2 receptors are reported in Table 1. All of
these metabolites are EP3 selective antagonists and only
slightly less potent than 3p, suggesting that they may
also contribute to the in vivo activity.
5. (a) Breault, G. A.; Oldfield, J.; Tucker, H.; Warner, P. EP
752421, 1997; Chem. Abstr. 1998, 126, 157515; (b) Breault,
G. A.; Oldfield, J.; Tucker, H.; Warner, P. WO 96/11902,
1996; Chem. Abstr. 1997, 125, 114673; (c) Mewshaw, R.;
Hamilton, G. S. WO 96/25383, 1996; Chem. Abstr. 1997,
125, 114301.
6. More detailed experimental procedures are given in:
Belley, M.; Lachance, N.; Labelle, M.; Gallant, M.;
Chauret, N.; Li, C.; Trimble, L. A. WO Patent 0020371,
2000; Chem. Abstr. 2000, 132, 278987.
7. Larock, R. C.; Leung, W.-Y.; Stolz-Dunn, S. Tetrahedron
Lett. 1989, 6629.
8. The ratio of isomers 2:3 could vary from 1:1 to 1:5 but,
since the difference of activity between them is only 2-fold
on the EP3 receptor, this variation would not significantly
change the SAR described here.
The EP2 agonist 9 was also quite selective against the
other prostanoid receptors (Ki for the IP, DP, and FP
receptors >0.7 lM), with the exception of TP (Ki
0.030 lM). Its pharmacokinetic profile is reported in
Table 2. When dosed PO in 1% methocel, the EP2 ago-
nist 9 inhibited carrageenan-induced rat paw edema18 in
a dose-dependent manner with an ED50 of 3.3 mg/kg
PO. In a carrageenan-induced hyperalgesia model,18
9
9. (a) Miyaura, N.; Ishiyama, T.; Ishikawa, M.; Suzuki, A.
Tetrahedron Lett. 1986, 27, 6369; (b) Miyaura, N.;
Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.; Suzuki,
A. J. Am. Chem. Soc. 1989, 111, 314.
was active when given IV (ED50 4.5 mg/kg), but was
inactive when dosed PO (ED50 > 30 mg/kg) in rats,
probably due to its low bioavailability.
10. Kottwitz, J.; Vorbruggen, H. Synthesis 1975, 636.
11. 1-(Benzyloxy)-2-vinylbenzene was prepared from a Wittig
reaction on 2-benzyloxybenzaldehyde with MePPh3+Brꢀ
and BuLi in THF (0 °C, then rt 2 h, 98% yield).
12. Compound 4f was prepared in 56% yield from the
allylation of 3-(benzyloxy)bromobenzene with allylSnBu3
(1.2 equiv), Ph3P (2 equiv), LiCl (4 equiv) and
(Ph3P)2PdCl2 (0.4 equiv) in DMF at reflux for 2 h.
13. Reaction of sodium phenoxide with 1,3-dibromobenzene
(5 equiv) in the presence of Cu2O (0.5 equiv) in DMF at
reflux for 4 h gave 1-bromo-3-phenoxybenzene, which was
allylated12 at 100 °C for 3 h to produce 4k (81% yield).
14. Compound 2k/3k were prepared from the NaOH hydro-
lysis of the products of the Heck reaction between 4a and
ethyl 2-bromobenzoate in 56% overall yield.
In summary, we have provided examples demonstrating
that changing the substitution pattern around the aro-
matic cores of known EP1 antagonists can dramatically
alter the selectivity toward prostanoid receptors. We
have also described the synthesis, biological activity,
pharmacokinetic profile and metabolism of a new series
of ortho-substituted cinnamic acids. Compound 9 is a
very good EP2 agonist and shows promising anti-inflam-
matory and analgesic properties. Compounds 3a and 3p
are very potent and selective EP3 antagonists and their
pharmacological properties in vivo will be discussed in
a future publication.
15. Schaefer, J. P.; Horvath, B. Tetrahedron Lett. 1964, 5,
2023.
16. Boie, Y.; Stocco, R.; Sawyer, N.; Slipetz, D. M.; Ungrin,
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