Structure-activity relationships of 1,5-biaryl pyrroles as EP1 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2006.04.073

The preliminary SAR of a series of novel 1,5-biaryl pyrrole EP₁ receptor antagonists derived from compound 1 is described. Replacement of the benzyl group of 1 with isosteric groups was investigated. The most effective replacement was found to be the isobutyl group. The cyclopentylmethyl and cyclohexylmethyl groups were also effective benzyl replacements. The cyclohexylmethyl derivative 19 demonstrated the lowest metabolic clearance within this series. In addition, several high affinity substituted benzyl analogues were also identified. Compound 39 was found to have good bioavailability in rats and demonstrated efficacy in the established FCA preclinical model of inflammatory pain with a calculated ED₅₀ of 9.2 mg/kg.

Full text of DOI:10.1016/j.bmcl.2006.04.073

Bioorganic & Medicinal Chemistry Letters 16 (2006) 3657–3662
Structure–activity relationships of 1,5-biaryl pyrroles
as EP1 receptor antagonists
Adrian Hall,* Stephen Atkinson, Susan H. Brown, Iain P. Chessell, Anita Chowdhury,
Nicholas M. Clayton, Tanya Coleman,ꢀ Gerard M. P. Giblin, Robert J. Gleave,
Beverley Hammond, Mark P. Healy, Matthew R. Johnson, Anton D. Michel, Alan Naylor,
Riccardo Novelli, David J. Spalding and Sac P. Tang
Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park,
Third Avenue, Harlow, Essex CM19 5AW, UK
Received 11 April 2006; accepted 23 April 2006
Available online 11 May 2006
Abstract—The preliminary SAR of a series of novel 1,5-biaryl pyrrole EP1 receptor antagonists derived from compound 1 is
described. Replacement of the benzyl group of 1 with isosteric groups was investigated. The most effective replacement was found
to be the isobutyl group. The cyclopentylmethyl and cyclohexylmethyl groups were also effective benzyl replacements. The cyclo-
hexylmethyl derivative 19 demonstrated the lowest metabolic clearance within this series. In addition, several high affinity substitut-
ed benzyl analogues were also identified. Compound 39 was found to have good bioavailability in rats and demonstrated efficacy in
the established FCA preclinical model of inflammatory pain with a calculated ED50 of 9.2 mg/kg.
Ó 2006 Elsevier Ltd. All rights reserved.
Prostaglandin E2 (PGE2) is a pro-inflammatory media-
tor1 that exerts its physiological actions by activating
four 7-transmembrane receptor subtypes, EP1–4.2 Stud-
ies with prostaglandin E synthase (PGES) knockout
(KO) mice have shown that PGE2 plays an important
role in pain1 and EP1 receptor KO mice have implicated
the EP1 receptor subtype in the sensation of PGE2-med-
iated allodynia3 and inflammatory pain.4 In conjunction
with this, EP1 receptor antagonists have shown efficacy
in preclinical models of postoperative pain,5 neuropathic
pain6 and allodynia.7 There is also evidence to suggest
that PGE2mediated pyrexia is controlled by the EP1
receptor.8 Furthermore, a recent report described the
efficacy of the AstraZeneca compound ZD6416 in a hu-
man model of visceral hypersensitivity.9 Thus, an EP1
receptor antagonist has the potential to deliver efficacy
in various pain states. By sparing the beneficial effects
of PGE2, at other EP receptors, and the synthesis of
prostaglandin I2 (PGI2) and thromboxane A2
(TxA2),10 an improved side-effect profile over COX-2
inhibitors may be achieved.
Several EP1 antagonists are known in the literature,
such as ZD6416,11 ONO-871312 and ONO-8711,13 SC-
5132214 and analogues15 and the 2,3-biaryl thiophenes
from Merck Frosst.16
We recently disclosed the structures of several novel EP1
receptor antagonists, such as the pyrrole 1.17
Herein we describe the initial structure–activity relation-
ships (SAR) in this series.
Compound 117 showed good in vitro activity at the EP1
receptor, 8 nM in a [3H]PGE2 binding assay in CHO
cells and 0.7 nM in a functional assay (FLIPR) in
CHO cells.17,18 It has also shown low intrinsic clearance
in both rat and human liver microsomes (Fig. 1).
However, the rat in vivo pharmacokinetic profile was
not optimal. Thus, our goals were to explore the SAR
of this template and to optimise EP1 activity,whilst
improving the in vivo DMPK profile, which we hoped
would lead to in vivo efficacy in preclinical models of
inflammatory pain.
Keywords: EP1 antagonist; Pyrrole; Isostere; Pain; Established FCA.
*
Corresponding
adrian.2.hall@gsk.com
author.
Tel.:
+44
1279
643464; e-mail:
ꢀ
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.2006.04.073

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A. Hall et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3657–3662
Table 2. In vitro binding data for compounds 8–15
EP1 binding pIC50 = 8.1
EP1 functional pKi = 9.15
O
Z
O
Cl
N
OH
X
N
rat CLi = 1.4 mL/min/g liver
OH
human CLi = 1.6 mL/min/g liver
O
O
rat pharmacokinetics
CLb = 67 mL/ming/kg
Vss = 3.0 L/kg
Y
1
t1/2 = 0.5h
a
Compound
X
Y
H
Z
Binding pIC50
Figure 1. Profile of lead compound 1.
8
Cl
Cl
Cl
Cl
Cl
Br
Cl
Cl
H
8.0 0.1
6.7 0.1
7.0 0.1
7.6 0.1
7.0 0.2
7.1 0.1
8.2 0.2
8.4 0.2
9
4-F
2,4-DiF
H
CF3
CF3
Cl
10
11
12
13
14
15
One of the first areas we sought to investigate was the
role of the chlorine atom, para to the benzyloxy group.
Initial data suggested that the bromo analogue 2 had an
improved in vivo DMPK profile relative to 1. Hence, we
were interested in exploring whether replacement of the
chlorine atom would improve EP1 receptor affini-
ty,whilst simultaneously optimising the pharmacokinetic
parameters of the series. Results show that the chlorine
atom can be replaced by isosteric electron-withdrawing
moieties such as Br and CF3 and even the larger methyl
sulfone group, compounds 2–4. Deletion of this elec-
tron-withdrawing moiety appeared to have little effect
on activity, as evidenced by compound 5. However,
replacement by aromatic groups such as phenyl or thi-
ophenyl led to a marked decrease in activity, compounds
6 and 7, Table 1. Despite the fact that 5 was essentially
equipotent with analogues 1–3, we chose the Cl, Br and
CF3 substituents for further exploration.
H
Et
Et
H
4-F
Me
Me
2,4-DiF
a Mean of at least three experiments.
Table 3. In vitro binding data for compounds 16–18
X
O
Cl
N
OH
O
a
Compound
X
Binding pIC50
Next, we investigated substitution of the pyrrole ring.
We had previously discovered that the methyl group
on the pyrrole ring could be removed without effecting
activity, compound 8.17 In this instance, replacement of
the Me group by CF3 led to a substantial decrease in
activity, compounds 9 and 10, compared to the analo-
gous methyl derivatives 14 and 15. This may be due
to the increased steric nature of the CF3 group relative
to the Me group as it was found that the Me group
could be replaced by a chlorine atom, compound 11,
therefore implying that electron-withdrawing groups
are tolerated in this position. The steric restrictions of
this region of the molecule were further highlighted
16
17
18
Cl
Br
<6
6.1 0.2
<6
Ph
a Mean of at least three experiments.
when the methyl group was replaced by an ethyl group,
compounds 12 and 13, which resulted in a considerable
loss of activity, approximately 10-fold, relative to the
corresponding methyl analogues (compounds 1 and
2), Table 2.
Further substitution of the pyrrole ring by addition of a
halogen atom or a phenyl group led to a marked de-
crease in EP1 activity, compounds 16–18, hence no fur-
ther analogues were pursued in this series, Table 3.
Table 1. In vitro EP1 binding data for compounds 1–7
O
X
N
OH
We were interested in exploring the role of the benzyl
group in binding to the EP1 receptor and its potential
in modulating the intrinsic clearance and CYP450 pro-
file of compounds.
O
Y
a
Compound
X
Y
Binding pIC50
To this end, we synthesized a range of analogues where
the benzyl group was replaced by potential non-aromat-
ic isosteric groups, Table 4.
1
2
3
4
5
6
7
Cl
Br
H
H
H
H
H
H
H
8.1 0.4
8.1 0.2
8.3 0.1
7.6 0.1
7.7 0.3
6.4 0.5
6.2 0.7
CF3
SO2Me
H
We were pleased to find that the benzyl group could be
replaced by a cyclohexylmethyl group, compounds 19–
21, with a modest decrease in activity (5- to 16-fold).
Furthermore, the cyclohexyl ring could be replaced by
a tetrahydropyran (22) ring without further affect on
Ph
Thiophen-3-yl
a Mean of at least three experiments.

A. Hall et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3657–3662
Table 4. In vitro EP1 binding data for compounds 19–29 Table 5. In vitro EP1 binding data for compounds 2 and 30–53
3659
O
O
X
N
Br
N
OH
OH
O
R
O
a
Compound
X
R
Binding pIC50
Y
19
20
21
22
23
24
25
26
27
28
Cl
Br
CH2Cyclohexyl
CH2Cyclohexyl
6.9 0.5
7.4 0.1
7.5 0.2
7.4 0.2
7.6 0.3
7.8 0.3
7.4 0.2
8.3 0.1
8.3 0.1
7.6 0.1
a
Compound
Y
H
Binding pIC50
CF3 CH2Cyclohexyl
2
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
8.0 0.2
7.7 0.2
8.6 0.1
6.6 0.1
7.4 0.1
7.3 0.0
7.3 0.3
7.1 0.1
7.8 0.0
8.5 0.1
8.2 0.1
8.3 0.2
8.1 0.1
8.2 0.1
9.0 0.3
8.8 0.5
7.9 0.2
8.0 0.2
8.0 0.2
8.3 0.2
7.0 0.3
7.8 0.1
7.9 0.3
7.9 0.1
7.0 0.2
Cl
Cl
Br
Cl
Cl
Br
Br
CH2tetrahydropyran-4-yl
CH2Cyclopentyl
CH2Cyclopentyl
CH2tetrahydrofuran-2-yl
i-Bu
2-Me
4-Me
3-CF3
4-CF3
3-OMe
4-OMe
3-OCHF2
4-OCF3
2-F
i-Bu
(5-Methyl-3-isoxazolyl)
methyl
29
Br
(3,5-Dimethyl-4-isoxazolyl) 6.7 0.1
methyl
4-F
a Mean of at least three experiments.
3,4-DiF
2,5-DiF
2,3-DiF
2,6-DiF
2,4,6-TriF
2-Cl
activity. Replacement of the benzyl group by the less
bulky cyclopentylmethyl moiety yielded more promising
analogues (23 and 24), with activity 2- to 3-fold lower
than their benzyl analogues. Again, we found that an
oxygen atom could be incorporated into the ring with
minimal detriment to binding affinity, compound 25.
The most potent analogues were obtained when the ben-
zyl group was replaced by an iso-butyl group, (26 and
27), as these compounds were equipotent with the origi-
nal benzyl analogues. These results suggest that the
benzyl group forms a lipophilic interaction with the
receptor, but that the environment may be limited steri-
cally, as the bulky cyclohexylmethyl group has lower
activity than the sterically less demanding cyclopentylm-
ethyl group and the smaller iso-butyl group. These re-
sults demonstrate the utility of the cyclohexylmethyl,
cyclopentylmethyl and iso-butyl groups as isosteres for
the benzyl group in this instance.
3-Cl
4-Cl
2,4-DiCl
3,4-DiCl
2-Cl, 4-F
2-Cl, 6-F
2-F, 4-CF3
2-F, 6-CF3
a Mean of at least three experiments.
The pharmacokinetic parameters of several compounds
were assessed in vivo in a rat iv pharmacokinetic screen.
Results are summarized in Table 6.
The data in Table 6 show that substitution of the benzyl
group could be used to modulate the rate of clearance of
the compounds although the cyclohexylmethyl deriva-
tive (19) showed the lowest blood clearance. Derivative
39 also showed similar metabolic stability to analogue
2 and displayed a good CYP450 profile (IC50 values
all P17 lM, except the 2C9 isoform which displayed
an IC50 of 3.9 lM). When administered orally to rats
in 1% (w/v) methylcellulose aqueous formulation at a
dose of 3 mg/kg, 39 was found to have 44% bioavailabil-
ity. Due to these encouraging results, 39 was tested in
Freund’s complete adjuvant (FCA) model of inflamma-
tory pain.19 A dose-related effect was observed, 1 h post-
dose, at doses of 3, 10 and 30 mg/kg with a calculated
ED50 of 9.2 mg/kg, Figure 2.20
We also investigated replacement of the phenyl moiety
of the benzyl group by aromatic heterocycles such as
isoxazole, (28 and 29). Results show that 28 was well tol-
erated indicating that the 5-methylisoxazol-3-yl group is
a good isostere for a phenyl ring in this instance.
Synthesis of substituted benzyl analogues was undertak-
en in the bromo series as compound 2 had previously
demonstrated lower metabolic clearance than 1 in rat
in vivo study, Table 5.
The addition of both electron-donating and electron-
withdrawing substituents was explored. In general, elec-
tron-withdrawing groups were well tolerated. Addition
of a halogen atom to the 2-position, 38, the 4-position,
47, and the 2,4-position, 48, was well tolerated. The
most preferred substitution patterns were the 2,6- and
the 2,4,6-positions. The 2,6-difluoro derivative 43
showed excellent activity with an IC50 of 1 nM making
it the most potent compound in this series.
Compounds were synthesized as described in Schemes
1–5. Full experimental details and characterizing data
for key compounds have been described.18
The methyl-pyrrole derivatives were prepared as out-
lined in Scheme 1.21 Briefly, chlorosalicylaldehydes were

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A. Hall et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3657–3662
Table 6. In vivo pharmacokinetic data for selected compoundsa
Table 7. Yields for the synthesis of compounds 1–3 and 5
Compound
CLb (mL/min/kg)
Vss (L/kg)
t1/2 (h)
Compound
X
Yields
1
2
67
41
48
62
54
28
42
51
48
3.0
0.6
0.9
0.9
1.0
0.5
0.7
0.8
0.8
0.5
0.3
nd
1
2
3
5
Cl
81%,a 60%,b 100%d
78%,a 55%,b 100%d
32%,a 56%,c 96%e
72%,a 88%,b 91%e
Br
CF3
H
14
15
17
19
39
47
50
nd
0.3
0.4
nd
a Yield for conditions a.
b Yield for conditions b.
c Yield for conditions c.
d Yield for conditions d.
e Yield for conditions e.
0.2
0.3
a Compounds administered intravenously in 0.9% and (w/v) saline
solution containing 2% (v/v) DMSO and 10% (w/v) hydroxypropyl-
b-cyclodextrin at a dose of 1 mg/kg.
O
O
X
X
X
d or e
a, b
or c
OH
OH
OR
125
56a, X =CF3
56b, X = SO2Me
57a, X =CF3
57b, X = SO2Me
54c X =CF3; R = Bn
58, X = SO2Me; R = PMB
ED50 = 9.2mg/kg
100
Scheme 2. Reagents and conditions: (a) 3,4-dihydro-2H-pyran, DCM,
HCl in dioxane, 78%; (b) n-BuLi, TMEDA, À15 °C then DMF,
À15 °C to rt, then aq HCl, 75%; (c) HMTA, TFA, 100 °C; (d) BnBr,
K2CO3, DMF, 60 °C; (e) PMBCl, K2CO3, DMF, 70 °C.
75
50
25
0
Table 8. Yields for the synthesis of compounds 54c and 58
Compound
X
Yields
54c
58
CF3
SO2Me
78%,a 75%,b 19%d
30%,c 100%e
a Yield for conditions a.
b Yield for conditions b.
c Yield for conditions c.
d Yield for conditions d.
e Yield for conditions e.
1
10
100
Dose (mg/kg p.o)
Figure 2. Dose–response graph for compound 39 in FCA.
O
O
O
Cl
Cl
a, b
OH
OBn
BrMg
8
O
OBn
O
O
X
X
a
b or c
59
61
c
d
O
1, 2, 3 or 5
O
then d or e
OBn
OBn
60
O
55
54
a, X = Cl
b, X = Br
c, X = CF3
a, X = Cl
b, X = Br
c, X = CF3
N
CO2Et
Cl
e, d
11
d, X = H
d, X = H
OBn
62
Scheme 1. Reagents and conditions: (a) MVK, TEA, 3-ethyl-5-
(2-hydroxyethyl)-4-methyl-thiazolium bromide, reflux; (b) ethyl
3-aminobenzoate, PhMe, pTSA, reflux; (c) ethyl 3-aminobenzoate,
reacti-vial, 145 °C; (d) 2 M NaOH, EtOH, reflux; (e) 2 M NaOH,
EtOH, reacti-vial, 100–200 °C.
Scheme 3. Reagents and conditions: (a) DCM, SOCl2, reflux; (b) 60,
THF, À60 °C to rt, 65%; (c) ethyl 3-aminobenzoate, NMP, pTSA,
150 °C, microwave 10 min, 50%; (d) 2M NaOH, EtOH, 100 °C,
microwave 2 min, 100%; (e) NCS, THF, 100%.
alkylated with benzyl bromide (K2CO3, DMF, 60 °C) to
give 2-benzyloxy-5-chlorobenzaldehyde 54a–d. Imple-
mentation of the Stetter reaction22 with methylvinylke-
tone (MVK) gave the corresponding 1,4-diketones
55a–d which underwent Paal–Knorr condensation23
with ethyl-3-aminobenzoate to give the requisite pyr-
roles 1–3 and 5, upon basic hydrolysis of the esters,
Scheme 1 and Table 7. The ethyl ester of Br-derivative
2 underwent Suzuki reaction with phenylboronic and
thiophene-3-boronic acid to give derivatives 6 and 7,
respectively, under standard conditions (PhMe–EtOH,
Pd(PPh3)4, K2CO3, reflux). The ethyl pyrrole derivatives
12 and 13 were prepared in an analogous fashion to the
corresponding methyl derivatives 1 and 2 using ethylvi-
nylketone (EVK).

A. Hall et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3657–3662
3661
O
N
CO2Et
Cl
d, e then f or g
Cl
a, b, c
OH
OMe
9 or 10
OMe
64
63
Scheme 4. Reagents and conditions: (a) DCM, SOCl2, reflux; (b) 57, THF, À60 °C to rt; (c) ethyl 3-aminobenzoate, NMP, pTSA, 150 °C, microwave
12 min, 92%; (d) ICF3, 30% H2O2, FeSO4Æ7H2O, DMSO, 43%; (e) NaSMe, DMF, 100 °C, 4h; (f) 4-fluorobenzyl bromide, KI, K2CO3, MeOH, 60 °C;
(g) 2,4-difluorobenzyl bromide, KI, K2CO3, MeOH, 60 °C.
The ester of compound 1 could be chlorinated or
brominated with NCS or NBS to yield 16 and 17,
respectively, upon saponification. Suzuki reaction of
17 with phenylboronic acid, under standard conditions,
furnished 18.
O
N
CO2Et
X
X
a, b, c
d, e
20, 21, 24
27 - 29
30 - 53
OH
OH
65a, X = Br
57a, X = CF3
66a, X = Br
66b, X = CF3
2-Benzyloxy-5-trifluoromethylbenzaldehyde 57a was
prepared from 4-trifluoromethylphenol 56a as described
by Scha¨fer.24 Alkylation under standard conditions
furnished 54c, Scheme 2. 2-para-Methoxybenzyl-
5-methylsulfoxidebenzaldehyde was prepared from 4-
(methylsulfonyl)-phenol 56b by Duff reaction25 with
hexamethylenetetramine (HMTA) to give salicylalde-
hyde derivative 57b which was alkylated with para-
methoxybenzyl chloride to give 58 as illustrated in
Scheme 2 and Table 8.
Scheme 5. Reagents and conditions: (a) PMBCl, K2CO3, DMF, 60 °C;
(b) MVK, TEA, 3-ethyl-5-(2-hydroxyethyl)-4-methyl-thiazolium bro-
mide, reflux; (c) PhMe, pTSA, reflux 4–6 h then ethyl 3-aminobenzo-
ate, reflux, 53% (X = Br), 74% (X = SO2Me); (d) substituted benzyl
bromide derivative, alkyl halaide or alkyl tosylate, K2CO3, DMF,
60 °C; (e) 2 M NaOH, EtOH, reflux or 2 M NaOH, EtOH, 100 °C,
microwave 2 min or 2 M NaOH, EtOH, reacti-vial, 100–200 °C.
and b. Sequential alkylation and ester hydrolysis
furnished the desired compounds, Scheme 5.
The des-methyl pyrrole 8 was prepared as outlined in
Scheme 3.26 2-Benzyloxy-5-chlorobenzoic acid 59 was
converted to the corresponding acid chloride and react-
ed with the Grignard reagent 6026 to give the protected
acetal 61. Condensation with ethyl 3-aminobenzoate led
directly to 62 which underwent base-mediated ester
hydrolysis to give 8, Scheme 3.
In summary we have described the SAR of a range of
novel pyrrole EP1 receptor antagonists. The most potent
analogue 43 displayed an IC50 of 1 nM. We have also
shown that the Me group on the pyrrole ring could be
effectively replaced by a Cl-atom but not a CF3 group.
In addition, we have described several isosteric replace-
ments for the benzyl group of 1 and have shown that
replacement of this benzyl group by a cyclohexylmethyl
group, to give 19, resulted in lower metabolic clearance.
Finally, compound 39 showed good bioavailability in
rats and efficacy in a preclinical model of inflammatory
pain.
The Cl-pyrrole 11 was prepared by chlorination of 62
with NCS in THF followed by ester hydrolysis,
Scheme 3.
The CF3 pyrrole derivatives 9 and 10 were prepared as
described in Scheme 4. 5-Chloro-2-methoxybenzoic acid
63 was converted to the corresponding acid chloride and
reacted with Grignard reagent 60 then ethyl 3-amino-
benzoate to give pyrrole 64. The CF3 group was in-
stalled by reaction with CF3I in the presence of
FeSO4Æ7H2O and H2O2 in DMSO.21 Simultaneous
deprotection of the methyl ether and ethyl ester was
achieved by reaction with sodium thiomethoxide. Selec-
tive alkylation of the phenol, in the presence of the
carboxylic acid, was achieved by reaction with the requi-
site benzyl bromide derivative in methanol with KI and
K2CO3 as base, Scheme 4.
Acknowledgments
TheauthorsthankDr. IainMcLayforinformativediscus-
sions and computational chemistry input into the analysis
of benzyl analogues. We also thank Dr. Frank King for
insightful suggestions during the course of this work.
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of the PMB ether and pyrrole formation to give 66a

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