Discovery of novel, non-acidic 1,5-biaryl pyrrole EP1 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2006.12.021

Replacement of the carboxylic acid group in a series of previously described 1,5-biaryl pyrrole EP₁ receptor antagonists led to the discovery of various novel non-acidic antagonists. Several analogues displayed high binding affinity and high bi

Full text of DOI:10.1016/j.bmcl.2006.12.021

Bioorganic & Medicinal Chemistry Letters 17 (2007) 1200–1205
Discovery of novel, non-acidic 1,5-biaryl pyrrole
EP1 receptor antagonists
Adrian Hall,* Stephen Atkinson, Susan H. Brown, Iain P. Chessell, Anita Chowdhury,
Gerard M. P. Giblin, Paul Goldsmith, Mark P. Healy, Karamjit S. Jandu,
Matthew R. Johnson, Anton D. Michel, Alan Naylor and Jennifer A. Sweeting
Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park,
Third Avenue, Harlow, Essex CM19 5AW, UK
Received 10 October 2006; revised 7 December 2006; accepted 8 December 2006
Available online 12 December 2006
Abstract—Replacement of the carboxylic acid group in a series of previously described 1,5-biaryl pyrrole EP1 receptor antagonists
led to the discovery of various novel non-acidic antagonists. Several analogues displayed high binding affinity and high binding effi-
ciency indices.
Ó 2006 Elsevier Ltd. All rights reserved.
O
Prostaglandin E2 (PGE2), Figure 1, is a lipophilic, 20-
carbon atom, carboxylic acid. It is synthesized in vivo
CO2H
from arachidonic acid by the sequential action of cyclo-
oxygenase (COX) and prostaglandin E synthase (PGES)
HO
enzymes.1 PGE2 is known to activate four 7-transmem-
OH
2
brane (TM) G-protein coupled receptors, EP1–4
.
Figure 1. Prostaglandin E2 (PGE2).
It has been postulated that the carboxylic acid, present
in all prostanoid ligands, forms key binding
a
interaction (salt bridge) with a highly conserved arginine
residue, present on TM-7 of all the prostanoid recep-
tors.2a Hence, most of the known ligands for the prosta-
noid receptors contain acidic groups which are essential
to bind to the receptor.1,3 We, and others, have
described acidic EP1 receptor antagonists,4–8 however,
to date only three non-carboxylic acid based templates
have been described, exemplified by SC-51322 (1)9 and
analogues10 from Searle and 211 and 36 from Merck
Frosst, Figure 2. Progress in this area has been stifled
due to difficulties such as escalating molecular weight
which leads to a lower binding efficiency index (BEI).12
For example, compound 2 has a pKi of 7 and its
molecular weight is 620 Da which gives a BEI of 11.2.
Acidic ligands, on the other hand, have high affinity,
Keywords: EP1 antagonist; Pyrrole; Carboxylic acid replacement.
*
Figure 2. Selection of non-carboxylic acid based EP1 antagonists and
ONO-8713.
Corresponding author. Tel.: +44 1279 643464; e-mail: adrian.2.hall@
gsk.com
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.12.021

A. Hall et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1200–1205
1201
O
The results in Table 1 show that the meta-acylsulfona-
mides, 6a–d, retained the activity of the carboxylic acid
5, and affinity was not influenced by the functionality on
the left-hand side of the molecule (X-group or the ben-
zyloxy group). This indicated that sterically demanding
groups such as phenyl could be incorporated in the acyl-
sulfonamide, that is, in the acid binding region. Reversal
of the acylsulfonamide at the meta-position, 6e, was tol-
erated, albeit with a considerable decrease in activity.
However, translocation of the reversed acylsulfonamide
from the meta- to the para-position, 6f, restored activity.
The tetrazole 6g was also well tolerated.15 Pleasingly, the
hexafluoropropan-2-ol derivative 6h displayed good
activity, despite having a considerably higher calculated
pKa (8.79). The calculated pKa compares well with
reported pKa values (8.5) for similar compounds con-
taining this group.16a
Cl
N
OH
EP bindingpIC50 = 8.1
MW = 417.5 Da
calc. pKa = 3.7
1
O
5
Figure 3. Profile of lead compound 5.
for example ONO-8713 (4) has a Ki of 0.3 nM7 with a
molecular weight of 471 Da which gives a BEI of 20.2.
Compound 5,4 Figure 3, exhibits a binding pIC50 of 8.1
and has a MW of 417.5 Da, therefore giving a BEI of
19.4.
Due to the paucity of known non-acidic EP1 receptor
antagonists, we were interested in assessing whether
the carboxylic acid moiety could be replaced by non-
acidic groups and what effect this change would have
on in vitro affinity.
When compared to recent results from Merck Frosst
where a similar analogue (related to 3), with hexafluoro-
propan-2-ol group in the meta-position, had a Ki of
260 nM6 our results demonstrate that this group shows
higher activity when located at the para-position.
Based on the facile synthesis of 1,5-biaryl pyrroles, such
as 5, Figure 3, we felt this template offered the potential
to identify novel, lower molecular weight non-acidic
antagonists by utilizing array chemistry. Thus, Paal–
Knorr condensation13 of a 1,4-diketone with readily
available anilines would allow a high-throughput assess-
ment of novel carboxylic acid-replacement groups.
Based on the calculated pKa data for 6h we felt that the
hexafluoropropan-2-ol group could potentially form a
hydrogen bond with the receptor, rather than an ionic
interaction. This hypothesis is supported by recent crys-
tallographic data for a LXR receptor ligand containing
the hexafluoropropan-2-ol group, where this moiety
forms hydrogen bonds with histidine and tryptophan
residues.16b
Compound activities were determined in a [3H]-PGE2
binding assay at the recombinant human EP1 receptor
expressed in CHO cell membranes.4,5b,14
Hence, we sought to replace the carboxylic acid with
hydrogen bond acceptor (HBA) and hydrogen bond do-
nor (HBD) groups in the meta- and para-positions of the
phenyl ring.
Before commencing work with non-acidic groups we
first sought to profile some biosteric carboxylic acid
replacements such as acylsulfonamides and tetrazoles,
Table 1.
In the first instance we prepared the meta- and para-sulf-
ones and sulfonamides as these groups have HBA and
HBA/HBD potential, respectively, Table 2. In addition
these groups have been found to bind to the arginine res-
Table 1. SAR and calcd pKa values for biosteric carboxylic acid
replacements
o
X
N
m
A
p
Table 2. SAR of sulfone and sulfonamide carboxylic acid replace-
ments
O
o
Y
X
N
m
A
p
a
Compound
X
Y
H
A
pIC50
Calcd
b
pKa
O
5
Cl
m-CO2H
8.1 0.4 3.70
8.4 0.1 3.27
8.6 0.3 3.85
8.6 0.2 3.85
Y
6a
6b
6c
6d
6e
6f
6g
6h
Br 2,4-DiF m-CONHSO2Me
Cl
H
H
H
H
H
H
m-CONHSO2Ph
m-CONHSO2Ph
m-CONHSO2isoxc 8.3 0.2 2.88
a
Compound
X
Y
A
pIC50
H
7a
7b
7c
7d
7e
7f
H
H
H
H
H
H
H
H
m-SO2Me
m-SO2Me
m-SO2Me
p-SO2Me
p-SO2Me
p-SO2Me
p-SO2NH2
<6
Cl
Cl
m-SO2NHCOPh
p-SO2NHCOPh
7.1 0.2 3.40
8.1 0.2 3.60
8.2 0.2 3.81
7.6 0.3 8.79
Cl
Br
H
6.9 0.1
6.7 0.2
6.3 0.1
7.7 0.1
7.5 0.2
7.7 0.2
Br 2,4-DiF m-Tetrazole
Br 2,4-DiF p-C(CF3)2OH
Cl
Br
Cl
a Values are means of at least three experiments.
7g
b Calculated pKa values using ACD software version 8.0.
c isox, 3,5-dimethylisoxazol-4-yl.
a Values are means of at least three experiments.

1202
A. Hall et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1200–1205
idue in the COX-2 enzyme,17 thus we hypothesized that
they may be able to form a similar interaction with the
arginine residue in the EP1 receptor.
Table 4. SAR of the p-amide derivatives
X
N
Z
The meta-sulfones had low affinity, 7a–c. However, the
para-sulfones showed good activity, although it was
found that a halogen such as Cl, 7e,18 or Br, 7f, was nec-
essary on the left-hand side phenyl ring. Similarly, the
primary sulfonamide, 7g, also showed good activity
when located at the para-position. These initial results
implied the HBA ability of the new functionality was
important.
O
O
Y
a
Compound
X
Y
Z
pIC50
9a
9b
9c
9d
9e
9f
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
2,4-DiF –NH2
8.1 0.3
8.4 0.1
7.8 0.2
7.3 0.2
7.8 0.1
7.6 0.2
2,4-DiF –NHMe
2,4-DiF –NMe2
2,4-DiF –NEt2
2,4-DiF –NHt-Bu
Furthermore, these results compare well with recent
data published by Merck Frosst on a related 2,3-biaryl-
thiophene template (related to 3), where a meta-sulfon-
amide was found to display similar affinity to the
corresponding carboxylic acid.6
H
H
H
H
H
H
–NHCH2Ph
9g
9h
9i
–NHCH2-(2-pyridyl) 8.6 0.3
–NHCH2-(3-pyridyl) 7.9 0.3
–NHCH2-(4-pyridyl) 7.2 0.2
9j
9k
(S)-NHCH(Me)Ph
(R)-NHCH(Me)Ph
8.3 0.1
8.8 0.1
Encouraged by our preliminary investigations, we syn-
thesized several meta-amide derivatives, Table 3.19
a Values are means of at least three experiments.
The primary amides 8a and b displayed encouraging
activity; however, their activity appeared to be heavily
influenced by the interactions formed by the left-hand
side of the molecule. Thus, activity could be improved
when X was halogen. Investigation of further substitut-
ed derivatives, 8c–e, indicated that the amide could be
substituted and the activity of the dimethyl amide 8d
suggested that the amide was acting as a hydrogen bond
acceptor (HBA). Although the anilide 8e had signifi-
cantly lower activity, we synthesized the benzyl amide
8f as this compound can be viewed as an analogue of
6b, where the SO2 moiety has been replaced by a meth-
ylene group, thus the compound has similar steric de-
mands but is no longer acidic. Pleasingly 8f
demonstrated good affinity with an IC50 of 25 nM
(pIC50 7.6). The phenyl group of the benzyl amide could
be replaced by pyridine, 8g–i, with little effect on activi-
ty. Furthermore, the benzylic position could be substi-
tuted, although this position was sensitive to the
stereochemistry, 8j–k. Again, results correspond with re-
cent observations in a related series.6
Based on the results for the acylsulfonamides, we sought
to ascertain if the amide could be moved from the meta
to the para-position, Table 4.20
Results in Table 4 show that the para-amides displayed
similar activity to their analogous meta-counterparts,
and in some instances actually displayed higher activity,
8g versus 9g. It was also found that the substitution of
the benzylic carbon atom was less sensitive to stereo-
chemistry than in the meta-amide series, 9j–k.
Due to the insight gained from the SAR in the amide
and sulfone/sulfonamide series, we synthesized com-
pounds that contained a heterocycle or fused heterocycle
that could form a HBA and/or HBD interaction with
the receptor. Representative examples from this series
are summarized in Table 5.21,22
Table 3. SAR of the m-amide derivatives
O
X
N
Z
O
Several derivatives displayed encouraging affinity. Nota-
bly, the most active derivatives contained both HBA
and HBD groups, with the exception of oxadiazole 10i
which showed higher affinity than other derivatives with
only HBA functionality. This is contrary to the results in
the amide and sulfone series, where the HBA interaction
appeared predominant. Of note are the benzotriazole
10b, indazoles 10c and 10d, benzimidazole 10h, the oxa-
diazole 10i and the imidazole 10m. These results demon-
strate the feasibility of replacing the carboxylic acid with
novel non-acidic groups. The reversed amide deriva-
tives, 10k and 10l (where the amide group is reversed
with respect to the amides derived from the carboxylic
acid) also displayed good affinity, Table 5.
Y
a
Compound
X
Y
Z
pIC50
8a
8b
8c
8d
8e
8f
H
2,4-DiF
H
2,4-DiF
–NH2
–NH2
6.3 0.2
7.2 0.2
7.7 0.1
8.0 0.2
6.3 0.2
7.6 0.4
7.3 0.3
7.2 0.3
7.2 0.2
6.5 0.2
7.4 0.1
Cl
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
–NHMe
–NMe2
2,4-DiF
2,4-DiF
–NHPh
–NHCH2Ph
H
H
H
H
H
H
8g
8h
8i
–NHCH2-(2-pyridyl)
–NHCH2-(3-pyridyl)
–NHCH2-(4-pyridyl)
(S)-NHCH(Me)Ph
(R)-NHCH(Me)Ph
8j
8k
Compounds were synthesized as shown in Schemes 1–3.
Full experimental procedures and characterizing data
a Values are means of at least three experiments.

A. Hall et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1200–1205
Table 5. SAR of various novel carboxylic acid replacements
1203
X
N
A
O
Y
a
Compound
X
H
Y
A
pIC50
H
N
10a
2,4-DiF
6.2 0.1
N
N
N
H
N
10b
10c
10d
Cl
Cl
Cl
H
H
H
7.6 0.2
7.4 0.3
7.4 0.2
N
H
N
N
N
N
H
N
10e
10f
10g
Br
Br
Br
2,4-DiF
2,4-DiF
2,4-DiF
6.9 0.2
6.6 0.1
6.9 0.1
N
N
N
N
N
N
10h
10i
Br
Br
2,4-DiF
2,4-DiF
7.2 0.1
7.4 0.1
N
H
N
O
O
10j
Br
Cl
2,4-DiF
H
6.7 0.1
7.2 0.1
N
O
H
N
10k
H
N
O
10l
Cl
Br
Cl
Br
H
7.2 0.3
7.4 0.1
6.3 0.1
6.8 0.1
N
N
10m
10n
10o
2,4-DiF
H
N
H
N
N
O
2,4-DiF
NH
O
a Values are means of at least three experiments.
for key compounds have been published.5 The starting
salicylaldehydes were commercially available. Alkyl-
ation of 5-chlorosalicylaldehyde 11 gave the correspond-
ing O-benzylsalicylaldehyde. Stetter reaction23 with
methylvinylketone (MVK) yielded the correspond-
ing 1,4-diketone 12. Paal–Knorr condensation13 with

1204
A. Hall et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1200–1205
a,b
c,d
5
11
12
Scheme 1. Reagents and conditions: (a) BnBr, DMF, K2CO3, 60 °C, 100%; (b) MVK, TEA, EtOH, 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium
bromide, reflux, 81%; (c) ethyl 3-aminobenzoate, PhMe, pTSA, reflux, 60%; (d) 2 M NaOH, EtOH, reflux, 100%.
b (R = Me)
a
c (R = NH2)
d (R = NHCOPh)
10h
7e R = Me
12:X = Cl, Y =H
7g R = NH2
6f R = NHCOPh
13:X = Br, Y =2,4-diF
Scheme 2. Reagents and conditions: (a) 13, 1H-(benzimidazol-2-yl)-phenylamine, pTSA, PhMe, reflux, 53%; (b) 12, 4-(methylsulfonyl)aniline
hydrochloride, TEA, PhMe, reflux, 50%; (c) 12, sulfanilamide, pTSA, PhMe, reflux; (d) 12, sulfabenzamide, pTSA, PhMe, reflux, 72%.
a
b
6b
5
8f
Scheme 3. Reagents and conditions: (a) PhSO2NH2, CDI, DIPEA, DCM, rt, 44%; (b) PhCH2NH2, EDC, HOBt, DCM, rt, 58%.
anilines (refluxing PhMe in the presence of pTSA) gave
the desired products as outlined in Scheme 1. Alterna-
tively, the condensation reaction could be carried out
under microwave irradiation (in NMP, with a catalytic
amount of pTSA, 150 °C, 15 min) to yield the desired
products. The anilines were generally commercially
available, or were prepared as described.5,6 The reverse
acylsulfonamides, for example 6f, were prepared directly
via condensation with sulfabenzamide, Scheme 2. Acyl-
sulfonamides such as 6b were prepared from the corre-
sponding carboxylic acid, Scheme 3. Several anilines
were available with amides already installed. Alterna-
tively, the amides could be prepared from the carboxylic
acid under standard conditions, for example, 8f, Scheme
3.
ing the CYP450 and intrinsic clearance data quoted in
the notes section of the manuscript.
References and notes
´
1. Benoit, P.; de Laval, X.; Pirotte, B.; Dogne, J.-M. Expert
Opin. Ther. Patents 2002, 12, 1225.
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Chessell, I. P.; Coleman, T.; Giblin, G. M. P.; Hurst, D.
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In conclusion, we have discovered several potent non-
acidic EP1 receptor antagonists. We have shown that
the substitution on the left-hand side of these molecules
has a greater influence on activity than in the corre-
sponding carboxylic acid series. Furthermore, we have
described the first non-acidic antagonists for the EP1
receptor with high binding efficiency indices (BEIs), such
as compound 7g with a BEI of 17.0 and 9g with a BEI of
16.9. Several interesting heterocyclic replacements were
also discovered, such as the benzimidazole derivative
10h and the imidazole 10m.
5. (a) Giblin, G. M. P.; Hall, A.; Healy, M. P.; Lewell, X. Q.;
Miller, N. D.; Novelli, R., WO2003/101959A1.; (b) Giblin,
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Acknowledgments
The authors thank members of the Drug Metabolism
and Pharmacokinetic (DMPK) department for generat-
`
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18. Compound 7e displayed a half-life of 2.1 h when admin-
istered intravenously to male Sprague–Dawley rats at a
dose of 1 mg/kg. CYP450 IC50 values P10 lM at 1A2,
2C9, 2D6 and 3A4 isoforms, IC50 = 5.0 lM at 2C19
isoform.
19. In vitro metabolic stability data (intrinsic clearance, CLi)
for compounds 8b, 8d, 8f and 8g in rat and human liver
microsomes: 8b rat CLi 39.0 mL/min/g liver, human CLi
25.0 mL/min/g liver; 8d rat CLi >50.0 mL/min/g liver,
human CLi >50.0 mL/min/g liver, CYP450 IC50 values
P10 lM at 1A2 and 2D6, the 2C19, 2C9 and 3A4
isoforms displayed IC50 values between 1 and 6 lM; 8f rat
CLi 42.0 mL/min/g liver, human CLi >50.0 mL/min/g
liver; 8g rat CLi >50.0 mL/min/g liver, human CLi
>50.0 mL/min/g liver.
20. In vitro metabolic stability data (intrinsic clearance, CLi)
for compounds 9a, 9b, 9f, 9g and 9k in rat and human liver
microsomes: 9a rat CLi 11.0 mL/min/g liver, human CLi
12.0 mL/min/g liver, CYP450 IC50 values all >4 lM (1A2,
2C19, 2C9, 2D6 and 3A4 isoforms); 9b rat CLi 16.0 mL/
min/g liver, human CLi 22.0 mL/min/g liver, CYP450 IC50
values P11 lM at 1A2, 2C19, 2C9, 2D6 and 3A4
isoforms; 9f rat CLi 26.0 mL/min/g liver, human CLi
19.0 mL/min/g liver; 9g rat CLi 23.0 mL/min/g liver,
human CLi 44.0 mL/min/g liver; 9k rat CLi 32.0 mL/
min/g liver, human CLi 26.0 mL/min/g liver.
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human CLi 3.2 mL/min/g liver, CYP450 IC50 values 1–
8 lM at 1A2, 2C19, 2C9 and 3A4 isoforms, IC50 value
22 lM at 2D6 isoform; 10h rat CLi >50.0 mL/min/g liver,
human CLi 15.0 mL/min/g liver, CYP450 IC50 values
P10 lM at 2D6 and 3A4 isoforms, IC50 6.9 lM (1A2),
7.6 lM (2C19) and 2.2 lM (2C9); 10l rat CLi 9.1 mL/min/
g liver, human CLi 4.9 mL/min/g liver, CYP450 IC50
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isoform IC50 3.6 lM.
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14. Data from the [3H]PGE2 binding assay are quoted as
pIC50 values. These data can be converted to pKi values by
subtracting 0.04 from the pIC50 values.
15. In vitro metabolic stability data (intrinsic clearance, CLi)
for compounds 6a, 6c and 6h in rat and human liver
microsomes: 6a rat CLi 2.7 mL/min/g liver, human CLi
5.4 mL/min/g liver; CYP450 IC50 values all >10 lM at
1A2, 2C19, 2D6 and 3A4 isoforms, IC50 = 0.63 lM at the
2C9 isoform; 6b rat CLi 3.1 mL/min/g liver, human CLi
5.2 mL/min/g liver; 6c rat CLi 8.8 mL/min/g liver, human
CLi 6.5 mL/min/g liver; 6f rat CLi 6.7 mL/min/g liver,
human CLi 3.4 mL/min/g liver; 6h rat CLi 3.5 mL/min/g
liver, human CLi 0.8 mL/min/g liver.
16. (a) Li, L.; Liu, J.; Zhu, L.; Cutler, S.; Hasegawa, H.; Shan,
B.; Medina, J. C. Bioorg. Med. Chem. Lett. 2006, 16, 1638;
¨
(b) Svensson, S.; Ostberg, T.; Jacobsson, M.; Norstro¨m,
´
C.; Stefansson, K.; Hallen, D.; Johansson, I. C.; Zachris-
son, K.; Ogg, D.; Jendeberg, L. EMBO J. 2003, 22, 4625.
17. (a) Trummlitz, G.; van Ryn, J. Curr. Opin. Drug Discov.
Devel. 2002, 5, 550; (b) Fitzgerald, G. A. Nat. Rev. Drug
Discov. 2003, 2, 879.
23. Stetter, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 639.