Biarylimidazoles as inhibitors of microsomal prostaglandin E2 synthase-1

Article abstract of DOI:10.1016/j.bmcl.2010.09.129

Microsomal prostaglandin E₂ synthase (mPGES-1) represents a potential target for novel analgesic and anti-inflammatory agents. High-throughput screening identified several leads of mPGES-1 inhibitors which were further optimized for potency and

Full text of DOI:10.1016/j.bmcl.2010.09.129

Bioorganic & Medicinal Chemistry Letters 20 (2010) 6978–6982
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Biarylimidazoles as inhibitors of microsomal prostaglandin E2 synthase-1
⇑
Tom Y. H. Wu, Hélène Juteau , Yves Ducharme, Richard W. Friesen, Sébastien Guiral, Lynn Dufresne,
Hugo Poirier, Myriam Salem, Denis Riendeau, Joseph Mancini, Christine Brideau
Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Hwy, Kirkland, Quebec, Canada H9H 3L1
a r t i c l e i n f o
a b s t r a c t
Article history:
Microsomal prostaglandin E2 synthase (mPGES-1) represents a potential target for novel analgesic and
anti-inflammatory agents. High-throughput screening identified several leads of mPGES-1 inhibitors
which were further optimized for potency and selectivity. A series of inhibitors bearing a biaryl imidazole
scaffold exhibits excellent inhibition of PGE2 production in enzymatic and cell-based assays. The synthe-
sis of these molecules and their activities will be discussed.
Received 24 August 2010
Revised 23 September 2010
Accepted 24 September 2010
Available online 19 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
mPGES-1
Inhibitor
Biarylimidazole
PGE2
Inflammation
Inducible microsomal prostaglandin E2 synthase-1 (mPGES-1)
appears to be the predominant synthase involved in cyclooxygen-
ase-2 (COX-2) mediated PGE2 production.1 Mice deficient in
mPGES-1 show both a reduction in the production of inflammatory
PGE2 and a decrease in inflammatory responses in the collagen-in-
duced arthritis model.2,3 Furthermore, mPGES-1 knock-out mice
exhibited no thrombogenesis nor blood pressure changes.4 Thus,
mPGES-1 inhibitors may achieve coxib-like efficacy in relieving
pain and inflammation, while avoiding the adverse cardiova-
scular consequences associated with COX-2 mediated PGI2
suppression.
An indole carboxylic acid series of mPGES-1 inhibitors derived
from the FLAP (5-lipoxygenase activating protein) inhibitor,
MK-886, has been previously described.5 However, this series
suffered from high protein binding, which resulted in decreased
potency in cells. Hence, high-throughput screenings were carried
out to search for other molecular scaffolds that may address this
issue. The assay involved a 30-s mPGES-1 enzymatic reaction fol-
lowed by detection of PGE2 using EIA (enzyme immune assay).6
Compound 2 was identified as a moderately potent mPGES-1
inhibitor (IC50 = 660 nM; Table 1). In IL-1b stimulated A549 epithe-
lial lung carcinoma cells in presence of 2% and 50% FBS, compound
2 inhibited the production of PGE2 (IC50 = 3100 and 7000 nM,
relationship (SAR) studies were initiated on this series of
compound.
The biarylimidazole scaffold could be divided into four
segments for SAR analysis: the 2-imidazole position, the central
imidazole ring, the 4-imidazole position, and the 5-imidazole
position. At the 2-imidazole position, three compounds have been
prepared. Compound 1 which contains a mono-ortho-cyanophenyl
(IC50 = 1400 nM) and compound 3 with a bis-ortho-cyanofluoro
phenyl (IC50 = 1000 nM) showed less affinity for the mPGES-1 en-
zyme (Table 1). Hence, the inhibitors described hereafter all con-
tain the bis-ortho-chlorofluoro substitution pattern at the 2-
imidazole position as in compound 2 (IC50 = 660 nM).
Moving the nitrogen on the central imidazole ring led to
reduced activity against mPGES-1 (Table 2). Replacement of the
central imidazole ring with an oxadiazole resulted in the complete
loss of activity (compound 5). A triazole derivative (compound 6)
showed superior inhibition in both the enzymatic (mPGES-1) and
whole cell (A549) assays. These preliminary results suggest that
the position of the H-bond donating NH is important for mPGES-1
activity.
For the 4-imidazole position, SAR studies show that para-
relationship between the imidazole and R3 is better than meta-
and ortho- (data not shown). Hydrophobic groups are generally
tolerated at the R3 position (Table 3). Added flexibility of the linker
resulted in lost of potency as can be seen with the alkyne linkage
(compound 14; IC50 = 8 nM) which is superior over the alkene
respectively) but not PGF2 (data not shown). Given its low
a
molecular weight and structural simplicity, structural–activity
(compound 12; IC50 = 35 nM) and the alkane (compound 13; IC50
150 nM). However, any polar substitutions on the phenyl alkyne
=
⇑
Corresponding author. Tel.: +1 514 428 8687; fax: +1 514 428 4900 (H.J.).
E-mail address: helene_juteau@merck.com (H. Juteau).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.09.129

T. Y. H. Wu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6978–6982
6979
Table 1
SAR at the 2-imidazole position
X
3
N
4
2 R1
5
N
H1
Entry
R1
X
mPGES-1
IC50 (nM)
a
NC
1
Br
1400
660
Cl
2
3
Cl
Cl
F
NC
1000
F
a
Mean of two or more experiments.
Table 2
Replacing the central imidazole ring
X
Cl
R2
F
Entry
R2
X
mPGES-1
IC50 (nM)
A549 PGE2
a
(2%/50% FBS)
a
IC50 (nM)
N
2
Cl
660
3100/7000
N
H
H
N
4
5
Br
Br
3700
N/A
N/A
N
O
N
>30,000
N
N
6
Br
110
620/1900
N
N
H
a
Mean of two or more experiments.
(e.g., carboxylic acid, amide, sulfone, sulfonamide, and tertiary
alcohol, compounds 15a–e) led to the complete loss of enzyme
inhibition. Although polar groups are not tolerated at all in the
R3 region of the inhibitors, introduction of a nitrogen atom on
the 4-phenyl ring boosted cellular activities of PGE2 synthesis inhi-
bition, as exemplified by comparing compound 16 (Table 4) with
compound 14 (Table 3). Subsequent derivatization all contained
a triple bond linker extending from the 4-pyridyl group. Non-polar
substituents on the phenyl alkyne afforded good mPGES-1 inhibi-
tors, as did cyclohexyl (19) and cyclohexenyl (20) alkynes. The
smaller cyclopropyl alkyne moiety (21) gave an inhibitor with
slightly decreased potency, while the terminal alkyne analog (22)
showed dramatically reduced potency. More polar heterocycle
substituted alkynes were less potent inhibitors as well (compound
23).
Addition of a substituent at the 5-imidazole position affected
mPGES-1 activity (Table 5). In general, electron-withdrawing
groups further increased the enzymatic potency (compounds 24

6980
T. Y. H. Wu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6978–6982
Table 3
Table 4
SAR extending from the 4-phenyl group
SAR extending from the 4-pyridyl group
R3
R4
Cl
Cl
3
N
3
N
N
4
4
2
2
5
5
N
N
H1
H1
F
F
R3
mPGES-1
IC50 (nM)
A549 PGE2
Entry
R4
mPGES-1
IC50 (nM)
A549 PGE2
Entry
a
a
(2%/50% FBS)
(2%/50% FBS)
a
a
IC50 (nM)
IC50 (nM)
Cl
2
7
660
320
3100/7000
16
23
29/520
O
S
2100/27,000
N
17
480
410/1800
8
9
180
1700/27,000
O O
S
ortho-9
meta-4
43/610
64/640
Cl
1400
>5000/>50,000
18a–c
19
para-31
28/280
10
11
12
110
570
35
380/8700
33
290/620
1600/19,000
190/3300
20
13
82/400
13
14
150
8
920/13,000
280/3200
21
22
170
350/1800
2500
3300/4000
S
23
940
440/1400
N
Y
a
15a–e
>5000
NA
Mean of two or more experiments.
Y = CO2H, CONH2,
SO2CH3, SO2NH2, C(CH3)2OH
30 were then condensed with amidine 31 in refluxing aqueous
KHCO3/THF.10 The amidine was prepared in a separate reaction by
addition of LHMDS to the corresponding benzonitrile, followed by
cleavage of the silyl groups under aqueous acidic conditions.11 The
resulting imidazoles 32 were coupled with alkynes under standard
Sonogashira coupling conditions. Compounds 33 were brominated
through an electrophile substitution using N-bromosuccinimide,
followed by aqueous workup, to give the desired 5-bromo-biarylim-
idazoles 34.
In summary, the present study demonstrates that biarylimidaz-
ole can serve as an excellent scaffold to design potent and selective
mPGES-1 inhibitors with good rat pharmacokinetic properties.
Even though this series still display a large serum shift, probably
due to their high lipophilicity, several biarylimidazole inhibitors
are less shifted in presence of serum proteins when compared
to the indole carboxylic acid series.5 In HWBA, the activity of
compound 27 is approaching that of extensively-characterized
COX-2 inhibitors rofecoxib and etoricoxib. It remains to be seen
if inhibitors of mPGES-1 will demonstrate equivalent efficacy in
inflammatory pain.
a
Mean of two or more experiments.
and 25). Selected inhibitors were also tested in the human whole
blood assay (HWBA) for inhibition of lipopolysaccharide-induced
PGE2 production.7 Compound 25, containing a bromo substituent
on the 5-imidazole position, showed an IC50 of 1.6
which is only threefold less active than rofecoxib (IC50 = 0.53
and 1.5-fold less active than etoricoxib (IC50 = 1.1
M).8,9
Compound 25 also showed excellent bioavailability (127%) and a
half-life of 4.8 h in rats (PO: 20 mpk in 60% PEG 200; IV: 5 mpk in
80% PEG 200). Inhibitors bearing a triazole (e.g., compound 28) were
not pursued further, since they generally exhibited lower potencies
compared with the 5-bromo imidazoles.
The synthesis of compound 25 and similar biarylimidazole
analogs is described in Scheme 1. Starting from commercially
available arylmethylketones 29, alpha bromination using bromine
under acidic conditions gave alpha-bromoketones 30. Intermediates
l
M in the HWBA,
l
M)
l

T. Y. H. Wu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6978–6982
6981
Table 5
SAR at the 5-imidazole position
Cl
3
N
N
4
2
R5
N
5
H1
F
R5
mPGES-1
IC50 (nM)
A549 PGE2
HWBA IC50
(nM)
a
Entry
a
(2%/50% FBS)
a
IC50 (nM)
16
24
25
26
H
Cl
Br
CH3
23
5
1
29/520
25/480
13/160
21/340
3300
6800
1600
4800
20
27
180
160/700
N/A
OH
Cl
28
16
130/850
9500
N
N
N
N
H
F
a
Mean of two or more experiments.
O
O
H2N
NH
Cl
Br
+
b
a
F
Br
X
Br
Br
X
29
30
31
R
Cl
Cl
X
X
N
N
c
N
H
N
H
R
F
F
32
33
R
Cl
d
X
N
N
H
Br
F
X = C or N
R = aryl or alkyl
34
Scheme 1. Reagents and conditions: (a) Br2, HBr, AcOH, 0–40 °C, 1 h (54–74%); (b) KHCO3 aq, THF, reflux, 3 h (50–70%); (c) Pd(PPh3)4, CuI, Et3N, DMF, 65 °C, 18 h (50–80%);
(d) NBS, CCl4, rt, 2 h; 1% HBr aq (65–85%).
2. Uematsu, S.; Matsumoto, M.; Takeda, K.; Akira, S. J. Immunol. 2002, 168, 5811.
3. Trebino, C. E.; Stock, J. L.; Gibbons, C. P.; Naiman, B. M.; Wachtmann, T. S.;
References and notes
Umland, J. P.; Pandher, K.; Lapointe, J. M.; Saha, S.; Roach, M. L.; Carter, D.;
Thomas, N. A.; Durtschi, B. A.; McNeish, J. D.; Hambor, J. E.; Jakobsson, P. J.;
1. Murakami, M.; Naraba, H.; Tanioka, T.; Semmyo, N.; Nakatani, Y.; Kojima, F.;
Ikeda, T.; Fueki, M.; Ueno, A.; Oh, S.; Kudo, I. J. Biol. Chem. 2000, 275, 32783.

6982
T. Y. H. Wu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6978–6982
Carty, T. J.; Perez, J. R.; Audoly, L. P. Proc. Natl. Acad. Sci. U.S.A. 2003, 100,
9044.
4. Cheng, Y.; Wang, M.; Yu, Y.; Lawson, J.; Funk, C. D.; Fitzgerald, G. A. J. Clin.
Invest. 2006, 116, 1391.
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.
5. Riendeau, D.; Aspiotis, R.; Ethier, D.; Gareau, Y.; Grimm, E.; Guay, J.; Guiral, S.;
Juteau, H.; Mancini, J.; Méthot, N.; Rubin, J.; Friesen, R. W. Bioorg. Med. Chem.
Lett. 2005, 15, 3352.
6. Masse, F.; Guiral, S.; Fortin, L. J.; Cauchon, E.; Ethier, D.; Guay, J.; Brideau, C. J.
Biomol. Screen. 2005, 10, 599.
9. Riendeau, D.; Percival, M. D.; Brideau, C.; Charleson, D.; Dubé, D.; Ethier, D.;
Falgueyret, J.-P.; Friesen, R. W.; Gordon, R.; Greig, G.; Guay, J.; Mancini, J.;
Ouellet, M.; Wong, E.; Xu, L.; Boyce, S.; Visco, D.; Girard, Y.; Prasit, P.; Zamboni,
R.; Rodger, I. W.; Gresser, M.; Ford-Hutchinson, A. W.; Young, R. N.; Chan, C.-C.
J. Pharmacol. Exp. Ther. 2001, 296, 558.
7. Brideau, C.; Kargman, S.; Liu, S.; Dallob, A. L.; Ehrich, E. W.; Rodger, I. W.; Chan,
C.-C. Inflamm. Res. 1996, 45, 68.
10. Li, B.; Chiu, C. K.-F.; Hank, R. F.; Murry, J.; Roth, J.; Tobiassen, H. Org. Process Res.
Dev. 2002, 6, 682.
8. 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.
11. Thurkauf, A.; Hutchison, A.; Peterson, J.; Cornfield, L.; Meade, R.; Huston, K.;
Harris, K.; Ross, P. C.; Gerber, K.; Ramabhadran, T. V. J. Med. Chem. 1995, 38,
2251.