Discovery of disubstituted phenanthrene imidazoles as potent, selective and orally active mPGES-1 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2009.08.085

Phenanthrene imidazoles 26 and 44 have been identified as novel potent, selective and orally active mPGES-1 inhibitors. These inhibitors are significantly more potent than the previously reported chlorophenanthrene imidazole 1 (MF63) with a human whole blood IC₅₀ of 0.20 and 0.14 μM, respectively. It exhibited a significant analgesic effect in a guinea pig hyperalgesia model at oral doses as low as 14 mg/kg. Both active and selective mPGES-1 inhibitors (26 and 44) have a relatively distinct pharmacokinetic profile and are suitable for clinical development. Crown Copyright

Full text of DOI:10.1016/j.bmcl.2009.08.085

Bioorganic & Medicinal Chemistry Letters 19 (2009) 5837–5841
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of disubstituted phenanthrene imidazoles as potent, selective
and orally active mPGES-1 inhibitors
*
André Giroux , Louise Boulet, Christine Brideau, Anh Chau, David Claveau, Bernard Côté, Diane Ethier,
Richard Frenette, Marc Gagnon, Jocelyne Guay, Sébastien Guiral, Joseph Mancini, Evelyn Martins,
Frédéric Massé, Nathalie Méthot, Denis Riendeau, Joel Rubin, Daigen Xu, Hongping Yu, Yves Ducharme,
Richard W. Friesen
Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Hwy, Kirkland, Que., Canada H9H 3L1
a r t i c l e i n f o
a b s t r a c t
Article history:
Phenanthrene imidazoles 26 and 44 have been identified as novel potent, selective and orally active
Received 20 July 2009
Revised 24 August 2009
Accepted 25 August 2009
Available online 28 August 2009
mPGES-1 inhibitors. These inhibitors are significantly more potent than the previously reported chlor-
ophenanthrene imidazole 1 (MF63) with a human whole blood IC50 of 0.20 and 0.14 lM, respectively.
It exhibited a significant analgesic effect in a guinea pig hyperalgesia model at oral doses as low as
14 mg/kg. Both active and selective mPGES-1 inhibitors (26 and 44) have a relatively distinct pharmaco-
kinetic profile and are suitable for clinical development.
Keywords:
mPGES-1
Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
Inhibitors
Phenanthrene imidazole
Activity
Pharmacokinetic
Prostaglandin E2 (PGE2), a prostanoid, is widely recognized as a
key mediator in fever, pain and the inflammatory response.1 PGE2
is produced by sequential conversion of arachidonic acid to PGH2
by cyclooxygenases (COX-1/COX-2) followed by the isomerization
of PGH2 to PGE2 by mPGES-1, a microsomal, glutathione-depen-
dent, inducible enzyme.2 Selective inhibition of mPGES-1 would
be expected to preclude PGE2 production3 without any potential
Herein, we report the identification of two potent, selective and
orally active phenanthrene imidazole inhibitors (compounds 26
and 44), showing an improved pharmacokinetic profile and supe-
rior in vitro and in vivo activities compared to inhibitor 1.11
Based on the discovery of inhibitor 1 (MF63), both the phenan-
threne imidazole core and the phenyl ring bearing a bis-cyano
ortho substitution is optimal and is crucial for potency. Our initial
medicinal chemistry approach was to find the optimal structure–
activity relationship (SAR) for the substitution of the phenanthrene
backbone. For ease of synthesis, the previously reported 2-chloro-
6-fluorophenyl group was selected in this initial study. As we can
see from the Table 1, substitution at the 60-position leads to more
active inhibitors (compounds 3 and 5) compared to 40, 50 and 70
substituted analogues (compounds 4, 6, 7 and 8). The bromo
substituted inhibitor 5 has increased enzyme activity compared
to the chloro analogue (compound 3) and maintained whole cell
activity. Substitution at the 90-position is tolerated, as observed
in the symmetrical dibromo inhibitor 9. Since this inhibitor is equi-
potent to the mono substituted analogue 5, we decided to further
characterize this position through SAR. For ease of synthesis, the
60-bromo substituent was selected and a variety of 90-substituted
analogues were generated. In order to explain the phenomena
we observed, a selection of protypical inhibitors are described in
Table 1. Although equipotent on the enzyme, the presence of a
lipophilic isopropyl group at 90 leads to a diminished potency in
the whole cell assay (compound 10). The introduction of a group
side effects, resulting from the inhibition of PGD2, PGF2
a, PGI2
and TXA2 biofunctions.4
We recently reported that the phenanthrene imidazole
1
(MF63) is a potent and selective mPGES-1 inhibitor (Fig. 1).5 This
inhibitor is significantly more potent than our previously reported
mPGES-1 inhibitors6 with an intrinsic inhibitory potency7 of
IC50 = 0.001
thermore, it has a PGE2 whole cell inhibition8 in A549 cells of
0.42 M (see Fig. 1) and a human whole blood (HWB) activity of
1.3
lM on the recombinant human mPGES-1 enzyme. Fur-
l
l
M.9 It also exhibited an analgesic effect in a guinea pig hyper-
algesia model when dosed orally at 100 mg/kg.10
Despite its interesting activity profile, the phenanthrene imid-
azole 1 demonstrated less than desirable pharmacokinetics which
precluding its development. The mPGES-1 inhibitor 1 has a short
half life of 1.5 h when dosed at iv in rats. A short half life was also
observed in the rhesus monkey (1.3 h).
* Corresponding author. Tel.: +1 514 428 3451; fax: +1 514 428 4900.
E-mail address: andre_giroux@merck.com (A. Giroux).
0960-894X/$ - see front matter Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.08.085

5838
A. Giroux et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5837–5841
Cl
NC
IC50 (µM)
N
h-mPGES-1 0.001
A549 PGES 0.42
N
H
HWBA
1.3
NC
1 (MF63)
O
Cl
NC
NC
NC
N
N
F
N
H
N
H
NC
HO
HO
26
44
Figure 1. mPGES-1 inhibitors.
Table 1
Table 2
mPGES-1IC50 data for mono- and bis-substituted phenanthrene imidazoles
mPGES-1 IC50 data for 90-substituted chlorophenanthrene imidazoles
R1
6'
Cl
NC
Cl
N
N
N
H
N
H
NC
R1
F
9'
R2
Compd
R1
mPGES-1
inhibition
A549, 50%
FBS PGE2
HWB PGE2
Compd
R1
R2
mPGES-1
inhibition
A549, 50%
FBS PGE2
a
IC50
(lM)
a
IC50
(
l
M)
1
18
19
20
H
0.001
0.004
0.009
0.001
0.42
0.034
0.11
1.3
1.4
>10
0.38
HO(CH3)2C
MeSO2
NCCH2CH2CH2O
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
H
H
H
H
H
H
H
H
0.036
0.005
0.011
0.002
0.11
0.025
0.008
0.003
0.004
0.006
0.008
0.001
0.007
0.007
0.122
0.045
2.6
0.71
4.3
60-Cl
50-Cl
60-Br
40-Br
50-Br
70-Br
60-Br
60-Br
60-Br
60-Br
60-Br
60-Br
60-Me
60-COMe
0.038
1.1
5.0
21
0.001
0.021
0.38
N CH2CH2O
7.4
3.0
1.0
2.0
0.73
0.33
0.45
0.28
1.1
22
23
24
25
26
p-MeSO2C6H4
MeOCH2C„C
3-PyridylC„
4-PyridylC„C
HO(CH3)2CC„C
0.002
0.002
0.001
0.001
0.001
0.045
0.060
0.057
0.075
0.013
0.41
1.1
0.53
0.39
0.20
90-Br
90-iPr
90-OMe
90-COMe
90-C(CF3)2OH
90-C(CH3)2OH
90-Me
OH
27
0.001
0.027
0.26
60-COMe
>50
2.3
90-C(CH3)2OH
90-C(CF3)2OH
a
Values are means of at least two experiments.
a
Values are means of at least two experiments.
viously disclosed.5 Looking at the SAR we can observe that the
presence of a tertiary alcohol (compound 18) or a methylsulfonyl
group (compound 19) provides inhibitors with good whole cell
potencies, however, they are highly shifted in presence of protein.
Then we examined a number of phenol ether inhibitors exempli-
fied by inhibitors 20 and 21. In general, all analogues benefited
from increased A549 whole cell and human whole blood activities.
Rigidifying the substituent by the introduction of a phenyl or an al-
kyne group was also explored. Reduced whole cell and human
whole blood activities were seen with methyl phenyl sulfone 22,
methyl propargyl ether 23, 3-ethynylpyridyl 24 and the 4-ethynyl-
pyridyl 25. On the other hand, tertiary alcohol substituted alkynes
demonstrated increased whole cell and whole blood activities
(compounds 26 and 27). Phenanthrene imidazole 26 proved to be
the most potent mPGES-1 inhibitor we have prepared thus far. It
containing a heteroatom such as a methoxy, a methylketone or a
tertiary alcohol (compounds 11–14) increases activity in the whole
cell assay. Conversely, the presence of two lipophilic substituents
such as in compound 15 or two heteroatom containing groups
(compound 17) is detrimental to the activity. The right balance
of one lipophilic group and one slightly polar substituent in an
unsymmetrical fashion is optimal and leads to potent inhibitors
having a reduced cellular shift. Based on these observations we fur-
ther investigated the SAR at the 90-position with the less lipophilic
chloro substituent at the 60-position and the optimal bis-orthocy-
ano group found in mPGES-1 inhibitor 1 (MF63).
The structure–activity relationship of the 60-chloro-90-substi-
tuted inhibitors is summarized in Table 2. These analogues contain
the more potent bis-cyanophenyl group found inhibitor 1 and pre-

A. Giroux et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5837–5841
5839
Table 3
has a human whole blood activity of 0.20
TXB2, PGF2
l
M with no concomitant
SAR at the 60- and 90-positions of the phenanthrene imidazole
a
and PGI2 inhibitions (Table 5) and PGD2 inhibition
(data not shown).
R2
The general synthetic route for phenanthrene imidazole ana-
logues is outlined in Scheme 1. The synthesis started with a Perkin
condensation of 4-bromophenylacetic acid 28 with 4-chloro-2-
nitrobenzaldehyde to afford the (E)-arylcinnamic acid 29 in 60%
yield.12 Nitro reduction with iron provided the amine 30 which
NC
N
N
H
NC
R1
underwent
a diazotization and a subsequent intramolecular
Compd
R1
R2
mPGES-1
inhibition
HWB
PGE2
Rat
t1/2 (h)
Pschorr13 cyclization resulting in the formation of the phenan-
threne 31 in 95% yield. Oxidation and decarboxylation in the pres-
ence of chromium (IV) oxide in acetic acid at 110 °C afforded the
corresponding quinone 32 in 60% yield. The core of the molecule
was assembled by the reaction of phenanthrenedione 32, 2,6-dib-
romobenzaldehyde and ammonium acetate in acetic acid which
provided the phenanthrene imidazole 33 in 85% yield. The dibromo
intermediate 33 was then treated with CuCN in DMF at 80 °C to af-
ford the bis-nitrile 34 in 80% yield.14 Finally, installation of the ace-
tylinic tertiary alcohol group under Sonogashira conditions
provided the desired target compound 26 in 70% yield.
a
b
IC50
(lM)
HO
HO
26
35
Cl
Et
0.001
0.001
0.2
20
0.37
7.0
HO
HO
36
0.001
0.076
40
The selective mPGES-1 inhibitor 26 demonstrated oral in vivo
efficacy in a LPS-induced hyperalgesia guinea pig model (guinea
pig mPGES-1 whole blood = 0.10 l
M) with a ED50 of 30 mg/kg.10
37
38
Cl
Cl
0.001
0.002
0.20
0.25
14
Pharmacokinetic (PK) studies in rat revealed a long half life of
20 h and slow absorption rate (Cmax @ 6 h). This correlates well
with the rat hepatocyte incubation studies that showed very little
metabolism (3%, see Table 5) after the 2 h incubation period at
37 °C. Similarly, the human hepatocyte incubation studies demon-
strated minimal metabolism (3%). The main cytochrome P450’s
responsible for metabolism were identified to be the extrahepatic
CYP1A1 and CYP2J2, suggesting a potentially long half life in hu-
mans. Furthermore, excretion studies showed that the phenan-
threne imidazole 26 was mainly eliminated as the parent in the
bile, supporting low metabolism. Although, the phenanthrene
imidazole 26 is selective, potent and orally active, further SAR
studies to identify a mPGES-1 inhibitor with a shorter half life.
8.4
HO
a
Rat half life after single iv dosing at 5 mg/kg.
Values are means of at least two experiments.
b
As shown in Table 3, keeping the propargylic alcohol in place
and modifying the lipophilic group afforded a mean of modulation
for the pharmacokinetics. For example, inhibitor 35 in which the
chloro was replaced by an ethyl group demonstrated a much short-
er half life compared to inhibitor 36. Saturating the triple bond as a
Cl
Br
NH2
Cl
Br
NO2
OH
b
a
c
OH
OH
O
Br
Cl
O
O
28
29
30
Cl
Cl
Br
Br
O
O
d
N
e
OH
N
H
Br
O
Br
Cl
Br
31
32
33
NC
NC
Cl
NC
NC
N
g
f
N
N
H
N
H
HO
Br
34
26
Scheme 1. Reagents and conditions: (a) 4-chloro-2-nitrobenzaldehyde, K2CO3, Ac2O, 100 °C, 60%; (b) Fe, AcOH, H2O 50 °C, 96%; (c) (i) NaNO2, NaOH, 0 °C (ii) H2SO4, H2NSO3,
FeCp2, 0 °C, 95%; (d) CrO3, AcOH, 110 °C, 60%; (e) 2,6-dibromobenzaldehyde, NH4OAc, AcOH, reflux, 85%; (f) CuCN, DMF, 80 °C, 80%; (g) 2-methyl-3-butyn-2-ol, Pd(Ph3)4,
iPr2NH, DMF, CuI, 70 °C, 70%.

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A. Giroux et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5837–5841
Table 4
SAR at the 60-position of the 90-(2-methyl-2-propanol) phenanthrene imidazole
R1
NC
NC
N
R2
N
H
HO
R1
R2
mPGES-1 inhibition
HWB PGE2
Rat t1/2 (h)
% Fb
% of Parent remainingc
a
Compd
d
IC50
(lM)
Rat
Human
39
40
41
42
43
44
H
H
H
H
H
F
0.003
0.001
0.0004
0.003
0.0009
0.001
0.35
0.25
0.15
0.29
0.22
0.14
5.5
3.3
4.8
1.3
1.6
2.3
36
85
46
30
76
68
n.d.e
92
>99
O
F3C
O
98
O
8
30
n.d.
n.d.
68
n.d.
n.d.
81
O
O
O
a
b
c
Rat half life after single iv dosing at 5 mg/kg.
Bioavailability in the rat after single po dosing at 20 mg/kg.
% of parent remaining after 2 h of incubation in presence of hepatocytes.
Values are means of at least two experiments.
Not determined.
d
e
mean to introduce a metabolic soft spot provided the potent inhib-
itor 37, however its inherent pharmacokinetics revealed a long half
life of 14 h. Interestingly, the shortened tertiary alcohol found in
inhibitor 38 had in vivo activities comparable to 26. This pharma-
cophore provided an inhibitor with a shorter half life, but unfortu-
nately this inhibitor exhibited CYP 3A4 induction. Encouraged by
these findings and our desire to address this undesired property,
further SAR investigations were initiated while maintaining the
2-methyl-2-propanol group in the hydrophilic region and modify-
ing the lipophilic region (see Table 4).
an increased metabolism compared to inhibitor 26 support our
confidence in avoiding an excessively long half life in humans.
Overall, this inhibitor was found to have excellent in vivo activities,
mPGES-1 enzymatic activity of 0.001
blood activity of 0.14 M. Furthermore, it does not inhibit the bio-
synthesis of PGD2, PGF2 , PGI2 and TXA2. The selective inhibitor 44
lM and a human whole
l
a
is thermally stable as a tosylate salt and showed a fast absorption
rate in rat, reaching Cmax after 1 hour.15 Conversely, the inhibitor
26 had potential stability issues since dehydration of the tertiary
alcohol was detected in thermal stability analysis of several salt
The introduction of a cyclopropylmethyl ether or a 3-trifluo-
robutyl group leads to potent inhibitors with an adequate half life
(compounds 39 and 40). Unfortunately, as previously seen with
phenanthrene imidazole 26, these inhibitors showed little metab-
olism after an incubation period in the presence of human hepato-
cytes. Conversely, the incorporation of a 3-methylbutylether group
(compound 41) led to an inhibitor having a very good in vitro pro-
file and pharmacokinetics, however, it had a high degree of metab-
olism in rat (92%) and human hepatocytes (70%) incubation
studies. Introduction of 2-methylpropylether and cyclopropylethyl
ether groups (compounds 42 and 43) give rise to inhibitors that
possess good overall in vivo activities and good bioavailabilities.
More interestingly, the incorporation of a para-fluoro on the bis-
cyanophenyl ring resulted in the identification of phenanthrene
imidazole 44, our most active mPGES-1 inhibitor to date. The
phenanthrene imidazole 44 has a half life in the rat of 2.3 h and
bioavailability of 68%. In the human hepatocyte metabolism stud-
ies, phenanthrene imidazole 44 was more extensively metabolized
than its predecessors with 81% parent remaining after the 2 h incu-
bation period at 37 °C compared to 97% for the inhibitor 26. The
main cytochrome P450 responsible for the metabolism of 44 is
the hepatic CYP 3A4. The shorter rat half life observed along with
Table 5
Comparative data of mPGES-1 inhibitors 1, 26 and 44
a
Enzyme or cell assay
IC50
(
lM)
1
26
44
Human mPGES-1
Guinea pig mPGES-1 whole blood
Human mPGES-2
TX synthase
A549 cells, PGE2, 50% FBS
A549 cells, PGF2 , 50% FBS
Human whole blood, PGE2
Human whole blood, TXB2
0.001
0.10
>30
3.0
0.42
>40
1.3
0.001
0.10
>30
0.8
0.020
>40
0.0009
n.d.
>30
30
0.010
>40
a
0.20
>40
0.14
>40
>40
In vitro and in vivo data
Rat t1/2 (h)
Rat hepatocyte metabolism
(parent remaining)
Human hepatocyte metabolism
(parent remaining)
Guinea Pig hyperalgesia
model ED50 (mg/kg)
1.5
n.d.
20
97%
2.3
68%
90%
100
97%
30
81%
14
a
Values are means of at least two experiments.

A. Giroux et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5837–5841
5841
OH
OTf
O
OH
OH
OEt
b,c
a
48
B(OH)2
O
d
O
OH
O
45
47
46
O
O
O
f
O
e
OEt
O
O
H
O
Br
Br
HO
HO
49
50
51
F
O
O
NC
Br
Br
g
N
N
F
F
N
H
N
H
NC
HO
HO
52
44
Scheme 2. Reagents and conditions: (a) 2-cyclopropylethyl methanesulfonae, K2CO3, acetone, reflux, 78%; (b) TiCl4, ClCOCO2Et, CH2Cl2, ꢀ78 °C, 53%; (c) Tf2O, Et3N, CH2Cl2,
ꢀ78 °C, 99%; (d) 48, PdCl2(dppf)ꢁCH2Cl2, K2CO3, DME, 70 °C; (e) (i) NaOH, H2O, MeOH, THF, rt (ii) CDI, CH2Cl2, 50 °C, rt (iii) TiCl4, CH2Cl2, rt, 0 °C; (f) 51, NH4OH, AcOH, 85 °C,
(60%, five steps); (g) CuCN, DMF, 80 °C, 80%.
Wachtmann, T. S.; 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.; Carty, T. J.; Perez, J. R.; Audoly, L. P. Proc. Natl. Acad. Sci. U.S.A.
forms. The mPGES-1 inhibitor 44 demonstrated enhanced oral
in vivo efficacy over its predecessors in the LPS-induced hyperalge-
sia guinea pig model with a ED50 of 14 mg/kg (see Table 5).
The synthesis of 44 started with the mono-alkylation of com-
mercially available resorcinol 45 with 2-cylclopropylethyl meth-
anesulfonate. The phenol 46 underwent a Friedel–Crafts reaction
in the presence of ethyl oxalyl chloride. The intermediate was then
submitted to triflic anhydride in the presence of triethylamine in
dichloromethane affording the corresponding oxalyl ester 47 in
an overall yield of 53%. The biaryl 49 is generated by the palladium
cross-coupling of 47 with the boronic acid 48.16 Ester hydrolysis
under basic conditions followed by activation in the presence of
carbonyl diimidazole and a subsequent Friedel–Crafts reaction pro-
vided the quinone 50. Product elaboration was accomplished as
described previously by the addition of the quinone 50 in the pres-
ence of 2,6-dibromo-4-fluorobenzaldehyde17 51 and ammonium
acetate affording the phenanthrene imidazole 52 in an overall yield
of 60% for the five reaction steps. Finally, the cyano groups were
incorporated by reacting the dibromo precursor 52 with CuCN in
DMF at 80 °C which provided the target inhibitor 44 in 80% yield
(see Scheme 2).
In summary, we have identified two potent, selective and orally
active mPGES-1 phenanthrene imidazole inhibitors (compounds
26 and 44). These new inhibitors showed in vitro and in vivo superi-
ority over the previously reported phenanthrene imidazole 1. In par-
ticular, a 10-fold increase in whole blood activity and in vivo efficacy
is demonstrated with the mPGES-1 inhibitor 44. Finally, the mPGES-
1 inhibitors 26 and 44 demonstrate distinct pharmacokinetic pro-
files where both are suitable for further pre-clinical studies.
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dosing in rats at 20 mg/kg in PEG400, the respective tmax were 1 h and greater
than 6 h for 38 and 20, respectively.
16. The boronic acid 48 is prepared by first forming the Grignard of 3-bromobenzyl
bromide in the presence of magnesium in ether followed by the addition of
acetone. The tertiary alcohol intermediate is then treated with n-butyllithium
and trimethyl borate providing after acidic treatment the boronic acid 48 in a
70% yield.
References and notes
17. Synthesis of benzaldehyde 51 is as follows: Diazotization of 4-amino-2,6-
dibromotoluene in the presence of sodium nitrite and hydrochloric acid
followed by fluoronation with HPF6 at 200 °C provides the 2,6-dibromo-4-
fluorotoluene in 85% yield. Bromination with NBS followed by oxidation in the
presence of trimethylamine oxide (TMNO) and DMSO in dichloromethane
affords the aldehyde 51 in 80% yield.
1. Funk, C. D. Science 2001, 294, 1871.
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2004, 279, 33684; (b) Trebino, C. E.; Stock, J.; Gibbons, C. P.; Naiman, B. M.;