Discovery of substituted-2,4-dimethyl-(naphthalene-4-carbonyl)amino-benzoic acid as potent and selective EP4 antagonists

Article abstract of DOI:10.1016/j.bmcl.2015.11.023

A novel series of EP4 antagonists, based on a quinoline scaffold, has been discovered. Medicinal chemistry efforts to optimize the potency of the initial hit are described. A highly potent compound in a clinically relevant human whole blood assay was iden

Full text of DOI:10.1016/j.bmcl.2015.11.023

Bioorganic & Medicinal Chemistry Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of substituted-2,4-dimethyl-(naphthalene-4-carbonyl)
amino-benzoic acid as potent and selective EP4 antagonists
⇑
Maria-Jesus Blanco , Tatiana Vetman, Srinivasan Chandrasekhar, Matthew J. Fisher, Anita Harvey,
Daniel Mudra, Xu-Shan Wang, Xiao-Peng Yu, Matthew A. Schiffler, Alan M. Warshawsky
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of EP4 antagonists, based on a quinoline scaffold, has been discovered. Medicinal chemistry
efforts to optimize the potency of the initial hit are described. A highly potent compound in a clinically
relevant human whole blood assay was identified. Selectivity and pharmacokinetic profiles of this
compound are discussed.
Received 19 August 2015
Revised 5 November 2015
Accepted 8 November 2015
Available online xxxx
Ó 2015 Published by Elsevier Ltd.
Keywords:
Arthritis pain
EP4 receptor antagonist
Prostaglandin E2
Human whole blood assay
Arthritis pain affects millions of patients in the United States
alone and is a leading cause of disability.1,2 Treatments often
include NSAIDs (nonsteroidal anti-inflammatory drugs) or
cyclooxygenase 2 (COX-2) inhibitors, which provide broad anal-
gesic efficacy but also carry substantial cardiovascular (CV) and
gastrointestinal (GI) risk.3 Arthritis patients with a poor cardiovas-
cular profile, such as hypertension, or an intolerance to NSAIDS
may be precluded from using these types of analgesics. Thus, there
is a need for safer alternative therapies for osteoarthritis and
rheumatoid arthritis pain.
Multiple literature reports in the past decade demonstrate that
prostaglandin E2 (PGE2) plays an important role in the pathogen-
esis of arthritis pain and that inhibition of PGE2 production either
by using NSAIDs or COX-2 inhibitors provides predictable and
marketable efficacy. PGE2 is known to exert its effects through four
G-protein coupled receptors (GPCR) receptors, EP1-4. Studies with
selective prostaglandin receptor knockout animals have shown
that EP4 is the primary receptor involved in joint and inflammatory
pain.4 Hence, a selective EP4 antagonist may be useful in treating
arthritis pain. In addition, it has been suggested that since EP4
antagonism does not interfere directly with the biosynthesis of
prostanoids, such as PGE2, prostacyclin (PGI2), and thromboxane
A2 (TxA2),5–7 a selective EP4 antagonist may not exhibit the CV
and GI side effects seen with NSAIDs and COX-2 inhibitors.8
This therapeutic potential has triggered significant efforts in the
pharmaceutical industry that have led to the discovery of a variety
of EP4 antagonists.9 Several examples of compounds advancing to
clinical studies have been reported, in particular CJ-02342310,11 (1)
and PGN-153112 (2) have been studied extensively (Fig. 1).
From a drug discovery perspective, in vitro assays have been
developed to understand both potency, and prostanoid selectivity,
as well as function of EP4 in a native tissue assay. For example,
Murase et al reported13 that CJ-042794 (3, Fig. 1) competitively
inhibited PGE2-evoked elevations of intracellular cAMP levels in
HEK293 cells overexpressing human EP4 receptor. Similar assays
for the other EP receptor subtypes have been reported as well. It
is also known that EP4 antagonism modulates PGE2 mediated pro-
duction of TNF
whole blood (hWB).13 In this assay, CJ-042794 reliably reversed
the inhibitory effects of PGE2 on LPS-induced TNF production in
a in lipopolysaccharide (LPS) stimulated human
a
a concentration-dependent manner. The whole blood assay pro-
vides a measure of EP4 antagonist function in a clinically relevant
tissue and provides a means to assess the potential for in vivo
activity.14,15 This type of assay provides both a measure of preclin-
ical potency and an effective target engagement biomarker to
facilitate clinical translation.16
In this manuscript we will disclose our efforts towards the
identification and optimization of substituted 2,4-dimethyl-
(quinoline-4-carbonyl)amino-benzoic acid derivatives as EP4
antagonists. During the course of our research, commercially avail-
able quinoline 5 (Table 1) was identified as a hit from screening. It
had reasonable in vitro antagonist activity (128 nM) at hEP4, with
⇑
Corresponding author. Tel.: +1 317 433 612.
E-mail address: blanco_maria@lilly.com (M.-J. Blanco).
http://dx.doi.org/10.1016/j.bmcl.2015.11.023
0960-894X/Ó 2015 Published by Elsevier Ltd.
Please cite this article in press as: Blanco, M.-J.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.11.023

2
M.-J. Blanco et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
O
O
N
O
S
O
N
N
O
N
O
H
O
O
N
S
N
Na+
N
H
O
H
1
2
O
Cl
O
O
N
H
OH
OH
O
F
O
HO
H
HO
3
4
Figure 1. Examples of EP4 antagonists and PGE2 (4).
Table 1
Compound profile for initial hit from screening
N
N
O
O
O
NH
N
S
N
N
H
O
Property
H
N
1
5
MW
352.44
512 + 254 (5)
128 42.8 (7)
0.26
>30000 (3)
64
491.61
hEP4 binding Ki (nM)a
hEP4 functional cAMP IC50 (nM)a,b
LEANc
448 276 (8)
11.7 8 (6)
0.23
hWB IC50 (nM)d
Rat hepatic microsome metabolism (%)
Human hepatic microsome metabolism (%)
1520 1030 (82)
5
2
71
Measured aqueous solubility, pH = 6, (mg/mL)
<0.001
6.28
0.977
3.55
cLogPe
a
b
c
Data is shown as Ki or IC50 values + SEM and number of experiments (n) in parenthesis.
The EP4 functional assay measured the inhibition of PGE2-induced cAMP accumulation in HEK 293 cells.
LEAN values based on functional activity. LEAN is an internal metric for ligand efficiency and is defined as ꢀlog(IC50)/number of non-hydrogen atoms.
d
Results are expressed as the geometric mean standard deviation; n = number of independent determinations. The standard deviation is calculated by the delta method,
being SDlogIC50 ꢁ geometric mean ꢁ ln(10).
e
cLogP, calculated using Marvin and calculator plugin freeware (www.chemaxon.com, ChemAxon Kft, Budapest, Hungary).
a LEAN ratio17,18 of 0.26 [LEAN is an internal metric for ligand effi-
ciency and is defined as ꢀlog(IC50)/number of non-hydrogen
atoms]. Unfortunately, compound 5 was inactive in the hWB assay.
Furthermore, high lipophilicity (cLogP > 6) and significant in vitro
metabolic liability in rodent microsomes (>60%, Table 1), suggested
poor PK properties for this compound. Understanding these prop-
erty issues, we decided to launch a medicinal chemistry effort to
explore optimization of this scaffold.
Our overall effort was influenced by the expectation that the
relationship between the human whole blood activity and the
plasma exposure profile would ultimately drive clinical efficacy.
This approach relied on the ability of a compound to maintain pro-
jected human plasma concentrations in excess of the hWB IC50
value. The focus of our SAR effort was to understand the potential
of this series to achieve potent hWB activity, while incorporating
modifications to obtain a suitable PK profile.
We also explored changes to the central core of the molecule to
include naphthalene analogs. Structures of these compounds are
shown in Table 2. Known EP4 antagonist 1 and initial hit 5 are also
highlighted for comparison in Table 2. Compounds were character-
ized initially with their in vitro binding activity and functional
potencies and then evaluated in the more demanding hWB assay
as warranted.
As shown in Table 2, introduction of a benzoic acid was not tol-
erated as an R2 substituent (6a). However, introduction of the same
moiety as an R1 substituent led to potent compound (6b) with a
functional activity of 11 nM. Compound 6b showed activity in
the hWB assay comparable to clinical compound 1. Further modi-
fication to a benzylic alcohol as R2 substituent (6c, 6d) provided
slight improvements in the functional as well as in hWB assay.
The incorporation of a benzoic acid in R1 with either para- or meta-
substitution seemed to be beneficial for the binding and functional
activity, giving >10-fold improvement over 5. Remarkably, meta-
benzoic acid analog 6d was >5-fold more potent in hWB activity
than standard 1.
PGE2 (4, Fig. 1), the endogenous ligand of EP4, contains both
hydroxyl and carboxyl functional groups indicating that significant
polarity is tolerated by the receptor. We hypothesized that intro-
duction of polar groups in compound 5, might have positive effect
in modulating the overall lipophilicity addressing metabolism and
solubility issues while potentially affording more activity.
In the naphthalene scaffold, we observed similar trends for the
phenyl R2 analogs. Compounds 7a and 7b demonstrated robust
binding and functional activity that translated well to hWB activity
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M.-J. Blanco et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
3
Table 2
SAR efforts to optimize initial hit
R1
HN
R 1
HN
O
O
HN
O
N
R2
R 2
N
6
7
5
R1
R2
hEP4 Kia (nM)
hEP4 cAMP IC50 (nM)
LEAN valuec
hWB IC50 (nM)
cLogDe
a,b
d
Compound
1
5
—
—
—
—
448 276 (8)
512 254 (5)
11.7 8 (6)
128 42.8 (7)
0.23
0.26
1520 1030 (82)
>30,000 (3)
cLogP = 3.08
cLogP = 6.28
O
6a
>19,200
>25,000
—
>30,000 (3)
2.75
OH
O
OH
OH
6b
39.2 36.4 (2)
11.2 2.32 (4)
0.26
1980 1650 (5)
2.88
O
O
O
OH
OH
6c
6d
7a
7b
7c
52.3 (1)
3.08 1.76 (7)
5.20 2.94 (3)
3.48 2.11 (5)
5.65 1.91 (3)
1.11 0.73 (4)
0.26
0.26
0.28
0.27
0.28
501 495 (6)
312 295 (5)
623 244 (3)
577 175 (6)
136 86 (2)
2.11
2.03
3.33
3.24
2.56
O
OH
17 (1)
OH
8.04 4.63 (2)
6.72 6.32 (3)
3.54 0.48 (3)
O
OH
OH
OH
OH
O
OH
OH
7d
7e
1.98 1.24 (3)
3.49 2.7 (10)
2.42 1.1 (5)
3.62 0.74 (3)
0.28
0.27
6.2 4.5 (3)
2.48
3.85
O
Cl
243 116 (6)
a
b
c
Data is shown as Ki or IC50 values + SEM and number of experiments (n) in parenthesis.
The EP4 functional assay measured the inhibition of PGE2-induced cAMP accumulation in HEK 293 cells.
LEAN values based on functional activity. LEAN is an internal metric for ligand efficiency and is defined as ꢀlog(IC50)/number of non-hydrogen atoms.
d
Results are expressed as the geometric mean standard deviation; n = number of independent determinations. The standard deviation is calculated by the delta method,
being SDlogIC50 ꢁ geometric mean ꢁ ln(10).
e
cLogD at pH = 7.4, calculated using Marvin and calculator plugin freeware (www.chemaxon.com, ChemAxon Kft, Budapest, Hungary).
(IC50 ꢂ0.6
l
M). The benzylic alcohol R2 substituent (7c and 7d) led
activity and hWB activity was not apparent. Since the hWB assay
uses a native tissue matrix, additional parameters such as protein
binding and cell type influence the response.
In general, the incorporation of a carboxylic acid group into the
phenyl amide portion of our initial hit compound 5 led to signifi-
cant improvement of the in vitro activity with meaningful transla-
tion to our whole blood assay. Lean values for these compounds
again to improve binding and functional potency. Compound 7d
showed outstanding hWB potency (IC50 ꢂ6 nM), >250 fold more
potent than clinical compound 1. Chlorophenyl substitution also
provided a potent in vitro compound (7e), although the effect on
hWB activity was not as pronounced as with benzylic alcohol 7c.
Noteworthy, a linear correlation between binding or functional
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4
M.-J. Blanco et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
Table 3
Rat in vitro and in vivo ADME profiling
c
c
Compound
hWB (nM)
Rat hepatic microsome metabolisma (%)
Clearance, ivb (mL/min/kg)
po, Cmax (ng/mL)
po, Tmax (h)
% Fb,c
Cmax/IC50
6c
7d
7e
501
6.2
243
<1
<1
7
59.6
23.8
1.9
42.3
85.7
10,900
0.25
0.25
1
3
6
100
0.20
33
104
a
b
c
Microsomal incubation was a 30-min incubation in the presence of rat liver microsomes and NADPH.
Dosed 1 mg/kg iv.
Dosed 5 mg/kg po.
Table 4
In vitro data for 7e
O
OH
O
O
O
O
(a)
(b)
O
OH
NO2
NO2
NH2
12
13
14
O
NH
Scheme 2. Synthesis of para-substituted amino benzoic ester. Reagents and
conditions: (a) SOCl2, MeOH, 80 °C, 16 h, (98%); (b) Fe powder, MeOH, concd HCl,
0 °C–80 °C, 16 h, (99%).
Cl
was not directly connected to the microsomal stability. The iv
clearance ranged from minimal clearance (7e) to greater than hep-
atic flow (6c, Table 3). Upon oral administration, compound 7e
showed much greater Cmax than the other two compounds and
was 100% bioavailable. Compound 7d delivered a Cmax with 33-fold
over the hWB IC50 whereas the Cmax for compound 7e was >100-
fold the hWB IC50 value.
Based on these data, compound 7e was selected for additional
evaluation. It was submitted to assess selectivity against the other
known EP receptors (Table 4). No detectable binding was observed
with either EP1 or EP3. Binding to EP2 was >800-fold weaker than
the EP4 binding. Compound 7e was found to have no inhibitory
7e
Assay
Resultsa
hEP1 binding
hEP2 binding
hEP3 binding
hEP4 binding
Ki > 19.5
l
M; IC50 > 25
M; IC50 = 3.7
M; IC50 > 25
l
l
l
M (2)
M (2)
M (2)
Ki = 2.8
l
Ki > 17.5
Ki = 3.49 nM (10)
IC50 = 5.62 nM (10)
IC50 > 10 lM for all
l
CYP1A2, CYP2B6, CYP2C19, CYP2C8,
CYP2C9, CYP2D6 CYP3A4 inhibition
a
Value represents mean of two or more experiments.
activity against several CYP enzymes in vitro up to 10 lM. The risk
of drug-drug interactions with 7e was deemed low.
The compounds described in Table 2 were synthesized15 by the
representative method shown below in Scheme 1. Amino ester
intermediates 14 and 18 were prepared as shown in Schemes 2
and 3. T3P mediated coupling19 of 3-chloro or 3-bromo substituted
quinoline 8 or naphthalene 9 carboxylic acids with para- or meta-
substituted amino-benzoic esters led to key intermediates 10 or
11. Suzuki coupling of quinoline 10 or naphthalene 11 derivatives
with relevant substituted phenyl boronic acids allowed for the ver-
satile synthesis of diverse precursors. Finally, hydrolysis of these
penultimate intermediates under basic conditions led to corre-
sponding quinolone (6a–d) and naphthalene (7a–e) analogs in
good yields.
were >0.26 which is better than known EP4 antagonist 1 with a
LEAN = 0.23. The naphthalene yielded more potent in vitro com-
pounds as reflected in the greater LEAN values.
After positively assessing the scaffold for hWB activity, the next
step was the evaluation of ADME parameters for this new scaffold.
To be thorough, the assessment was conducted for a few com-
pounds, including 7d, and others with some structural differences.
The pharmacokinetic profiles for representative compounds are
given in Table 3.
An initial evaluation of rat hepatic microsome stability showed
that all compounds (6c, 7d and 7e) were more stable than initial
hit 5 (<10% vs 64% respectively). However, the in vivo rat PK profile
In conclusion, we have discovered a new scaffold with potent
EP4 binding and antagonist activity (<15 nM). More importantly,
O
R
O
O
R
O
O
OH
HO
O
NH2
(a)
HN
O
HN
O
(b), (c)
X
Y
2
R
X
Y
X
8, X = N; Y = Cl, Br
9, X = CH; Y = Cl, Br
10, X = N; Y = Cl, Br
11, X = CH; Y = Cl, Br
6a-d, X = N
7a-e, X = CH
R = CH3, CH2CH3
Scheme 1. General synthetic route to quinoline and naphthalene derivatives. Reagents and conditions: (a) T3P, CH2Cl2, DIEA, room temperature, 24 h, (11–48%);
(b) 1,4-dioxane, water, substituted phenyl boronic acid, K2CO3, PdCl2(dppf), CH2Cl2, 110 °C, 3 h, (57–90%); (c) 1 N NaOH, 1:1 THF/MeOH, (47–85%).
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M.-J. Blanco et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
5
O
O
I
(a)
(b)
O
(c)
O
NO2
NO2
NO2
NH2
15
16
17
18
Scheme 3. Synthesis of meta-substituted amino benzoic esters. Reagents and conditions: (a) AcOH, H2SO4, I2, and HIO4, 90 °C, 7 days, (95%); (b) Pd(OAc)2, dppb, CH3CN, Et3N,
MeOH, CO (80 psig), 100 °C, 2 h, (98%); (c) MeOH, 10% Pd/C, H2 (atm), 6 days, (65%).
13. Murase, A.; Nakao, K.; Takada, J. Pharmacology 2008, 82, 10.
14. Blood is collected from normal volunteer donors into sodium heparin
efforts incorporating a carboxylic acid moiety rendered com-
pounds with clinically relevant hWB activity. Additional optimiza-
vacutainer tubes. Donors have not taken NSAIDs or celecoxib within 48 h or
tion introducing hydroxy benzylic substituents led to the discovery
of compound 7d (hWB = 6 nM), one of the most potent EP4 antag-
onist reported to date. ADME assessment of a set of representative
compounds, showed favorable PK profile for compound 7e with
human whole blood potency of 250 nM, yielding the best combina-
tion of activity and exposure for this series. Compound 7e was
selective against other EP receptor subtypes and CYP enzymes. Fur-
ther exploration of this series of compounds is in progress and will
be disclosed in due course.
glucocorticoids within two weeks of the donation. AU tubes/donor are pooled
into 50 mL Falcon conical centrifuge tubes and 98 pL/well is distributed into
96-well tissue culture plates (Falcon 3072). Compounds are diluted into DMSO
to 100ꢁ final and I pL/well in triplicate is added to the blood to give 7 point
concentration response curves. The blood is pretreated with the compounds at
37 °C., in a 5% CO2 humidified atmosphere, for 30 min, after which I pL/well of
a solution of I mg/mL of lipopolysaccharide (LPS) (Sigma 0111:B4) in 0.2 mg/
mL bovine serum albumin (BSA)/PBS+/ꢀ1 mM PGE2 (Cayman 14010) is added
to give a final LPS concentration of 10 pg/mL+/ꢀ10 nM PGE2. The plates are
incubated for 20–24 h at37 °C in a 5% CO2 humidified atmosphere. The plates
are centrifuged at 1800ꢁg, 10 min at 22 °C., in an Eppendorf 5810R centrifuge.
Plasma is removed from the cell layer and is transferred to v-bottom
polypropylene plates. TNFa levels in 2 pL plasma are quantified by
a
References and notes
commercially available enzyme immunoassay (R&D Systems DY210), using
Immulon 4 HBX plates (Thermo 3855) and 3,30,5,50 tetramethylbiphenyl-4,40-
diamine substrate (KPL 50-76-03). The plates are read at A450-A650 on a plate
reader (Molecular Devices Versamax) using SOFTmaxPRO (v. 4.3.1) software.
IC50S are calculated using Graphpad Prism (v. 4) nonlinear regression,
sigmoidal dose response curve fitting. Results are expressed as the geometric
mean standard deviation; n = number of independent determinations.
15. Synthesis protocols, compound characterization, and assay protocols have
been published. Blanco-Pillado, M. -J.; Manninen, P. R.; Schiffler, M. A.; Vetman,
T. N.; Warshawsky, A. M.; York, J. S. WO2015094912.
16. Durham, T. B.; Blanco, M.-J. Bioorg. Med. Chem. Lett. 2015, 25, 998.
17. Hopkins, A. L.; Keserue, G. M.; Leeson, P. D.; Rees, D. C.; Reynolds, C. H. Nat. Rev.
Drug Disc. 2014, 13, 105.
18. (a) Hann, M. M.; Keserue, G. M. Nat. Rev. Drug Disc. 2012, 11, 355; (b) May, P. C.;
Dean, R. A.; Lowe, S. L.; Martenyi, F.; Sheehan, S. M.; Boggs, L. N.; Monk, S. A.;
Mathes, B. M.; Mergott, D. J.; Watson, B. M.; Stout, S. L.; Timm, D. E.; Smith
Labell, E.; Gonzales, C. R.; Nakano, M.; Jhee, S. S.; Yen, M.; Ereshefsky, L.;
Lindstrom, T. D.; Calligaro, D. O.; Cocke, P. J.; Greg Hall, D.; Friedrich, S.; Citron,
M.; Audia, J. E. J. Neurosci. 2011, 31, 16507.
1. Dancevic, C. M.; McCulloch, D. R. Arthritis Res. Ther. 2014, 16, 429.
2. Lenssinck, M.-L. B.; Burdorf, A.; Boonen, A.; Gignac, M. A.; Hazes, J. M. W.;
Luime, J. J. Ann Rheum Dis 2013, 72, 493.
3. Bidaut-Russell, M.; Gabriel, S. E. Best Pract. Res. Clin. Gastroenterol. 2001, 15, 739.
4. Clark, P.; Rowland, S. E.; Denis, D.; Mathieu, M.-C.; Stocco, R.; Poirier, H.; Burch,
J.; Han, Y.; Audoly, L.; Therien, A. G.; Xu, D. J. Pharmacol. Exp. Ther. 2008, 325,
425.
5. McAdam, B. F.; Catella-Lawson, F.; Mardini, I. A.; Kapoor, S.; Lawson, J. A.;
FitzGerald, G. A. Proc. Natl. Acad. Sci. U. S. A. 1999, 96, 272.
6. FitzGerald, G. A.; Patrono, C. N. Engl. J. Med. 2001, 345, 433.
7. Funk, C. D.; FitzGerald, G. A. J. Cardiovasc. Pharmacol. 2007, 50, 470.
8. Boyd, M. J.; Berthelette, C.; Chiasson, J.-F.; Clark, P.; Colucci, J.; Denis, D.; Han,
Y.; Levesque, J.-F.; Mathieu, M.-C.; Stocco, R.; Therien, A.; Rowland, S.; Wrona,
M.; Xu, D. Bioorg. Med. Chem. Lett. 2011, 21, 484.
9. Borriello, M.; Stasi, L. P. Pharm. Pat. Anal. 2013, 2, 387.
10. Nakao, K.; Murase, A.; Ohshiro, H.; Okumura, T.; Taniguchi, K.; Murata, Y.;
Masuda, M.; Kato, T.; Okumura, Y.; Takada, J. J. Pharmacol. Exp. Ther. 2007, 322,
686.
19. Dunetz, J. R.; Xiang, Y.; Baldwin, A.; Ringling, J. Org. Lett. 2011, 13, 5048.
11. Okumura, T.; Murata, Y.; Taniguchi, K.; Murase, A.; Nii, A. J. Pharm. Pharmacol.
2008, 60, 723.
12. Sutton, J.; Clark, D. E.; Higgs, C.; de Groot, M. J.; Harris, N. V.; Taylor, A.; Lockey,
P. M.; Maubach, K.; Woodrooffe, A.; Davis, R. J.; Coleman, R. A.; Clark, K. L.
Bioorg. Med. Chem. Lett. 2014, 24, 2212.
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