2-Aryl substituted pyridine C-region analogues of 2-(3-fluoro-4- methylsulfonylaminophenyl)propanamides as highly potent TRPV1 antagonists

Article abstract of DOI:10.1016/j.bmcl.2014.05.072

A series of 2-aryl pyridine C-region derivatives of 2-(3-fluoro-4- methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Multiple compounds showed highly potent TRPV1 antagonism toward capsaicin comparable to previous lead 7. Among them, compound 9 demonstrated anti-allodynia in a mouse neuropathic pain model and blocked capsaicin-induced hypothermia in a dose-dependent manner. Docking analysis of 9 with our hTRPV1 homology model provided insight into its specific binding mode.

Full text of DOI:10.1016/j.bmcl.2014.05.072

Accepted Manuscript
2-Aryl Substituted Pyridine C-region Analogues of 2-(3-Fluoro-4-methyl sul-
fonylaminophenyl) propanamides as Highly Potent TRPV1 Antagonists
HyungChul Ryu, Sejin Seo, Myeong Seop Kim, Mi-Yeon Kim, Ho Shin Kim,
Jihyae Ann, Phuong-Thao Tran, Van-Hai Hoang, Jieun Byun, Minghua Cui,
Karam Son, Pankaz Kumar Sharma, Sun Choi, Peter M. Blumberg, Robert
Frank-Foltyn, Gregor Bahrenberg, Babette-Yvonne Koegel, Thomas Christoph,
Sven Frormann, Jeewoo Lee
PII:
S0960-894X(14)00581-2
DOI:
http://dx.doi.org/10.1016/j.bmcl.2014.05.072
BMCL 21686
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 April 2014
16 May 2014
21 May 2014
Please cite this article as: Ryu, H., Seo, S., Kim, M.S., Kim, M-Y., Kim, H.S., Ann, J., Tran, P-T., Hoang, V-H.,
Byun, J., Cui, M., Son, K., Sharma, P.K., Choi, S., Blumberg, P.M., Frank-Foltyn, R., Bahrenberg, G., Koegel, B-
Y., Christoph, T., Frormann, S., Lee, J., 2-Aryl Substituted Pyridine C-region Analogues of 2-(3-Fluoro-4-methyl
sulfonylaminophenyl) propanamides as Highly Potent TRPV1 Antagonists, Bioorganic & Medicinal Chemistry
Letters (2014), doi: http://dx.doi.org/10.1016/j.bmcl.2014.05.072
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Bioorganic & Medicinal Chemistry Letters
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2-Aryl Substituted Pyridine C-region Analogues of 2-(3-Fluoro-4-methyl
sulfonylaminophenyl) propanamides as Highly Potent TRPV1 Antagonists
HyungChul Ryu a, Sejin Seo a, Myeong Seop Kim a, Mi-Yeon Kim a, Ho Shin Kim a, Jihyae Ann a, Phuong-
Thao Tran a, Van-Hai Hoang a, Jieun Byun b, Minghua Cui b, Karam Son b, Pankaz Kumar Sharma b, Sun
Choi b, Peter M. Blumberg c, Robert Frank-Foltyn d, Gregor Bahrenberg d, Babette-Yvonne Koegeld,
Thomas Christoph d, Sven Frormann d, Jeewoo Lee a,*
a Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea
b National Leading Research Lab of Molecular Modeling & Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top 5
Research Program, Ewha Womans University, Seoul, 120-750, Korea
c Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
d Grunenthal Innovation, Grunenthal GmbH, D-52078 Aachen, Germany
ARTICLE INFO
ABSTRACT
Article history:
Received
A
series of 2-aryl pyridine C-region derivatives of 2-(3-fluoro-4-
methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists.
Multiple compounds showed highly potent TRPV1 antagonism toward capsaicin
comparable to previous lead 7. Among them, compound 9 demonstrated anti-allodynia
in a mouse neuropathic pain model and blocked capsaicin-induced hypothermia in a
dose-dependent manner. Docking analysis of 9 with our hTRPV1 homology model
provided insight into its specific binding mode.
Revised
Accepted
Available online
Keywords:
Vanilloid Receptor 1
TRPV1 Antagonist
Capsaicin
Resiniferatoxin
Molecular modeling
ⓒ 2014 Elsevier Ltd. All rights reserved.
TRPV1 (transient receptor potential vanilloid 1) has emerged
as a promising therapeutic target for neuropathic pain as well as
a broad range of other indications.1 Located predominantly in C-
fiber sensory afferent neurons, TRPV1 is a nociceptor which
integrates stimuli from exogenous compounds such as capsaicin,
endogenous endovanilloids, heat and acidity.2-7 TRPV1 is
further co-regulated by the signaling milieu of the cell, as
reflected in the activity of kinases such as protein kinase C,
protein kinase A, or the level of phosphatidylinositol-4,5-
bisphosphate. Development of antagonists represents the leading
therapeutic strategy, while defunctionalization/desensitization
subsequent to agonist stimulation also holds promise.8 Starting
with capsaicin as the lead structure, intense research efforts have
generated substantial insights into vanilloid structure activity
relations and are yielding potent, orally active antagonists.9-15
Figure 1. Lead TRPV1 antagonist template
We previously reported
a
series of 2-(3-fluoro-4-
methylsulfonylaminophenyl)propanamides as potent hTRPV1
antagonists in which the three pharmacophores were designated
as A-region (3-fluoro-4-methylsulfonylaminophenyl), B-region
(propanamide) and C-region ((6-trifluoromethyl-pyridin-3-
yl)methyl), respectively (Figure 1).16 The structure activity
relationships of the 2-substituent in the pyridine C-region have
been investigated extensively by introducing various groups,
including amino,16 oxy,17 thio18 and alkyl19 groups. In the series, a
number of compounds showed highly potent and stereospecific
antagonism to multiple TRPV1 activators including capsaicin,
pH, heat (45 oC) and N-arachidonoyl dopamine (NADA). In
_________
＊ Corresponding author. Tel.: +82 2 880 7846; fax: + 82 2 888 0649.
E-mail address: jeewoo@snu.ac.kr (J. Lee).

addition, the selected compounds demonstrated strong analgesic
activity in the mouse neuropathic pain model and blocked
capsacin-induced hypothermia, consistent with its in vitro
mechanism of action. The modeling analysis using our hTRPV1
homology model indicated that a new hydrophobic interaction by
the 2-substituents with the receptor in addition to that by the 6-
trifluoromethyl group in the C-region was critical for their potent
antagonism.16
The synthesized TRPV1 ligands were evaluated in vitro for
antagonism as measured by inhibition of TRPV1 activation by
capsaicin (100 nM). The assays were conducted using a
fluorometric imaging plate reader (FLIPR) with human TRPV1
heterologously expressed in Chinese hamster ovary (CHO)
cells.16 The results are summarized in Tables 1-3, together with
the potencies of the previously reported 7 (Ki(CAP) = 0.3 nM) as a
reference.16
In continuation of our effort to further optimize the 2-
substitutent in the N-(6-trifluoromethyl-pyridin-3-ylmethyl) C-
region, here we have investigated the structure activity
relationships of 2-aryl type derivatives as hTRPV1 antagonists.
With a selected potent antagonist in the series, we have further
characterized its analgesic activity and inhibition of capsaicin-
induced hypothermia in animal models and we also have
performed molecular modeling with our hTRPV1 homology
model.
To investigate the SAR for 2-aryl derivatives of the pyridine
C-region, we began with the 2-(substituted phenyl) pyridine
derivatives (Table 1). First, we examined the 2-phenyl derivative
8, which showed a reasonable antagonism and was found to be
ca. 10-fold less potent than the corresponding saturated
surrogate, the 2-cyclohexyl derivative (Ki(CAP) = 0.6 nM)
previously reported19. However, the incorporation of a 4-fluoro
atom into 8 led to very potent antagonist 9 with Ki(CAP) = 0.4 nM,
which exhibited a 16-fold increase in potency compared to 8.
Whereas the 3-fluorophenyl derivative 10 also exhibited a 5-fold
increase in potency compared to 8, the 2-fluorophenyl derivative
11 displayed instead a 10-fold reduction in potency, probably
due to conformational distortion between the pyridine and
phenyl rings by the polar 2-fluoro atom. A similar SAR pattern
was seen with the chlorophenyl derivatives.
The synthesis of the 2-aryl derivatives was accomplished
by two methods. First, a series of aryl boronic acids were reacted
with 2-chloropyridine 116 to afford 2-aryl pyridines 2 by a
Suzuki reaction. The 2-(1-imidazoyl)pyridine derivative of 2 was
an exception in that it was prepared by the direct condensation of
imidazole with 1. The nitrile groups of 2 were reduced to yield
the corresponding primary amines 3. The amines of 3 were
coupled with racemic propanoic acid 420 to provide the
corresponding final compounds (Scheme 1, Method A).
Alternatively, some 2-aryl analogues were synthesized directly
from the 2-chloro derivatives of the final compound 6 under
Suzuki conditions (Scheme 2, Method B).
Table 1. In vitro hTRPV1 antagonistic activities for 2-phenyl derivatives
F3C
H
N
N
F
O
S
O
R
N
H
O
-
Ki [CAP]
(nM)
Ki [CAP]
(nM)
R
R
F3C
F3C
F3C
a
b
7
0.3
6.4
0.4
1.3
63.3
0.7
17
NE
0.2
0.4
0.9
4.2
25.6
N
N
NH2
N
CN
CN
R
R
Cl
2
3
1
8
18
19
20
21
22
F3C
c
H
N
N
F
HO
F
9
O
O
S
R
O
O
N
H
S
N
H
5
O
4
O
10
11
12
Scheme 1. Syntheses of 2-aryl-6-trifluoromethyl pyridine C-region
derivatives (Method A)
Reagents and conditions: (a) R-B(OH)2, Pd(PPh3)4, Na2CO3, toluene/1,4-
dioxane, reflux, overnight, 55-90%, For 1-imidazole, imidazole, CH3CN,
reflux, overnight, 50%; (b) BH3-SMe2, THF, reflux, overnight, 40-90%; (c)
4, TBTU, HOBt, DIPEA, THF-DMF, 70-90%
13
0.5
23
58
14
15
16
1
24
25
5
3.2
0.5
3.4
Scheme 2. Syntheses of 2-aryl-6-trifluoromethyl pyridine C-region
derivatives (Method B)
Reagents and conditions: (a) BH3-SMe2, THF, reflux, overnight, 90%; (b) 4,
TBTU, HOBt, DIPEA, THF-DMF, 92%; (c) R-B(OH)2, Pd(PPh3)4, Na2CO3,
toluene-EtOH, 100 oC, microwave, 1 h, 32-98%;

Table 3. In vitro hTRPV1 antagonistic activities for 2-Ar(alk/alken/alkyn)yl
derivatives
The 4-chlorophenyl and 3-chlorophenyl derivatives, 12 and
13, displayed 9- and 13-fold increases in potency, respectively,
compared to 8. We also examined the phenyl derivatives with
electron-donating groups. The 4-methoxyphenyl 14, 4-
(dimethylamino)phenyl 15, and 4-(t-butyl)phenyl 16 derivatives
exhibited 6-, 2- and 13-fold better potency, respectively, than the
parent 8. The 3-methylsulfonylaminophenyl derivative 17
showed lack of activity. The analysis in the mono-substituted
phenyl series indicated that lipophilicity of the substituent at the
3- or 4-position on the phenyl was critical for potency.
Ki [CAP]
(nM)
Ki [CAP]
(nM)
R
R
8
6.4
141
1.4
2.2
38
39
40
0.8
0.6
1.8
35
36
37
Next, we sought to evaluate the SAR of disubstituted-phenyl
derivatives. Since 4-fluorophenyl and 3-chlorophenyl derivatives
showed excellent antagonism as described above, the combined
derivative, 3-chloro-4-fluorophenyl derivative 18, was designed
and proved to be an extremely potent antagonist with Ki(CAP)
=
0.2 nM, which was ca 30-fold more potent than the parent 8.
Other disubstituted phenyl derivatives, 19-25, were also
examined. Whereas the more lipophilic derivatives 19 and 20
retained high potencies, the less lipophilic derivatives 21-25
showed lower potencies for antagonism than did 8. These results
confirmed that the lipophilicity at the 3- and 4-positions of the
phenyl ring was a key determinant for antagonistic potency in
the series of 2-phenyl pyridine C-region derivatives.
Table 4. In vitro hTRPV1 antagonistic activities of 9 for multiple activators.
Activators, parameter
9
CAP, Ki (nM)
0.4
130.8
25.9
0.84
pH, IC50 (nM)
We next explored the SAR of 2-heterocyclic pyridine C-
region derivatives (Table 2). Among 2-heteromonocyclic
derivatives, the thiophen-2-yl derivative 26 exhibited excellent
antagonism with Ki(CAP) = 0.3 nM, indicating ca. 20-fold stronger
potency than that of the phenyl surrogate 8. The thiophen-3-yl
derivative 27 was also a potent antagonist, but less potent than
26. The furan-2 and 3-yl derivatives 28 and 29 showed lower
potency compared to the corresponding thiophenyl derivatives
but still retained higher potency than phenyl derivative 8. The
imidazol-1-yl derivative 30 was found to be a weak antagonist,
probably due to its low lipophilicity. The analysis indicated that
the antagonism in the 2-heteromonocyclic derivatives correlated
with the corresponding lipophilicities of the heterocyclic rings
heat 45oC, IC50 (nM)
NADA, Ki (nM)
Finally, we examined 2-alkylphenyl derivatives (Table 3).
The benzyl derivative 35 was found to be weak antagonist.
However, its elongation by one carbon, providing the 2-
phenylethyl derivative 36, led to a dramatic increase in
antagonism probably due to optimal hydrophobic interaction
with the receptor. This interpretation was confirmed with other
derivatives with C2-spacer between phenyl residue and
trifluoromethyl-pyridine moiety, 37-40, which likewise showed
potent antagonism in the range of Ki(CAP) = 0.6-2.2 nM.
(thiophene>furan>imidazole).
Several
2-heterobicyclic
derivatives, 31-34, were also investigated. However, except for
benzothiophene derivative 34, they were only moderate to weak
antagonists.
The in vitro activity of compound 9, selected as a
representive antagonist in this series, was further investigated as
an antagonist for other endogenous TRPV1 activators (Table 4).
Whereas compound 9 showed excellent antagonism toward
capsaicin and NADA, it exhibited only moderate antagonism
toward pH and heat.
Table 2. In vitro hTRPV1 antagonistic activities for 2-heterocyclic
derivatives
In order to confirm that compound 9 also blocked response to
capsaicin in vivo, consistent with its in vitro mechanism of action
as an hTRPV1 antagonist, it was administered orally to mice 15
min before intraperitoneal injection of 3 mg/Kg capsaicin,
following the procedure previously described.16 (Table 5A).
Compound 9 inhibited the hypothermic response to capsaicin,
assayed at 30 min after capsaicin injection, in a dose-dependent
manner, with 91% inhibition at the highest dose. We further
evaluated the analgesic activity of compound 9 administered
orally in the mouse chronic constriction injury (CCI) model21 for
neuropathic pain (Table 5B). We found that compound 9
showed excellent anti-allodynic potency with ED50 = 0.01
mg/Kg po, but with limited efficacy (53% MPE).
Ki [CAP]
(nM)
Ki [CAP]
(nM)
R
R
8
6.4
0.3
2
30
31
32
33
34
36.1
WE
WE
20.3
1
26
27
28
29
5.8
1.4

Table 5. (A) Effect of compound 9 on capsaicin-induced hypothermia in
mice (B) Analgesic activity of compound 9 on CCI-induced cold allodynia
after oral administration in mouse. Data, n = 10, mean SEM, * p<0.05 vs
vehicle. MPE, maximal possible effect. mpk, mg per Kg.
group occupied the deep bottom hole, making hydrophobic
interactions with Tyr511, Ile564, and Ile569. The sulfonamide
NH participated in hydrogen bonding with Tyr565, and the
phenyl ring in the A-region engaged in π-π stacking with the
phenyl ring of Tyr511. In the B-region, the amide group was
able to hydrogen bond with Tyr511 and contributed to the proper
positioning of the C-region. In the C-region, the 3-
trifluoromethyl group oriented toward the hydrophobic pocket
composed of Leu547 and Thr550 as previously examined16. The
pyridine ring formed a hydrophobic interaction with Phe587 on
the adjacent monomer, and the fluorine atom of the 3-
trifluoromethyl group made a hydrogen bond with Asn551.
Finally, the 4-fluorophenyl group, representing the 2-substituent
of pyridine, was involved in the crucial hydrophobic interactions
with Met514 and Leu515.
(A) CAP-induced Hypothermia
Dose (mpk)
Inhibition %
0.1
25
0.3
38
1
10
91
60
(B) CCI Model
Dose (mpk)
MPE
0.0001
21.9
0.001
0.01
0.1
30.5
52.9
47.1
(±4.2)
(±5.9)
(±5.6)
(±8.0)
CCI, mouse
In summary, we investigated the structure activity
relationships of 2-aryl pyridine C-region derivatives of the
previous lead as hTRPV1 antagonists. Several compounds (9, 18,
19, 26) in the series showed excellent TRPV1 antagonism with
Ki(CAP) = 0.2-0.4 nM comparable to reference compound 7. The
SAR analysis of 2-aryl groups indicated that the lipophilicity of
the substituent in the phenyl and heterocyclic derivatives was
critical for antagonistic activity. Among the potent derivatives in
the series, compound 9 was selected for further study. It was
shown to antagonize capsaicin-induced hypothermia in a dose-
dependent manner, consistent with its action in vivo being
through TRPV1, and it demonstrated anti-allodynia in a mouse
neuropathic pain model. Docking analysis of 9 with our hTRPV1
homology model indicated that 9 showed a binding mode similar
100
75
50
25
0
*
*
*
0.0001 0.001
0.01
0.1
1.0
Dose (mg/kg) p.o.
To develop insight into the nature of the binding interactions
of 9 with hTRPV1, we carried out a flexible docking study using
our human TRPV1 (hTRPV1) model16, constructed on the basis
of our rat TRPV1 (rTRPV1) model.22 Results are shown in
Figure 2. In the A-region, the 4-methylsulfonylaminophenyl
to that of reference compound 7 previously reported16
.
Figure 2. Docking study of 9 in the hTRPV1 model.
(A)
(B)
(C)
LP
0.14
Leu547
Asn551
0.12
0.09
0.07
Thr550
0.05 Met514
0.03
0.01
Leu515
-0.02
-0.04
-0.06
Phe587
-0.08
-0.11
-0.13
Tyr511
Tyr565
Ile569
-0.15
-0.17
-0.19
Ile564
(A) Binding mode and interactions of 9 at the binding site of hTRPV1. The important interacting residues are labeled and depicted as capped-stick with their
carbon atoms in white color. The secondary structure of hTRPV1 is in gray color, and the neighboring monomer helices are shown in line ribbon. 9 is displayed
in ball-and-stick with the carbon atoms in magenta color. The van der Waals surface representation of 9 is colored by the lipophilic potential property. Hydrogen
bonds are drawn in black dashed lines, and non-polar hydrogens are not displayed for clarity. (B) The Fast Connolly surface representation of hTRPV1 and the
van der Waals surface representation of the docked 9. The molecular surface of hTRPV1 was generated by MOLCAD and presented with the lipophilic potential
property. The surface of hTRPV1 is Z-clipped for clarity, and that of 9 is in magenta color. (C) Van der Waals surface of the docked 9 colored by the lipophilic
potential property.

22. Lee, J. H.; Lee, Y.; Ryu, H.; Kang, D. W.; Lee, J.; Lazar, J.;
Pearce, L. V; Pavlyukovets, V. A.; Blumberg, P. M.; Choi, S. J.
Comput. Aided Mol. Des. 2011, 25, 317.
Acknowledgements
We greatly acknowledge Elke Schumacher and Franz-Josef Butz
for technical assistance in CCI and Cap hypothermia studies,
resp. This research was supported by Research Grants from
Grunenthal, Grants from the National Research Foundation of
Korea (NRF) (R11-2007-107-02001-0), Grants from the
National Leading Research Lab (NLRL) program (2011-
0028885), and in part by the Intramural Research Program of
NIH, Center for Cancer Research, NCI (Project Z1A BC
005270).
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2-Aryl Substituted Pyridine C-region Analogues of
2-(3-Fluoro-4-methylsulfonylaminophenyl)
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propanamides as Highly Potent TRPV1 Antagonists
HyungChul Ryu, Sejin Seo, Myeong Seop Kim, Mi-Yeon Kim, Ho Shin Kim, Jihyae Ann, Phuong-Thao Tran,
Van-Hai Hoang, Jieun Byun, Minghua Cui, Karam Son, Pankaz Kumar Sharma, Sun Choi, Peter M. Blumberg,
Robert Frank-Foltyn, Gregor Bahrenberg, Babette-Yvonne Koegel, Thomas Christoph, Sven Frormann, Jeewoo
Lee*