Discovery of 2-(3,5-difluoro-4-methylsulfonaminophenyl)propanamides as potent TRPV1 antagonists

Article abstract of DOI:10.1016/j.bmcl.2018.05.043

A series of A-region analogues of 2-(3-fluoro-4-methylsufonamidophenyl) propanamide 1 were investigated as TRPV1 antagonists. The analysis of structure-activity relationship indicated that a fluoro group at the 3- (or/and) 5-position and a methylsulfonamido group at the 4-position were optimal for antagonism of TRPV1 activation by capsaicin. The most potent antagonist 6 not only exhibited potent antagonism of activation of hTRPV1 by capsaicin, low pH and elevated temperature but also displayed highly potent antagonism of activation of rTRPV1 by capsaicin. Further studies demonstrated that antagonist 6 blocked the hypothermic effect of capsaicin in vivo, consistent with its in vitro mechanism, and it showed promising analgesic activity in the formalin animal model.

Full text of DOI:10.1016/j.bmcl.2018.05.043

Accepted Manuscript
Discovery of 2-(3,5-Difluoro-4-methylsulfonaminophenyl)propanamides as
Potent TRPV1 Antagonists
Changhoon Kim, Jihyae Ann, Sunho Lee, Wei Sun, Peter M. Blumberg, Robert
Frank-Foltyn, Gregor Bahrenberg, Hannelore Stockhausen, Thomas Christoph,
Jeewoo Lee
PII:
S0960-894X(18)30455-4
https://doi.org/10.1016/j.bmcl.2018.05.043
BMCL 25860
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 March 2018
21 May 2018
22 May 2018
Please cite this article as: Kim, C., Ann, J., Lee, S., Sun, W., Blumberg, P.M., Frank-Foltyn, R., Bahrenberg, G.,
Stockhausen, H., Christoph, T., Lee, J., Discovery of 2-(3,5-Difluoro-4-methylsulfonaminophenyl)propanamides
as Potent TRPV1 Antagonists, Bioorganic & Medicinal Chemistry Letters (2018), doi: https://doi.org/10.1016/
j.bmcl.2018.05.043
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Graphical Abstract
Discovery of 2-(3,5-Difluoro-4-methylsulfonaminophenyl)
propanamides as Potent TRPV1 Antagonists
Leave this area blank for abstract info.
Changhoon Kim, Jihyae Ann, Sunho Lee, Wei Sun, Peter M. Blumberg, Robert Frank-Foltyn, Gregor
Bahrenberg, Hannelore Stockhausen, Thomas Christoph, Jeewoo Lee*
Activators, parameter
hTRPV1
6
CAP (f)Ki (nM)
pH, IC50 (nM)
0.2
8.7
8.1
heat 45oC, IC50 (nM)
rTRPV1
CAP (f)Ki (nM)
0.1

Bioorganic & Medicinal Chemistry Letters

Discovery of 2-(3,5-Difluoro-4-methylsulfonaminophenyl)propanamides
as Potent TRPV1 Antagonists
Changhoon Kim a, Jihyae Ann a, Sunho Lee a, Wei Sun b, Peter M. Blumberg c, Robert Frank-Foltyn d,
Gregor Bahrenberg d, Hannelore Stockhausen d, Thomas Christoph d, Jeewoo Lee a,*
a Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul 08826, Korea
b Shenyang Pharmaceutical University, Shenyang 110016, China
c Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892-4255, USA
d Grünenthal Innovation, Grünenthal GmbH, D-52078 Aachen, Germany
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
A
series of A-region analogues of 2-(3-fluoro-4-methylsufonamidophenyl)
propanamide 1 were investigated as TRPV1 antagonists. The analysis of structure-
activity relationship indicated that a fluoro group at the 3- (or/and) 5-position and a
methylsulfonamido group at the 4-position were optimal for antagonism of TRPV1
activation by capsaicin. The most potent antagonist 6 not only exhibited potent
antagonism of activation of hTRPV1 by capsaicin, low pH and elevated temperature
but also displayed highly potent antagonism of activation of rTRPV1 by capsaicin.
Further studies demonstrated that antagonist 6 blocked the hypothermic effect of
capsaicin in vivo, consistent with its in vitro mechanism, and it showed promising
analgesic activity in the formalin animal model.
Keywords:
Vanilloid Receptor 1
TRPV1 Antagonist
Analgesic
2017 Elsevier Ltd. All rights reserved.
The transient receptor potential vanilloid 1 (TRPV1), a key
nociceptor triggering C-fiber sensory neurons, represents a
promising therapeutic target for the treatment of neuropathic
pain and a wide range of other conditions in which C-fiber
sensory neurons are involved.1-3 The TRPV1 nociceptor is
activated by elevated temperature, by low pH, and by both
endogenous endovanilloids and exogenous agents such as
capsaicin, as well as being responsive to the state of the signaling
pathways in the cells.4-7 Although intense efforts has been
directed at the development of potent TRPV1 antagonists,8 side
effects such as hyperthermia or loss of sensitivity to heat pain
represent an on-going challenge. Recognition that different
modes of TRPV1 activation are differentially associated with
some side effects and are differentially manipulable by ligands
provides powerful motivation for detailed understanding of
TRPV1 structure-activity relations.3,9
mechanism of action, compound 1 antagonized capsaicin-
induced hypothermia in mice and demonstrated a strong
antiallodynic effect in neuropathic pain models. The basis for its
high potency was shown by molecular docking studies using our
established hTRPV1 homology model,10 indicating that the 6-
trifluoromethyl group and the 2-substituent in the pyridine C-
region made hydrophobic interactions with pockets composed of
Leu547/Thr550 and Met514/Leu515, respectively, regions that
have been identified as critical for potent antagonism.10-14
The pharmacophoric region of antagonist 1 can be divided
into so-called A, B and C-regions, as previously described for
capsaicin (Figure 1). The analysis of the structure activity
relationships (SAR) of 1 have initially focused on the C-region,
in which a variety of functional groups including the amino10,
oxy11, thio12, alkyl13, aryl14 and sulfonamido15 groups were
incorporated at the 2-position of 6-trifluorophenylpyridine along
with substitution at the 6-position with a tert-butyl group16 as
well as with the pyridine core modified by its isomers17 or
replaced by phenyl18 and pyrazole19 surrogates. In addition, the
SAR of the B-region propanamide group was also explored by
the substitution with alpha-substituted acetamide20 and urea21
surrogates.
Previously, we have investigated an extensive series of 2-(3-
fluoro-4-methylsulfonamidophenyl)propanamides as human
TRPV1 antagonist.10-21 Among them, antagonist 1 (R1=F, R2=H,
R3=H, R4=Me in Figure 1) showed highly potent antagonism for
multiple activators including capsaicin (Ki(CAP) = 0.2 nM, activity
of the S-isomer), N-arachidonoyl dopamine (NADA), low pH
As part of our continuing effort to optimize TRPV1
antagonists as clinical candidates for neuropathic pain, we herein
have investigated the SAR of the A-region corresponding to the
o
and heat (45 C). This antagonism was stereospecific to the S-
configuration in the propanamide. Consistent with the in vitro

3-fluoro-4-methylsulfonylaminophenyl group in 1. In this study,
we modified the 3-position (R1) and 5-position (R2) on the
phenyl ring, and incorporated various substituents on the
nitrogen (R3) and sulfur (R4) of the sulfonamide group (Figure
1).
For the synthesis of the 3-methoxy analogue (8), ethyl 2-(3-
hydroxyphenyl)acetate was nitrated and then O-methylated to
give the nitro intermediate. By following the preceding method,
the final 8 was readily obtained (Scheme 2).
We describe the synthesis of a series of 3,5-substituted 4-
sulfonamidophenyl derivatives and characterize their antagonism
toward activation of hTRPV1 by capsaicin. With a selected
potent antagonist in the series, we further characterized in detail
its in vitro activities and mode of action in vivo.
Scheme 2. Synthesis of the 3-methoxy analogues
o
Reagents and conditions: (a) cH2SO4, EtOH, reflux; (b) HNO3, AcOH, 0 C;
(c) K2CO3, MeI, acetone, r.t.; (d) NaH, MeI, 0 oC to r.t.; (e) Pd/C, H2,
THF/EtOH, rt; (f) MsCl, pyridine, 0 oC to r.t.; (g) LiOH∙H2O, THF/H2O
(1:1), r.t.; (h) RNH2, EDC, HOBt, TEA, CH3CN
Figure 1. Modification on the 4-methylsulfonamidophenyl A-region
For the syntheses of the 3-fluoro-5-methoxy (9) and 3,5-
The syntheses of 3,5-substituted 4-methylsulfonamido
phenyl analogues are described in Schemes 1-3. For the
synthesis of 3 (or/and 5)-halo analogues (Scheme 1),
dimethoxy
(10)
analogues,
ethyl
2-(3,5-difluoro-4-
nitrophenyl)propionate was selectively converted to either
monohydroxy or dihydroxy analogues under appropriate
hydrolysis and were then O-methylated to afford the 4-nitro
propionate intermediates. By following the preceding method, 9
and 10 were readily obtained (Scheme 3).
Scheme 3. Syntheses of the 3-fluoro-5-methoxy and 3,5-dimethoxy
analogues
Reagents and conditions: (a) LiOH, THF/H2O, reflux, 12 h; (b) NaOH,
DMSO, reflux, 12 h; (c) MeI, NaH, DMF, 0 ˚C to r.t.; (d) Pd/C, H2, EtOH,
o
r.t.; (e) MsCl, pyridine, 0 C to r.t.; (f) LiOH∙H2O, THF/H2O (1:1), r.t.; (e)
RNH2, EDC, HOBt, TEA, CH3CN
The syntheses of 3-fluoro-4-(substituted)sulfonamido
analogues are described in Scheme 4. Starting from ethyl 2-(4-
amino-3-fluorophenyl)propanoate prepared in Scheme 1, the N-
sulfonylation with various sulfonyl chlorides followed
Scheme 1. Synthesis of 3 (or/and 5)-halo analogues
Reagents and conditions: (a) t-BuOK, DMF, 30 ˚C; (b) Pd/C, H2, EtOH, r.t.
o
or SnCl2∙2H2O, EtOH, reflux; (c) MsCl, pyridine, 0 C to r.t.; (d) LiOH∙H2O,
THF/H2O (1:1), r.t.; (e) RNH2, EDC, HOBt, TEA, CH3CN (or DMF) (f)
oxone, NaBr, acetone/water; (g) Pd(PPh3)4, SnMe4, toluene, reflux.

Overall, the SAR analysis of ring substitution in 1 indicated that
the fluoro group at the 3- and 5- positions was the optimal
substituent for potent antagonism.
Next, we explored the SAR of the 4-methylsulfonamido
moiety in 1 (Table 2). The increase in the size of alkyl group,
providing 11 and 12, led to a progressive decrease in
antagonism. The substitution of the terminal methyl group in 11
with the electron-withdrawing trifluoromethyl group (13) led to a
further reduction in antagonism. Meanwhile, while the
replacement of the methyl group of 1 by the electron-
withdrawing trifluoromethyl group (14) almost abolished the
antagonism, the substitution with an electron-donating amino
group (15) led to only a 9-fold reduction in antagonism. The N-
dimethylsulfamoyl analogue (16) showed further reduction in
antagonism compared to 15 due to its increased size, in line with
the SAR of alkyl groups. The nitrogen of the 4-
methylsulfonamido group was also modified by adding different
substituents. The incorporation of alkyl groups, such as the
methyl (17), ethyl (18) and cyanomethyl (19) groups, led to
dramatic loss in antagonism. In addition, the incorporation of an
acyl group, such as the acetyl (20) and acryl (21) groups, also
caused a decrease in antagonism, but with less extent compared
to those of the alkyl groups. Overall, the SAR of the
methylsulfonamido group in 1 indicated that any modification
led to the reduction in antagonism, suggesting that the
methylsulfonamido group was the optimal group at the 4-
position for antagonism.
Scheme 4. Syntheses of 3-fluoro-4-(substituted)sulfonamido analogues
Reagents and conditions: (a) RSO2Cl, pyridine, 0 C to r.t.; (b) LiOH∙H2O,
THF/H2O (1:1), r.t.; (c) RNH2, EDC, HOBt, TEA, CH3CN; (d) MeI, K2CO3,
ACN, 18-C-6, reflux, 8 h for 17; EtI, K2CO3, ACN, 18-C-6, reflux for 18; 2-
iodoacetonitrile, K2CO3, ACN, 18-C-6, reflux for 19; Ac2O, pyridine/THF
(1:1), reflux, 12 h for 20; 3-bromopropanoyl chloride, K2CO3, ACN, 18-C-6,
reflux for 21.
o
The in vitro assay was conducted using a fluorometric
imaging plate reader (FLIPR) with hTRPV1 heterologously
expressed in Chinese hamster ovary (CHO) cells.10 The
antagonistic activity of the synthesized compounds was
measured by inhibition of TRPV1 activation by capsaicin (100
nM) and expressed as binding affinity (Ki(CAP)). The results are
summarized in Tables 1-3 and the activities are compared to that
of the potent antagonist 1 (Ki(CAP) = 0.3 nM) previously
reported.10
First, we investigated the SAR of 3,5-substituted A-region
analogues (Table 1). The unsubstituted analogue (2) was 4-fold
less active than 1. In the SAR of 3-substituted analogues, the
substitution of the 3-fluoro group with other halogens, including
chloride (3) and bromide (4), decreased the antagonism
progressively as the size increased. On the other hand, the
substitution with electron-donating groups, including methyl (5)
and methoxy (8) groups, led to relatively little reduction in
antagonistic potency. In the SAR of 3,5-disubstituted analogues,
incorporation of an additional fluoro group at the 5-position in 1
further enhanced the antagonism to afford the highly potent
antagonist 6 with a Ki(CAP) = 0.2 nM. On the other hand,
incorporation of bromo (7) and methoxy (9) groups caused a
slight reduction in antagonism. The 3,5-dimethoxy analogue (10)
exhibited a 2-fold reduction in antagonism compared to that of
the 3-methoxy analogue (8).
Table 2. In vitro hTRPV1 antagonistic activities for N-substituted 3-fluoro-
4-sulfonamidophenyl derivatives
R3
R4
CH3
Ki(CAP) (nM)
1
H
0.3
11
12
13
14
15
16
17
18
19
20
21
H
H
H
H
H
CH2CH3
CH(CH3)2
CH2CF3
CF3
NH2
N(CH3)2
CH3
CH3
CH3
CH3
CH3
4.4 (±0.89)
8.7 (±1.34)
43.7 (±6.8)
WE
2.7 (±0.73)
42 (±5.6)
55.5 (±8.3)
22.7 (±4.1)
WE
H
CH3
CH2CH3
CH2CN
C(=O)CH3
C(=O)CH=CH2
Table 1. In vitro hTRPV1 antagonistic activities for 3,5-substituted 4-
methylsulfonamidophenyl derivatives
11.9 (±2.2)
2.4 (±0.64)
Finally, since the 3,5-difluoro analogue (6) was found to be
the most potent antagonist in this series, we further investigated
its representative C-region analogues (Table 3). As anticipated,
all of the pyridine and pyrazole C-region analogues displayed
potent antagonism with a range of Ki(CAP) = 0.2 -1.2 nM.
R1
F
R2
H
Ki(CAP) (nM)
0.3a
1
2
3
4
5
8
6
7
9
10
H
Cl
Br
Me
OMe
F
F
F
OMe
H
H
H
H
H
F
Br
OMe
OMe
1.2 (±0.17)
2.3 (±0.38)
3.2 (±0.82)
0.6 (±0.13)
0.8 (±0.04)
0.2 (±0.07)
0.7 (±0.19)
0.3 (±0.02)
1.6 (±0.17)
Detailed in vitro activities of 6, the most potent antagonist in
this series, were investigated for the different TRPV1 activators,
viz. capsaicin, low pH and heat (45oC) (Table 4). Antagonist 6
showed excellent antagonism of hTRPV1 activation toward pH
and heat with IC50 = 8.7 and 8.1 nM, respectively. In addition,
antagonist 6 also proved to be a highly potent antagonist of
capsaicin action against rat TRPV1 (rTRPV1) with Ki(CAP) = 0.1
nM.
a refer 10

Table 3. In vitro hTRPV1 antagonistic activities for the C-region analogues
of 6
that antagonist 6 blocked the hypothermic effect of capsaicin in
vivo, consistent with its in vitro mechanism, and showed
promising analgesic activity in the formalin mouse pain model.
Acknowledgments
Ra
Ki[CAP] (nM)
This research was suppported by research grants from
Grünenthal in Germany and by Bio & Medical Technology
Development Program of the National Research Foundation
(NRF) funded by the Ministry of Science, ICT & Future
Planning (NRF-2016M3A9B5939892).
6
0.2
22
23
0.9 (±0.17)
0.8 (±0.12)
References and Notes
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Consistent with its in vitro mechanism of action, it was able
to block in vivo the acute hypothermic response to capsaicin (3
mg/kg) injected intraperitoneally (ip). The oral administration
(po) of 3 and 10 mg/kg 6 antagonized the effect of capsaicin on
body temperature with 57% and 100% inhibition, respectively,
of the hypothermia induced by capsaicin. The in vivo analgesic
activity of 6 was evaluated employing the formalin test24 in mice
(Table 4). It demonstrated a reasonable antinociceptive effect in
the second period (20–30 min after injection), with 43%
inhibition of response at the dose of 3 mg/kg by intravenous
injection (iv). However, it showed hyperthermia at 10 mg/kg po
as side effect probably due to strong antagonism to all activators
as shown in Table 4.9
Table 4. Antagonistic activities of 6 for multiple activators in hTRPV1 and
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hTRPV1
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pH, IC50 (nM)
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Anti-hypothermiaa
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a Inhibition percent to hypothermic response by 3 mg/kg ip capsaicin
In summary, a series of 3-fluoro-4-methylsufonamidophenyl
A-region analogues of potent antagonist 1 were investigated. The
analysis of SAR indicated that a fluoro group at the 3- (or/and)
5-position and a 4-methylsulfonamido group at the 4-position
were optimal for TRPV1 antagonism to capsaicin activation, and
any modification in the A-region led to a reduction in
antagonism except for incorporation of an additional fluoro
group into the 5-position. The most potent antagonist 6 exhibited
potent antagonism toward capsaicin, low pH and elevated
temperature for hTRPV1 and also displayed highly potent
antagonism to capsaicin for rTRPV1. Further studies indicated
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49
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-
A series of A-region analogues of 2-(3-
fluoro-4-
methylsufonamidophenyl)propanamide
were investigated as TRPV1 antagonists.
-
-
Compound
6
showed highly potent
antagonism toward capsaicin activation.
Compound 6 displayed anti-hypothermic
effect and promising analgesic activity in
vivo.