2-Alkyl/alkenyl 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.2014.05.074

A series of 2-alkyl/alkenyl pyridine C-region derivatives of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Multiple compounds showed excellent and stereospecific TRPV1 antagonism with better potency than previous lead 2. Among them, compound 15f demonstrated a strong analgesic profile in a rat neuropathic pain model and blocked capsaicin-induced hypothermia in a dose-dependent manner. Docking analysis of (S)-15f with our hTRPV1 homology model provided insight into its specific binding mode.

Full text of DOI:10.1016/j.bmcl.2014.05.074

Accepted Manuscript
2-Alkyl/Alkenyl Substituted Pyridine C-region Analogues of 2-(3-Fluoro-4-
methylsulfonylaminophenyl)propanamides as Highly Potent TRPV1 Antago-
nists
HyungChul Ryu, Sejin Seo, Seong-Hee Cho, Ho Shin Kim, Aeran Jung, Dong
Wook Kang, Karam Son, Minghua Cui, Sun-hye Hong, Pankaz Kumar Sharma,
Sun Choi, Peter M. Blumberg, Robert Frank-Foltyn, Gregor Bahrenberg,
Hannelore Stockhausen, Klaus Schiene, Thomas Christoph, Sven Frormann,
Jeewoo Lee
PII:
S0960-894X(14)00583-6
DOI:
http://dx.doi.org/10.1016/j.bmcl.2014.05.074
BMCL 21688
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., Cho, S-H., Kim, H.S., Jung, A., Kang, D.W., Son, K., Cui, M., Hong,
S-h., Sharma, P.K., Choi, S., Blumberg, P.M., Frank-Foltyn, R., Bahrenberg, G., Stockhausen, H., Schiene, K.,
Christoph, T., Frormann, S., Lee, J., 2-Alkyl/Alkenyl Substituted Pyridine C-region Analogues of 2-(3-Fluoro-4-
methylsulfonylaminophenyl)propanamides as Highly Potent TRPV1 Antagonists, Bioorganic & Medicinal
Chemistry Letters (2014), doi: http://dx.doi.org/10.1016/j.bmcl.2014.05.074
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Bioorganic & Medicinal Chemistry Letters
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2-Alkyl/Alkenyl Substituted Pyridine C-region Analogues of 2-(3-Fluoro-4-
methylsulfonylaminophenyl)propanamides as Highly Potent TRPV1 Antagonists
HyungChul Ryu a, Sejin Seo a, Seong-Hee Cho a, Ho Shin Kim a, Aeran Jung a, Dong Wook Kang a,e, Karam
Son b, Minghua Cuib, Sun-hye Hong b, Pankaz Kumar Sharma b, Sun Choi b, Peter M. Blumberg c, Robert
Frank-Foltyn d, Gregor Bahrenberg d, Hannelore Stockhausen d, Klaus Schiene d, 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
e Department of Pharmaceutical Science and Technology, College of Health and Medical Science, Catholic University of Deagu, Gyeongsan-si, Gyeongsangbuk-
do 712-702, Korea
ARTICLE INFO
ABSTRACT
Article history:
Received
A
series of 2-alkyl/alkenyl pyridine C-region derivatives of 2-(3-fluoro-4-
methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists.
Multiple compounds showed excellent and stereospecific TRPV1 antagonism with
better potency than previous lead 2. Among them, compound 15f demonstrated a
strong analgesic profile in a rat neuropathic pain model and blocked capsaicin-induced
hypothermia in a dose-dependent manner. Docking analysis of (S)-15f with our
hTRPV1 homology model provided insight into its specific binding mode.
Revised
Accepted
Available online
Keywords:
Vanilloid Receptor 1
TRPV1 Antagonist
Capsaicin
ⓒ 2014 Elsevier Ltd. All rights reserved.
Resiniferatoxin
Molecular modeling
The transient receptor potential V1 (TRPV1) receptor is a
non-selective cation channel with high Ca2+ permeability which
functions as a molecular integrator of nociceptive stimuli
predominantly expressed on sensory neurons.1 The receptor is
activated by a diverse range of stimuli including protons,2
noxious heat,3 endogenous mediators4,5 and natural products such
as capsaicin (CAP)6 and resiniferatoxin (RTX)7. Since the
increase in intracellular Ca2+ upon TRPV1 activation causes
excitation of the primary sensory neurons and the consequent
central perception of pain, the blocking of TRPV1 provides a
promising strategy for the development of novel analgesics,
particularly for neuropathic pain.8 In consequence, an intense
effort has been made to identify potent and selective TRPV1
antagonists, with numerous reviews summarizing their
therapeutic development and documenting their clinical
development.9-15
F3C
F3C
H
N
H
N
N
F
N
F
O
S
*
O
O
S
N
O
R
N
H
N
H
O
O
2
1
Figure 1. Structural series of TRPV1 antagonists (1) and lead antagonist (2)
Recently, we reported that compound 2, the lead structure
from series 1, showed highly potent antagonism to multiple
o
TRPV1 activators including capsaicin, pH, heat (45 C) and
NADA (for example, Ki(CAP) = 0.2 nM, IC50(pH) = 6.3 nM)
(Figure 1). In addition, compound 2 demonstrated strong
analgesic activity in the rat neuropathic pain model with almost
no off-target effects and it blocked capsacin-induced
hypothermia, consistent with its in vitro mechanism of action.16
The modeling analysis of 2 using our hTRPV1 homology model
suggested that its high potency could be attributed to a new
hydrophobic interaction provided by the 4-methylpiperidine
moiety in addition to that by the 6-trifluoromethyl group in the
_________
＊ Corresponding author. Tel.: +82 2 880 7846; fax: + 82 2 888 0649.
E-mail address: jeewoo@snu.ac.kr (J. Lee).

C-region. Consistent with the modeling, the SAR analysis with
other 2-substituents in the pyridine C-region, 2-oxy17 and 2-thio18
derivatives, indicated that a hydrophobic interaction by the 2-
substituents with the receptor was critical for its potent
antagonism.
in our previous report. The nitrile reduction of 3 and 4 followed
by coupling with propanoic acid 719 provided the final
compounds 8 and 9. The 2-methyl derivative 12 was synthesized
starting from commercially available nicotinic acid 10 in
conventional 4 steps (Scheme 1).
A library of alkynyl, alkenyl and alkyl groups were reacted with
2-chloropyridine 5 to afford 2-substituted pyridines 13 using a
palladium-catalyzed coupling reaction (Suzuki reaction for 13a
and 13f-13n and Sonogashira reaction for 13b-13e). Nitriles 13
were either fully reduced to yield the corresponding primary
amines 14a-14n with 2-alkyl substituents or chemoselectively
reduced to give the amines 14o-14u with 2-alkenyl substituents.
The amines of 14 were coupled with racemic or chiral propanoic
acid 7 to provide the corresponding final compounds 15a-15u,
(Scheme 2). Alternatively, the 2-alkenyl analogues (16a-e) were
synthesized directly from the 2-chloro substituted compound 8
by Suzuki coupling (Scheme 3).
In order 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-alkyl type
derivatives as hTRPV1 antagonists. With a selected potent
antagonist in the series, we have further characterized its
analgesic activity and its inhibition of capsaicin-induced
hypothermia in animal models and we have performed molecular
modeling with our hTRPV1 homology model.
The key intermediates of the C-region, 2-chloropyridine 3
and 2-bromopyridine 4, were prepared from the corresponding
pyridone using POCl3 or PBr3, respectively, using the procedure
Scheme 1. Synthesis of 2-halo and 2-methyl derivatives
Reagents and conditions: (a) BH3-SMe2 in THF, 80-90%; (b) Compoud 7, EDC, HOBt, TEA, CH3CN, 70-80% (c) LiAlH4, THF, 75%; (d) DPPA, NEt3, toluene,
72%; (e) PPh3, H2O, 85%
Scheme 2. Synthesis of 2-alkyl, 2-cycloakyl, and 2-cycloalkenyl derivatives
Reagents and conditions: (a) 13a: CH3CH=CH-B(OH)2, Pd(PPh3)4, Na2CO3, toluene/1,4-dioxane, reflux, overnight, 63%, 13b-13e: Pd(PPh3)4, CuI, NEt3 or
DIPEA, toluene or NMP, 90 oC, overnight, 50-75%, 13f-13n: R-B(OH)2, Pd(PPh3)4, Na2CO3, toluene/EtOH, 45-80%; (b) 14a-14n: H2, Pd-C, c-HCl, MeOH, RT,
overnight, 40-92%, 14o-14u: Raney Ni, NH3 in MeOH, 50-75%; (c) Compound 7, EDC, HOBt, TEA (or DIEA), CH3CN (or DMF), 70-90%
Scheme 3. Synthesis of 2-alkenyl derivatives
Reagents and conditions: (a) R-B(OH)2, Pd(PPh3)4, Na2CO3, toluene-EtOH, 100 oC, 1 h, microwave, 62-72%

The synthesized TRPV1 ligands were evaluated in vitro for
antagonism as measured by inhibition of 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 and 2, together
with the potencies of the previously reported racemate of 2
(Ki(CAP) = 0.3 nM) as a reference.16
The SAR of 2-alkenyl derivatives was also investigated. The
isobutenyl derivative 16a exhibited moderate antagonistic
activity intermediate between the activities of 15a (3 carbons)
and 15b (5 carbons). Whereas the trans-pentenyl derivative 16b
showed potency comparable to the corresponding saturated
derivative 15b, the cis-pentenyl derivative 16c was 2-fold less
potent than 15b. Compounds 16d and 16e exhibited similar,
potent antagonism comparable to the corresponding saturated
derivative 15e.
First, we examined the 2-chloro (8) and 2-bromo (9)
derivatives which were the synthetic precursors for the synthesis
of the 2-alkenyl derivatives. They were found to be weak
antagonists, probably due to low lipophilicity or insufficient size
to make hydrophobic interactions with the receptor.
Next, we sought to evaluate the SAR of 2-cyclohexyl
derivatives because previous reports indicated that the 2-
cyclohexyl analogues in a series of 2-oxy and 2-thio derivatives
provided potent antagonism (Table 2).17,18 The cyclohexyl
derivative 15f showed potent antagonism with Ki(CAP) = 0.6 nM,
To investigate the SAR for 2-alkyl/alkenyl derivatives of the
pyridine C-region, we began by examining the effect of linear
alkyl chains on the antagonism of capsaicin response.
Antagonistic activity increased with the number of carbons in the
chain up to 5 carbons as seen with 12, 15a, 15b. However, as
seen with 15c, the antagonism decreased after that, indicating
that the number of carbons in this series which appeared to be
optimal for antagonism was five. A similar pattern was observed
in our previous SAR analysis with the series of the
corresponding linear 2-alkyloxy17 and 2-alkylthio18 derivatives,
for which once again the 2-butyloxy and 2-butylthio derivatives,
corresponding to 5 carbons, were optimal with low lipophilicity
and potent antagonism. The branched derivatives 15d and 15e
showed better antagonism than the corresponding straight
derivative 15c by ca. 2-fold, suggesting that the hydrophobic
pocket for the 2-alkyl chain could be better filled by the
branched group.
which was
corresponding linear derivative 15c.
a
2.5-fold improvement over that of the
further 2-fold
A
improvement in potency, with Ki(CAP) = 0.3 nM, was obtained
with (S)-15f, the eutomer of 15f.
Table 2. In vitro hTRPV1 antagonistic activities for 2-cyclohexyl derivatives
Ki
[CAP]
(nM)
Ki [CAP]
(nM)
R
R
15f
0.6
0.3
0.4
0.3
0.2
0.3
1.3
0.3
0.4
0.3
1.5
15n
1.5
(S)-15f
15g
(S)-15n
15o
0.8
0.7
0.3
0.2
0.2
0.1
0.1
0.2
0.1
0.2
0.1
Table 1. In vitro hTRPV1 antagonistic activities for acyclic 2-alkyl and 2-
alkenyl derivatives
F3C
H
N
N
F
15h
15p
O
S
O
R
N
H
O
(S)-15h
15i
(S)-15p
15q
Ki [CAP]
(nM)
Ki [CAP]
(nM)
R
R
rac-2
8
0.3
WE
169
387
22.7
1
15d
15e
16a
16b
16c
16d
16e
0.9
0.6
11.5
0.9
2.1
0.7
0.7
15j
15r
15k
15s
9
15l
15t
12
(S)-15l
15m
(S)-15t
15u
15a
15b
15c
(S)-15u
1.6

We next explored 4-alkyl cyclohexyl derivatives based on
the previous SAR results from the series of 2-piperidinyl, 2-
cyclohexyloxy and 2-cyclohexylthio derivatives,16-18 which
indicated that alkyl substituents at the 4 position further
improved potency. The 4-methyl cyclohexyl derivative 15g
showed better antagonism than the parent 15f and the 4-ethyl
derivative 15h exhibited further enhanced potency with a 2-fold
increase compared to 15f. The 4-t-butyl cyclohexyl derivative
15i was found to be as potent as the 4-ethyl derivative 15h and
its trans isomer 15k was found to be the preferred geometric
isomer. The 4,4-dimethyl cyclohexyl derivative 15l also
exhibited potent antagonism comparable to the 4-monoalkyl
derivatives. However, the 4,4-difluoro cyclohexyl derivative
displayed reduced potency, presumably due to its polarity. The
bicyclic derivative 15n was 2.5-fold less potent than the
corresponding monocycle 15f. We conclude from this SAR
analysis of our series of cyclohexyl derivatives that 4-alkyl
groups further improved the potency, providing better
hydrophobic interaction with the receptor as found in 15h, 15i
and 15l.
Table 3. In vitro antagonism of 15f for various activators of human TRPV1
Activators, parameter
15f
CAP, K (nM)
i
0.6
43.4
14.1
0.2
pH, IC50 (nM)
heat 45oC, IC50 (nM)
NADA, Ki (nM)
Table 4. Inhibition of capsaicin-induced hypothermia and analgesic activity
of compound 15f on CCI-induced cold allodynia after oral administration in
mouse. Data, n = 10, mean SEM, * p<0.05 vs vehicle. MPE, maximal
possible effect.
0.1 mg/kg
24% inh.
0.3 mg/kg
78% inh.
1 mg/kg
10 mg/kg
CAP-induced
Hypothermia
Bennett Model
25 MPE
53 MPE
60 MPE
Finally, we examined 2-cyclohexenyl derivatives as rigid
analogues of the corresponding cyclohexyl derivatives.
Generally, the cyclohexenyl derivatives exhibited better potency
compared to the corresponding cyclohexyl derivatives. The
cyclohexenyl derivative 15o showed similar potency compared
to the parent cyclohexyl derivative 15f. Impressively, the
introduction of alkyl groups on the cyclohexene such as 4-
methyl (15p), 3-methyl (15q and 15r), 4-ethyl (15s), 4-t-butyl
(15t), and 4,4-dimethyl (15u) led to extremely potent antagonists
with a range of Ki(CAP) = 0.1-0.3 nM. As eutomers, the (S)-
isomers of 15h, 15l, 15n, 15p, 15t and 15u were synthesized
independently and found to be ca. 2-fold more potent than the
corresponding racemates as expected.
Using our human TRPV1 (hTRPV1) model16 built based on
our rat TRPV1 (rTRPV1) model21, we performed a flexible
docking study of (S)-15f. As illustrated in Figure 2, (S)-15f
displayed a binding mode generally similar to that of 216. The
sulfonylaminobenzyl group (A-region) occupied the deep bottom
hole and was involved in the hydrophobic interactions with
Val508, Tyr511, Ile564, Tyr565, and Ile569. A fluorine atom of
the A-region participated in hydrogen bonding with Ser512 and
the NH of the sulfonamide group made hydrogen bonds with
Tyr565. The amide group (B region) made a hydrogen bond with
Tyr511 and also contributed to the appropriate positioning of the
C-region for its hydrophobic interactions. In addition, the 3-
trifluoromethyl group (C-region) extended toward Thr550 in the
hydrophobic area. The pyridine ring (C-region) made
hydrophobic interactions with Tyr554 and the adjacent monomer
Phe587. Furthermore, the cyclohexyl group in the C-region made
an additional hydrophobic interaction with Leu515.
Overall SAR analysis indicated that the antagonism in a
series of 2-alkyl/alkenyl pyridine C-regions showed the
following order of potency: cycloalkenyl > cycloalkyl >
branched alkyl > linear alkyl. 4-Alkyl groups on the ring
improved the potency further.
Next, the in vitro activity of compound 15f, taken as a
representative antagonist in this series, was investigated by using
other TRPV1 activators (Table 3). We found that compound 15f
also showed excellent antagonism toward activators other than
capsaicin such as pH, heat (45oC) and N-arachidonoyl dopamine
(NADA), with potencies in the low nanomolar range.
In summary, we investigated the structure activity
relationships of 2-alkyl/alkenyl pyridine C-region derivatives of
the previous lead 2 as hTRPV1 antagonists. Multiple compounds
in the series, particularly cyclohexenyl derivatives, showed
excellent and stereospecific TRPV1 antagonism with better
potencies than reference 2. Compound 15f was selected for
further study and was shown to antagonize capsaicin-induced
hypothermia in a dose-dependent manner, consistent with its
action in vivo being through TRPV1, and it demonstrated strong
analgesic activity in a rat neuropathic pain model. Docking
analysis of (S)-15f with our hTRPV1 homology model indicated
that (S)-15f showed a binding mode similar to that previously
reported16 for compound 2.
Consistent with its in vitro mechanism of action as an
hTRPV1 antagonist, in vivo 15f also blocked response to
capsaicin (Table 4). 15f was administered orally at doses of 0.1
and 0.3 mg/kg 15 min before intraperitoneal injection of 3
mg/Kg capsaicin, following the procedure described
previously.16 These doses of 15f inhibited the hypothermic
response to capsaicin, assayed 30 min after capsaicin injection,
by 24% and 78%, respectively. We further evaluated the
analgesic activity of compound 15f administered orally in the rat
Bennett model20 for neuropathic pain (Table 4). We found that
the 15f showed dose-dependent anti-allodynic activity with ED50
= 1.6 mg/Kg po (max 60% at 10 mg/Kg). It was thus more
potent than pregabalin (ED50 = 42.2 mg/Kg, max 69% at 100
mg/Kg) and showed approximately comparable maximal effect.
Acknowledgements
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).

(A)
(B)
(C)
LP
0.14
0.12
0.09
Thr550
0.07
0.05
0.03
0.01
Phe587
Leu515
-0.02
-0.04
-0.06
-0.08
-0.11
-0.13
Tyr511
Tyr554
Ile569
Ser512
Val508
-0.15
-0.17
-0.19
Ile564
Tyr565
Figure 2. Flexible docking result of (S)-15f in the hTRPV1 model.
(A) Predicted binding mode of the (S)-15f. The key interacting residues are marked and displayed as capped-stick with carbon atoms in white. The helices are
colored by gray and the helices of the neighboring monomer are displayed in line ribbon. (S)-15f is depicted as a ball-and-stick with carbon atoms in magenta
and the van der Waals surface of the ligand is presented with its lipophilic potential property. Hydrogen bonds are shown as black dashed lines and non-polar
hydrogens are undisplayed for clarity. (B) Surface of hTRPV1 and the docked ligand. The Fast Connolly surface of hTRPV1 was generated by MOLCAD and
colored by the lipophilic potential property. For clarity, the surface of hTRPV1 is Z-clipped and that of the ligand is in its carbon color. (C) Van dar Waals
surface of the ligand colored by its lipophilic potential property.
Stockhausen, H.; Kögel, B. Y.; Schiene, K.; Christoph, T.; Lee,
J. J. Med. Chem. 2012, 55, 8392.
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2-Alkyl/Alkenyl Substituted Pyridine C-region Leave this area blank for abstract info.
Analogues of 2-(3-Fluoro-4-methylsulfonylaminophenyl)
propanamides as Highly Potent TRPV1 Antagonists
HyungChul Ryu, Sejin Seo, Seong-Hee Cho, Ho Shin Kim, Aeran Jung, Dong Wook Kang, Karam Son,
Minghua Cui, Sun-hye Hong, Pankaz Kumar Sharma, Sun Choi, Peter M. Blumberg, Robert Frank-Foltyn,
Gregor Bahrenberg, Hannelore Stockhausen, Klaus Schiene, Thomas Christoph, Sven Frormann, Jeewoo Lee*
F3C
H
N
N
F
*
O
O
R
N S
H
O
R = Alkyl, Alkenyl