Discovery of indane propanamides as potent and selective TRPV1 antagonists

Article abstract of DOI:10.1016/j.bmcl.2019.126838

A series of indane-type acetamide and propanamide analogues were investigated as TRPV1 antagonists. The analysis of structure–activity relationship indicated that indane A-region analogues exhibited better antagonism than did the corresponding 2,3-dihydrobenzofuran and 1,3-benzodioxole surrogates. Among them, antagonist 36 exhibited potent and selective antagonism toward capsaicin for hTRPV1 and mTRPV1. Further, in vivo studies indicated that antagonist 36 showed excellent analgesic activity in both phases of the formalin mouse pain model and inhibited the pain behavior completely at a dose of 1 mg/kg in the 2nd phase.

Full text of DOI:10.1016/j.bmcl.2019.126838

Journal Pre-proofs
Discovery of Indane Propanamides as Potent and Selective TRPV1 Antagonists
Songyeon Ahn, Yong Soo Kim, Myeong Seup Kim, Jihyae Ann, Heejin Ha,
Young Dong Yoo, Young Ho Kim, Peter M. Blumberg, Robert Frank-Foltyn,
Gregor Bahrenberg, Hannelore Stockhausen, Thomas Christoph, Jeewoo Lee
PII:
S0960-894X(19)30810-8
DOI:
https://doi.org/10.1016/j.bmcl.2019.126838
BMCL 126838
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 October 2019
5 November 2019
15 November 2019
Please cite this article as: Ahn, S., Kim, Y.S., Kim, M.S., Ann, J., Ha, H., Yoo, Y.D., Kim, Y.H., Blumberg, P.M.,
Frank-Foltyn, R., Bahrenberg, G., Stockhausen, H., Christoph, T., Lee, J., Discovery of Indane Propanamides as
Potent and Selective TRPV1 Antagonists, Bioorganic & Medicinal Chemistry Letters (2019), doi: https://doi.org/
10.1016/j.bmcl.2019.126838
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Graphical Abstract
Discovery of Indane Propanamides as Potent and Selective TRPV1 Antagonists
Songyeon Ahn, Yong Soo Kim, Myeong Seup Kim, Jihyae Ann, Heejin Ha, Young Dong Yoo, Young Ho Kim,
Peter M. Blumberg, Robert Frank-Foltyn, Gregor Bahrenberg, Hannelore Stockhausen, Thomas Christoph,
Jeewoo Lee*
36
F3C
In vitro
CAP (f)Ki
H
4.1 nM (hTRPV1)
13.4 nM (mTRPV1)
weak
N
N
N
*
low pH
O
heat (45 oC)
weak
Cl
36
Formalin Model
ED50 (1st phase)
0.19 mg/kg
0.067 mg/kg
100% MPE
ED50 (2nd phase)
1 mg/kg in 2nd phase

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Discovery of Indane Propanamides as Potent and Selective TRPV1 Antagonists
Songyeon Ahn a, Yong Soo Kim a, Myeong Seup Kim a, Jihyae Ann a, Heejin Ha b, Young Dong Yoo b,
Young Ho Kim 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, Republic of Korea
b Medifron DBT, Ansan-City, Gyeonggi-Do 15426, Republic of Korea
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 indane-type acetamide and propanamide analogues were investigated as
TRPV1 antagonists. The analysis of structure-activity relationship indicated that
indane A-region analogues exhibited better antagonism than did the corresponding
2,3-dihydrobenzofuran and 1,3-benzodioxole surrogates. Among them, antagonist 36
exhibited potent and selective antagonism toward capsaicin for hTRPV1 and
mTRPV1. Further, in vivo studies indicated that antagonist 36 showed excellent
analgesic activity in both phases of the formalin mouse pain model and inhibited the
pain behavior completely at a dose of 1 mg/kg in the 2nd phase.
Keywords:
Vanilloid Receptor 1
TRPV1 Antagonist
Analgesic
2017 Elsevier Ltd. All rights reserved.
The transient receptor potential vanilloid 1 (TRPV1),
expressed in primary sensory neurons, is a molecular integrator
of nociceptive stimuli. It is activated by multiple activators such
as noxious heat, low pH, endogenous endovanilloids and natural
vanilloids such as capsaicin.4-7 While TRPV1 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 extensive efforts directed at
the development of potent TRPV1 antagonists8 have so far
yielded no clinical candidates which have advanced to Phase 3
trials. The main obstacle has been mechanism-associated side
effects such as hyperthermia or loss of sensitivity to thermal
pain. Recent reports indicate that different modes of TRPV1
activation are differentially associated with the pattern of
response at the whole animal level, suggesting that ligands with
selective modes of antagonism would be of particular interest for
avoidance of such side effects.3,9
On the basis of the three pharmacophoric regions previously
designated for capsaicin, we have investigated an extensive
series of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides
as human TRPV1 antagonists (Figure 1).10-21 Among them,
antagonists 1 and 2, the two prototypes of our antagonist,
displayed excellent antagonistic activity against multiple
activators including capsaicin, N-arachidonoyl dopamine
(NADA), low pH and heat (45 oC). The antagonism was
stereospecific to the S-configuration in the propanamide B-
region regardless of the C-region. Consistent with the in vitro
mechanism of action, the compounds antagonized capsaicin-
induced hypothermia in mice and demonstrated strong
antiallodynic activity in neuropathic pain models. The basis for
this high potency was shown by molecular docking studies using
our established hTRPV1 homology model,10 indicating that the
6-trifluoromethyl and 2-(4-methylpiperidinyl) groups in the C-
region of 1 and the 1-(3-chlorophenyl) and 3-trifluoromethyl
groups in the C-region of 2, respectively, provided the two
hydrophobic interactions with the receptor that have been
identified as critical for potent antagonism.10-14
The analysis of the structure activity relationships (SAR) of
the prototype antagonists has focused on the C-region. In the
pyridine C-region of 1, a variety of functional groups including
the amino, oxy, thio, alkyl, aryl and sulfonamido groups10-15 were
incorporated at the 2-position, the trifluoromethyl group at the 6
position was substituted with the t-butyl group16 and the pyridine
core was modified by its isomers17 or replaced by phenyl.18 In
the pyrazole C-region of 2, 3-trifluoromethyl and 3-chlorophenyl
groups were also modified with t-butyl and 3-substituted phenyl
groups, respectively.19 In addition, the SAR of the B-region
propanamide group was explored by the substitution with -
substituted acetamide20 and urea21 surrogates.
As part of our continuing effort to discover TRPV1
antagonists as clinical candidates for neuropathic pain, we now

have investigated the indane-type A-region analogues (3, 4) in
which either acetamide or propanamide was employed as the B-
region and a variety of pyridine and pyrazole derivatives
previously studied were explored as the C-region (Figure 1). In
this study, we describe the syntheses of a series of indane, 2,3-
dihydrobenzofuran and 1,3-benzodioxole derivatives and
characterize their antagonism toward activation of hTRPV1 by
capsaicin. With the most potent antagonist in the series, we
further characterize in detail its in vitro activities and evaluate its
analgesic activity in the formalin pain model.
For the syntheses of 2,3-dihydrobenzofuran and 1,3-
benzodioxole propionate analogues, commercially available
dihydrobenzofuran-5-yl acetic acid or benzodioxol-5-yl acetic
acid was protected as the corresponding ethyl ester, respectively.
The -methylation of the esters with methyl iodide followed by
hydrolysis provided the corresponding propionic acids,
respectively (Scheme 2).
The prepared acetic/propionic acids corresponding to A/B
regions were coupled with the C-region amines previously
reported, including pyridine10,16, phenyl18, and pyrazole19 cores
using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) to
provide the final compounds, respectively.
C
B
A
O
OCH3
OH
N
Y
Y
R
H
R
H
X
NH2
X
N
A
B
capsaicin
HO
A
B
a
+
N
N
O
O
Y
F3C
R
H
H
N
X
N
N
F
A
B
O
S
R = H, CH3
X = N, Y = CF3
X = C, Y = CF3
X = N, Y = t-Bu
X = C, Y = t-Bu
N
O
N
O
N
H
A = CH2, B = CH2
A = CH2, B = O
A = O, B = O
O
A = B = CH2
A = B = O
A = O, B = CH2
3
1
X
X
R
X
F3C
R
H
R
N
NH2
N
N
HO
A
H
H
N
A
a
N
N
+
N
N
N
F
A
B
N
N
O
O
B
O
S
B
O
O
Y
Y
N
H
Y
O
Cl
R = H, CH3
A = B = CH2 or O
X = CF3, t-Bu
Y = substituents
4
2
Figure 1. Design of the indane-type A-region analogues
Scheme 3. The synthesis of final compounds
Reagents and conditions: (a) EDC, HOBt, NEt3, CH3CN, r.t, 5-15 h, 85-92%.
For the synthesis of indane analogues, commercially
available 5-aminoindane was converted to 5-iodoindane by the
Sandmeyer reaction using sodium nitrite in dilute hydrogen
chloride. The Ni-catalyzed cross coupling reaction22 of 5-
iodoindane with either ethyl 2-chloroacetate or ethyl 2-
chloropropanoate provided ethyl 2-indanylacetate or ethyl 2-
indanylpropanoate which was hydrolyzed to the corresponding
acid, respectively (Scheme 1).
The in vitro assay for TRPV1 antagonism was performed
using a fluorometric imaging plate reader (FLIPR) with hTRPV1
heterologously expressed in Chinese hamster ovary (CHO)
cells.10 The 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 1-5.
First, we investigated the antagonistic activities of the six
scaffolds of the indan-5-yl, dihydrobenzofuran-5-yl, 1,3-
benzodioxol-5-yl acetamide and propanamide. For comparison,
the scaffolds were fixed with the same prototype C-region, the 6-
R
O
I
H2N
EtO
a
b
Cl
+
O
O
R
R = H2 or CH3
R = H2 or CH3
trifluoromethyl-2-(4-methylpiperidinyl)pyridin-3-yl
group
R
(Table 1). Among the representatives studied (5-10), indan-5-yl
acetamide (5) and 1,3-benzo-1,3-dioxol-5-yl acetamide (9)
exhibited promising antagonism with Ki(CAP) = 13.3 and 15.9 nM,
respectively.
HO
c
O
R = H2 or CH3
Table 1. The SAR of the A- and B-regions
Scheme 1. Synthesis of indane A-region analogues
Reagents and conditions: (a) NaNO₂, KI, HCl, H₂O, 0-5 ℃, 2 h, 60%; (b)
Mn, NiBr2bipy, CF3CO2H, DMF, 50 ℃, 15 h, 30-42%; (c) LiOH, THF:H2O
= 1:1, r.t., 15 h, 83-94%.
F3C
R
H
N
N
A
B
*
N
O
HO
HO
EtO
A
B
A
B
A
B
a,b
c
R
H
A
B
Ki(CAP) (nM)a
13.3
O
O
O
5
6
CH2
CH2
CH2
CH2
O
CH2
CH2
O
A = CH2, B = O
A = O, B = O
A = CH2, B = O
A = O, B = O
A = CH2, B = O
A = O, B = O
CH3
H
57.4
7
20.5
Scheme 2. Syntheses of 2,3-dihydrobenzofuran and 1,3-benzodioxole A-
region analogues
Reagents and conditions: (a) H2SO4, EtOH, reflux, 15 h, 80-89%; (b) NaH,
CH3I, DMF, 0 °C, 1 h, 70-75%; (c) LiOH·H2O, THF/H2O (1:1), r.t., 15 h, 90-
95%.
8
CH3
H
O
29.7
9
O
15.9
10
CH3
O
O
43.8
a Values from triplicate experiments

The result encouraged us to explore further SAR of indane
and 1,3-benzodioxole A-region scaffolds. For the SAR of the
pyridine C-region, we examined 6-t-butyl pyridine and 6-CF3/t-
butyl phenyl C-region analogues (11-16) of the indan-5-yl and
1,3-benzodioxol-5-yl acetamide and propanamide scaffolds
(Tables 2 and 3). The SAR analysis indicated that, in the indane
A-region, only the 6-CF3 phenyl analogue of indan-5-yl
acetamide (11) displayed comparable antagonism to that of 5 and,
in the 1,3-benzodioxole A-region, any modification of the
pyridine did not improve antagonistic activity compared to 9.
at the 1-position of pyrazole. (2) Whereas 3-trifluoromethyl
pyrazoles exhibited full antagonism, 3-t-butylpyrazoles shifted
the activity to partial antagonism. (3) The indane A-region
analogues displayed better antagonism than did the
corresponding 1,3-benzodioxole A-region surrogates.
Table 4. The SAR of the pyrazole C-region of the indane A-region scaffold
X
R
H
N
N
N
O
Y
Table 2. The SAR of the pyridine C-region of the indane A-region scaffold
R
X
Y
Ki(CAP) (nM)a
5.2
Y
R
H
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
H
CF3
CF3
CF3
3-Cl
X
N
N
O
H
4-F
24
H
4-Cl
37.8
11.2
2.9
H
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
CF3
3-F
R
H
X
N
C
N
C
N
C
N
C
Y
Ki(CAP) (nM)a
13.3
H
3-Cl
5
CF3
CF3
t-Bu
t-Bu
CF3
CF3
t-Bu
t-Bu
H
3-CF3
4-F
7.1
11
12
13
6
H
12.0
H
49.9
11.1
78.6
12.8
7.5
H
39.9
H
4-Cl
H
46.5
H
4-CF3
3,4-F2
3-Cl,4-F
3,5-Cl2
3-F
CH3
CH3
CH3
CH3
57.4
H
14
15
16
96.4
H
44.0
H
15.7
pAG
4.1
61.7
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
a Values from triplicate experiments
CF3
3-Cl
CF3
3-CF3
4-Cl
7.5
Table 3. The SAR of the pyridine C-region of the 1,3-benzodioxole A-region
CF3
45
scaffold
CF3
4-CF3
4-OCH3
4-OCF3
3,4-F2
3-Cl,4-F
3,4-Me2
H
51.3
WE
Y
R
H
CF3
X
N
O
O
CF3
51.6
30.5
14.7
11.3
pAG
pAG
pAG
pAG
pAG
AG
N
O
CF3
CF3
R
H
X
N
C
N
C
N
C
N
C
Y
Ki(CAP) (nM)a
CF3
9
CF3
CF3
t-Bu
t-Bu
CF3
CF3
t-Bu
t-Bu
15.9
32.4
50.5
22.7
43.8
17.3
31.4
37.2
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
17
18
19
10
20
21
22
H
3-F
H
3-Cl
H
3-CF3
4-F
CH3
CH3
CH3
CH3
4-Cl
4-CF3
4-OCH3
4-OCF3
3,4-F2
3-Cl,4-F
3,5-Cl2
62.4
WE
a Values from triplicate experiments
65.9
AG
Next, we investigated the SAR of the pyrazole C-region of
the indan-5-yl and 1,3-benzodioxol-5-yl acetamide and
propanamide scaffolds. Previously, we demonstrated that 3-CF3
and 3-t-butyl pyrazole derivatives provided the most potent
antagonism among a series of pyrazole C-region derivatives.19
Therefore, a series of 1-phenyl 3-CF3/t-butyl pyrazole analogues
were explored as the C-region in the indane and benzodioxole A-
region analogues (Tables 4 and 5).
pAG
AG
a Values from triplicate experiments
Detailed in vitro activities of 36, the most potent antagonist
in this series, were investigated for antagonism toward different
hTRPV1 activators as well as for antagonism against capsaicin
in the case of mTRPV1. In contrast to the excellent antagonism
of hTRPV1 activation by capsaicin (Ki(CAP) = 4.1 nM), compound
36 exhibited weak antagonism toward low pH (5% inhibition at
The SAR analysis of the pyrazole C-region indicated that (1) the
3-substituted phenyl displayed better antagonism than did the
corresponding 4-substituted phenyl group at the 1-position.
Among them, the 3-chlorophenyl group appeared to be optimal
o
10 M) and heat (45 C) (15% inhibition at 2.5 M). As with
hTRPV1, antagonist 36 also proved to be a highly potent

antagonist of capsaicin action against mouse TRPV1 (mTRPV1)
with Ki(CAP) = 13.4 nM.
In summary, a series of indane, 2,3-dihydrobenzofuran and
1,3-benzodioxole A-region analogues of potent antagonists 1 and
2 were investigated. Either acetamide or propanamide was
employed as the B-region and various pyridine and pyrazole
derivatives previously studied were explored in the C-region.
The analysis of SAR indicated that the indane A-region scaffold
showed better antagonism than did the corresponding 2,3-
dihydrobenzofuran and 1,3-benzodioxole scaffolds. The most
potent antagonist 36 exhibited potent and selective antagonism
toward capsaicin but weak antagonism to low pH and elevated
temperature for hTRPV1. It also displayed highly potent
antagonism to capsaicin for mTRPV1. Further in vivo studies
indicated that antagonist 36 showed excellent analgesic activity
in the formalin mouse pain model in both the 1st and 2nd phases
and inhibited the pain behavior completely at a dose of 1 mg/kg
in the 2nd phase.
Table 5. The SAR of the pyrazole C-region of the 1,3-benzodioxole A-
region scaffold
X
R
H
N
N
O
O
N
O
Y
R
H
X
Y
Ki(CAP) (nM)a
28.3
WE
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
CF3
CF3
CF3
3-Cl
4-F
4-Cl
3-F
3-Cl
H
H
53.9
38.6
9.2
H
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
CF3
H
Acknowledgments
H
3-CF3
4-F
12.2
pAG
63.2
WE
This work was supported by the Midcareer Researcher Program
(NRF-2019R1A2C2006837) funded by the National Research
Foundation of Korea (NRF).
H
H
4-CF3
4-OCH3
4-OCF3
3,4-F2
3-Cl,4-F
3,5-Cl2
3-F
H
References and Notes
H
WE
H
25.8
10.7
71
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**
**
**
**
** **
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Declaration of interests
☒ The authors declare that they have no known
competing financial interests or personal
relationships that could have appeared to influence
the work reported in this paper.
☐The authors declare the following financial
interests/personal relationships which may be
considered as potential competing interests: