Synthesis of Analogues of BCTC Incorporating a Pyrrolidinyl Linker and Biological Evaluation as Transient Receptor Potential Vanilloid 1 Antagonists

Article abstract of DOI:10.1111/cbdd.12661

A series of novel pyrrolidinyl linker TRPV1 antagonists were prepared in an effort to lower the hyperthermic side-effects of first-generation antagonist BCTC. These compounds were investigated for antagonism of hTRPV1 activation by capsaicin and acid in vitro. Preliminary results suggested the compounds 10a, 10b, 10c and 10j had favorable TRPV1 antagonism activity. In further studies in vivo, 10b, comparable to BCTC, showed potent analgesic activity in capsaicin-induced and heat-induced pain models. In addition, 10b indicated a reduced risk of body temperature elevation. All of these demonstrated that 10b can be considered as a safe candidate for the further development of analgesic drugs. A series of novel pyrrolidinyl linker TRPV1 antagonists were prepared in an effort to lower the hyperthermic side-effects of first-generation antagonist BCTC. These compounds were investigated for antagonism of hTRPV1 activation by capsaicin and acid in vitro. Preliminary results suggested the compounds 10a, 10b, 10c and 10j had favorable TRPV1 antagonism activity. In further studies in vivo, 10b, comparable to BCTC, showed potent analgesic activity in capsaicin-induced and heat-induced pain models. In addition, 10b indicated a reduced risk of body temperature elevation. All of these demonstrated that 10b can be considered as a safe candidate for the further development of analgesic drugs.

Full text of DOI:10.1111/cbdd.12661

Chem Biol Drug Des 2016; 87: 306–311
Research Article
Synthesis of Analogues of BCTC Incorporating a
Pyrrolidinyl Linker and Biological Evaluation as
Transient Receptor Potential Vanilloid 1 Antagonists
Lin Yan1,†, Jingjie Wang2,†, Miaobo Pan2,†
,
high efficacy and potency have been identified (8,9). How-
Qianqian Qiu2, Wenlong Huang2,* and Hai Qian2,*
ever, few candidates have progressed into clinical trials
because of serious hyperthermic side-effect (10–12).
Therefore, the key challenge in developing TRPV1 antago-
nists for pain management is to try to avoid hyperthermia.
1Institute of Chemistry & Biology, Henan University,
Kaifeng 475004, China
2State Key Laboratory of Natural Medicines, Center of
Drug Discovery, China Pharmaceutical University, 24
Tongjiaxiang, Nanjing 210009, China
In 2003, Sun et al. (13) reported a potent and orally avail-
able TRPV1 antagonist, BCTC(1) effectively reversed the
behavioral effects of inflammatory and neuropathic pain in
rats, but its hyperthermia side-effect had led to poor
patient compliance, thus hindering its development
(14,15). We therefore initiated our SAR effort with the aim
of identifying novel potent TRPV1 antagonists based on
BCTC with minimized hyperthermic side-effect.
*Corresponding authors: Wenlong Huang,
ydhuangwenlong@126.com; Hai Qian,
qianhai24@163.com
†These authors contributed equally to this work.
A series of novel pyrrolidinyl linker TRPV1 antagonists
were prepared in an effort to lower the hyperthermic
side-effects of first-generation antagonist BCTC. These
compounds were investigated for antagonism of
hTRPV1 activation by capsaicin and acid in vitro. Prelim-
inary results suggested the compounds 10a, 10b, 10c
and 10j had favorable TRPV1 antagonism activity. In fur-
ther studies in vivo, 10b, comparable to BCTC, showed
potent analgesic activity in capsaicin-induced and heat-
induced pain models. In addition, 10b indicated a
reduced risk of body temperature elevation. All of these
demonstrated that 10b can be considered as a safe can-
didate for the further development of analgesic drugs.
During the past decade, diverse BCTC analogues have
been synthesized to improve the pharmaceutical and
pharmacological profile. These structural modifications
mainly focused on these positions (Figure 1). (i) Modifica-
tion of the linker 1: Central piperazine ring in BCTC was
replaced with a phenyl ring or tetrahydropyridine ring to
yield compounds with significant distribution into the CNS
(16). (ii) Modification of the region B: The urea in BCTC
act as H-bond interactions can be transformed into amide
(17) or quinazoline (18) and 6,6-heterocycle (19). (iii) Modi-
fication of the region B and C: Refinements of the urea
motif, such as restricting the number of accessible confor-
mations, have provided examples such as the benzimida-
zole and indazolone analogues (20,21). Analysis of the
structure of BCTC and analogues of BCTC indicated that
the linker between regions B and C is absent (22). On the
other hand, most recently, Rami et al. (23) reported a
pyrrolidinyl urea derivative (SB-705498, 2) as a potent
antagonist toward multiple modes of activation of TRPV1,
which was reported to significantly reduce both (i) cap-
saicin-evoked flare and heat-evoked pain on non-sensi-
tized skin and (ii) heat-evoked pain after ultraviolet B-
evoked inflammation in Phase I trials (24). It is worth point-
ing out that hyperthermia was not described as one of the
adverse effects for this compound, despite suggesting
redundancy in Phase II trials (25). Furthermore, pyrrolidinyl
skeleton has an extensive history of use in the pharma-
ceutical industry. With these concerns in mind, we first
synthesized novel analogues of BCTC incorporating a
pyrrolidinyl linker into regions B and C in an attempt to
lower the hyperthermic side-effect.
Key words: analgesic, BCTC, hyperthermia, transient recep-
tor potential vanilloid type 1
Abbreviations: %MPE, percent maximal possible effect;
BCTC, N-(4-(tert-butyl) phenyl)-4-(3-chloropyridin-2-yl) piper-
azine-1-carboxamide; TLC, thin layer-chromatography;
TRPV1, transient receptor potential vanilloid type 1.
Received 18 July 2015, revised 12 August 2015 and
accepted for publication 6 September 2015
TRPV1 is a non-selective cation channel that is polymodal,
being activated by multiple unrelated stimuli such as
exogenous ligands (e.g. capsaicin from chili peppers, pep-
tide toxins from tarantula venom) (1), heat (> 43 °C), low
pH (< 5.9), and certain endogenous substances [e.g.
anandamide (2), N-arachidonoyl-dopamine (3)] produced
by inflamed tissues. TRPV1 channel blocked leads to anal-
gesia in several animal models, which renders TRPV1 as
next molecular target for treating pain (4–7). During the
past decade, various classes of TRPV1 antagonists with
306
ª 2015 John Wiley & Sons A/S. doi: 10.1111/cbdd.12661

Novel BCTC Analogues as TRPV1 Antagonists
Linker-1
O
N
N
H
N
N
Cl
O
O
R
Region A
Region C
Region B
N
N
N
H
H-bond acceptor/
aryl interaction
Lipophilic
sidechain
H-bond
N
N
interactions
1 (BCTC)
Cl
Br
Linker-2
H
N
H
N
N
CF3
O
N
Figure 1: Design of analogues based on
BCTC as new TRPV1 antagonists.
2 (SB-705498)
All the animals were acclimatized for a week before use.
The institutional animal ethics committee has approved the
protocol adopted for the experimentation of animals.
Methods and Materials
General
All reagents were purchased from Shanghai Chemical
Reagent Company, Shanghai, China. Column chromatog-
raphy (CC, 100-200 mesh silica gel60) and thin-layer
chromatography (TLC) were purchased from Qingdao
Ocean Chemical Company, Qingdao, China. The struc-
tures of target compounds were ensured by NMR, MS,
IR, and elementary analysis. NMR spectra were recorded
in CDCl3 on a Bruker ACF-300Q instrument (300 MHz
for 1H, 75 MHz for 13C; Bruker Instruments, Inc., Biller-
ica, MA, USA). Chemical shifts are expressed in d values
in ppm with tetramethylsilane (TMS) as internal standard.
Data are reported as follows: chemical shift, multiplicity
Transient receptor potential vanilloid type1
antagonistic activity assays in vitro
-
Culture plates with Ca2+ and Mg2+-free phosphate-
buffered saline supplemented with 5 mM ethylenedi-
aminetetra-acetic acid were used for the TRPV1 aequorin
cells (Perkin Elmer, Waltham, MA, USA) growth. The cells
were pelleted for 2 min at 1000 g, resuspended in Dul-
becco’s minimum essentialmedium-F12 medium with
15 mM HEPES (pH 7.0) and 0.1% BSA (assay buffer) at a
density of 3 9 105 cells/mL, and incubated for 4 h in the
dark in the presence of 5 mM coelenterazine h (Promega,
Madison, WI, USA). After loading, cells were diluted with
assay buffer to a concentration of 5 9 106 cells/mL.
Twenty microliters of cells was injected over 20 lL of the
sample solution plated on 384-well plates, respectively,
unless otherwise indicated. The digitonin, ATP (Sigma-
aldrich, St Louis, MO, USA), and assay buffer were added
in the blank control wells for reference, and final concen-
tration of digitonin and ATP was 100 and 50 lM. The sam-
ple solutions at different concentrations and the cells were
incubated for 2.5 min before the addition of agonists cap-
saicin (Tocris, Bristol, UK) and HCl solution at pH 5 and
then immediately detected. The light emission was
recorded during variable times using EnVision2014 Multil-
abel Reader (PerkinElmer; 26,27).
(s = singlet,
d = doublet,
t = triplet,
q = quartet,
br = broad, m = multiplet), coupling constant (Hz), and
integration. ESI-MS was recorded with Waters ACQUITY
UPLC Systems with Mass (Waters, Milford, MA, USA). IR
spectra were recorded on Shimadzu FTIR-8400S spec-
trophotometer (Shimadzu, Tokyo, Japan). Elemental anal-
ysis was recorded on the CHN-O-Rapid instrument.
Melting points were measured using a Mel-TEMP II melt-
ing point apparatus, which was uncorrected. Percentage
purity of the target compounds (> 97%) were determined
by HPLC analysis (Shimadzu).
Pharmacology
The synthesized compounds were investigated for TRPV1
antagonistic activity in vitro, analgesic activity in vivo, and
the effect on body temperature. The test compounds and
the standard drugs were administered in the form of a
suspension (using 0.5% sodium carboxymethyl cellulose
Analgesic activity
Capsaicin test
as
a vehicle) by intragastric administration. Separate
As previously described, we evaluated analgesic activity in
the capsaicin-induced pain model (28). Mice were grouped
randomly according to the weight, and each group had
eight mice. Twenty microliters of solution of capsaicin
(16 lg/20 mL) was injected s.c. under the skin of the dor-
sal surface of the right hindpaw. The mouse was then
placed in an individual cage. The amount of time spent
groups of KM male mice (n = 8), weighing 18–22 g, were
pretreated with compounds (30 mg/kg unless otherwise
indicated) 30 min before the test. The animals were pro-
cured from the Comparative Medicine Centre of Yangzhou
University (Jiangsu, China) and were maintained in colony
cages at 25 Æ 2 °C, relative humidity 45–55%, under a
12-h light/dark cycle; they were fed standard animal feed.
Chem Biol Drug Des 2016; 87: 306–311
307

Yan et al.
licking the injected paw was measured and expressed as
the cumulative licking time for 5 min after the capsaicin
injection.
ture was presented as M temperature = the temperature
at the certain time after dosing – the temperature at
0 min after dosing.
Abdominal constriction test
Statistical analysis of the data
Abdominal constriction test was performed as described
previously to assess analgesia of pain activated by acid
(26). Mice were grouped randomly according to the
weight, and each group had eight mice. We placed mice
in individual glass cylinders for a 30-min acclimatization
period, injected with 0.6% acetic acid (0.1 mL/10 g/
mouse i.p.), and immediately placed inside transparent
glass cylinders. The number of writhes was recorded for
15 min.
Statistical analyses were performed using specific software
(GRAPHPAD INSTAT version 5.00; GraphPad Software, San
Diego, CA, USA). Comparisons were analyzed using a
one-way analysis of variance (ANOVA) followed by Dunnett’s
multiple comparison test, unless otherwise stated.
p < 0.05 is regarded as statistically significant.
Results and Discussion
Chemistry
Tail-flick test
The synthetic route employed to prepare the target com-
pounds is shown in Scheme 1. Commercially available
2,3-dichloropyridine(3) reacted with piperazine in n-bu-
tanol to produce the intermediate 5. Reaction of N-Boc-
L-proline (6) with substituted anilines produced intermedi-
ates 8a–j. The Boc protecting group was removed by
treatment with 1N HCl in acetic ether, leading to 9a–j as
hydrochloride salt in high yield. Subsequently, the target
compounds 10a–j were prepared by coupling 9a–j with
intermediate 5 in the presence of triphosgene. The chem-
ical synthesis details were presented as supporting infor-
mation.
Tail-flick test was carried out as previously performed (29).
Mice were grouped randomly according to the weight, and
each group had eight mice. Briefly, in a water bath main-
tained at 52 °C, the distal one-third of the mouse tail was
immersed. Latency times until a tail-flick response were
recorded before and after drug treatment. The antinoci-
ception response was presented as percent maximal pos-
sible effect (%MPE) as defined by %MPE = 100% 9 (drug
response time – basal response time)/(cutoff time – basal
response time). A cutoff time of 12 seconds was applied
to avoid tissue damage.
Effect on body temperature
Pharmacology
Mice were grouped randomly according to the weight,
and each group had eight mice. They were intragastric
administered with synthesized compounds (30 mg/kg,
i.g.), BCTC (30 mg/kg, i.g.), or an equal volume of vehi-
cle. The body temperature of mice was monitored by
inserting the electric probe thermometer (MT-1C/F; Rui-
dien, Shenzhen, China) into the anus at 0, 30, 60, 90,
and 120 min after dosing. The effect on body tempera-
The compounds were evaluated for their ability to block
capsaicin (CAP) or low pH-induced activation of human
TRPV1 channels and the results are shown in Table 1. We
found that the potency at TRPV1 was sensitive to the sub-
stitution on the aryl amides. Compounds possessing elec-
tron-withdrawing substituent showed no antagonist activity
in either the pH or CAP assays. In contrast, the unsubsti-
tuted analogue (10a) and electron-donating substituents,
H
N
N
N
Cl
a
+
N
Cl
O
O
N
H
R
Cl
N
N
N
H
N
H
d
N
N
3
4
5
Cl
O
10a-j
O
NH2
O
b
c
+
N
H
HN
N
Boc
HN
N
Boc
OH
R
R
R
.HCl
6
7a-j
9a-j
8a-j
Scheme 1: Synthesis of the target compounds 10. Reagents and conditions:(a) n-butanol, reflux; (b) EDCI/DMAP; (c) HCl/EtOAc; (d)
CH2Cl2, triphosgene/Et3N, one pot.
308
Chem Biol Drug Des 2016; 87: 306–311

Novel BCTC Analogues as TRPV1 Antagonists
Table 1: In vitro ability of compounds to inhibit the activation of
hTRPV1 receptors
It indicated that all test compounds are effective in treat-
ment of capsaicin-induced pain. In the abdominal constric-
tion test, all compounds significantly reduced the number
of writhes in proton-induced pain models and compound
10j exhibited better potency than BCTC, while 10b had
much weaker effects compared to other compounds. In
the tail-flick test, compounds 10a and 10b showed similar
%MPE to BCTC, while 10j exhibited no effects in treat-
ment of heat-induced pain, although it exhibited best anal-
gesic activity in treatment of proton-induced pain. All the
test compounds had antinociceptive activity to a certain
extent. Compound 10a showed effective treatment in pro-
ton- and heat-induced pain, and no improvement in the
tail-flick test. Compound 10b had significant effect on cap-
saicin-induced pain and good effect in the tail-flick test;
however, it exhibited very weak effect in the abdominal
constriction test, which was consistent with its in vitro abil-
ity. We assume that the different effects of test com-
pounds in the three models of pain may be attributed to
the different analgesic mechanisms with different effects
on the body temperature.
O
O
R
N
N
N
H
N
N
Cl
hTRPV1(CAP)
IC50 (lM)a
hTRPV1(pH)
IC50 (lM)b
Compounds
R
10a
10b
H
4-tBu
2-CH3
2-OCH3
4-CH3
4-F
0.115
0.237
0.334
3.3
5.4
ND
0.013
0.356
0.264
ND
ND
ND
10c
10d
10e
10f
10g
10h
3-Cl
4-Cl
ND
ND
ND
ND
10i
10j
2-Cl
2-C2H5
ND
ND
0.314
0.017
0.048
0.0058
0.0032
0.0088
BCTC
SB-705498
In a follow-up experiment, we next conducted body tem-
perature study for compounds 10a, 10b, 10c and 10j,
and compared their effects with positive control BCTC. In
our study, we found that compounds 10a, 10j, and BCTC
significantly increased the temperature relative to vehicle
from 30 min through 90 min after dosing, and with a maxi-
mum of Mtemperature occurring at 60 min (Figure 3). In
contrast, compound 10b did not exhibit significant effects.
It has previously been reported that blocking proton-in-
duced TRPV1 activation evokes the unwanted side-effect
of hyperthermia (30). These findings are particularly striking
when considered relative to BCTC, an agent which
induces robust increases in body temperature in mice in
30 mg/kg after oral administration and a potent blocker of
both capsaicin and acid activation of TRPV1 in vitro. In this
case, considering the data in the three analgesic tests,
10b was effective in treatment of capsaicin-induced and
heat-induced pain and showed a reduced risk of body
temperature elevation when compared to comparator
BCTC.
ND, not determined.
aHuman TRPV1 receptor activated by capsaicin.
bHuman TRPV1 receptor activated by low pH (5.0). Unless other-
wise stated, all values are the mean (SEM of at least three sepa-
rate experiments).
such as p-tert-butyl (10b), o-Me (10c), and o-Et (10j),
showed slight decrease when compared to compound
BCTC, while more potent than SB-705498 in CAP assay.
In pH assay, these compounds showed dramatic
decrease in potency than BCTC. So the compounds 10a,
10b, 10c and 10j that demonstrated acceptable in vitro
potency were advanced into our preliminary in vivo studies
(Table 1).
To attest the preferable compounds, three different models
of pain were selected for antinociceptive activity in vivo
(Figure 2). The total time spent licking the paw was
reduced by all test compounds in the capsaicin test, espe-
cially 10b and 10j were superior to positive control BCTC.
Figure 2: Analgesic activities of compounds in 30 mg/kg after oral administration. (A) The antinociceptive effects in the capsaicin test; (B)
suppression of acetic acid-induced writhing response; (C) inhibition of thermal nociception. Each bar represents the mean Æ SEM (n = 8).
Statistical analysis was evaluated using a one-way analysis of variance (ANOVA) followed by Dunnett’s multiple comparison test. *p < 0.05;
**p < 0.01; ***p < 0.001 compared with the vehicle group.
Chem Biol Drug Des 2016; 87: 306–311
309

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In conclusion, we have conducted SAR studies with the
goal of identifying a novel development analgesic candi-
date with minimized hyperthermic effects. This was
achieved through incorporating a pyrrolidinyl linker into
regions B and C of the lead molecule BCTC. Part of syn-
thesized compounds showed TRPV1 antagonistic potency
and exhibited different analgesic effects in the three mod-
els of pain. In particular, 10b showed good analgesic
potency in capsaicin-induced and heat-induced pain mod-
els with no meaningful hyperthermic effects. Therefore,
10b may be considered as a promising candidate for the
development of potent agents for the treatment of pain
with minimized side-effects.
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Additional Supporting Information may be found in the
online version of this article:
Appendix S1. Materials.
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