Hair growth stimulator property of thienyl substituted pyrazole carboxamide derivatives as a cb1 receptor antagonist with in vivo antiobesity effect

Article abstract of DOI:10.1016/j.bmcl.2009.03.046

A few thienyl substituted pyrazole derivatives were synthesized to aid in the characterization of the cannabinoid receptor antagonist and also to serve as potentially useful antiobesity agent. Structural requirements for selective CB1 receptor antagonistic activity of 5-thienyl pyrazole derivatives included the structural similarity with potent, specific antagonist rimonabant 1. Compound 3 has been identified as a hair growth stimulator and an antiobesity agent in animal models.

Full text of DOI:10.1016/j.bmcl.2009.03.046

Bioorganic & Medicinal Chemistry Letters 19 (2009) 2546–2550
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Hair growth stimulator property of thienyl substituted pyrazole carboxamide
derivatives as a cb1 receptor antagonist with in vivo antiobesity effect q
a,
Brijesh Kumar Srivastava a, , Rina Soni , Jayendra Z. Patel a, Amit Joharapurkar b, Nisha Sadhwani d,
*
Samadhan Kshirsagar b, Bhupendra Mishra a, Vijay Takale a, Sunil Gupta a, Purvi Pandya d,
Prashant Kapadnis a,à, Manish Solanki a, Harilal Patel c, Prasenjit Mitra d, Mukul R. Jain b, Pankaj R. Patel a
a Department of Medicinal Chemistry, Zydus Research Centre, Sarkhej-Bavla N. H. 8A, Moraiya, Ahmedabad 382 210, India
b Department of Pharmacology, Zydus Research Centre, Sarkhej-Bavla N. H. 8A, Moraiya, Ahmedabad 382 210, India
c Department of Pharmacokinetics, Zydus Research Centre, Sarkhej-Bavla N. H. 8A, Moraiya, Ahmedabad 382 210, India
d Department of Cell-Biology, Zydus Research Centre, Sarkhej-Bavla N. H. 8A, Moraiya, Ahmedabad 382 210, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A few thienyl substituted pyrazole derivatives were synthesized to aid in the characterization of the can-
nabinoid receptor antagonist and also to serve as potentially useful antiobesity agent. Structural require-
ments for selective CB1 receptor antagonistic activity of 5-thienyl pyrazole derivatives included the
structural similarity with potent, specific antagonist rimonabant 1. Compound 3 has been identified as
a hair growth stimulator and an antiobesity agent in animal models.
Received 4 October 2008
Revised 28 February 2009
Accepted 9 March 2009
Available online 17 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Hair growth stimulator
CB1 antagonist
Thienyl pyrazoles
Antiobesity effect
Bioisosteric replacement
Cannabinoid receptors present in the central nervous system
have been implicated in the control of appetite, cognition, mood
and drug dependency, thus indicating a promising new approach
for reducing body weight and decreasing co-morbidities.1 A large
number of CB1 receptor antagonists and their pharmacological ef-
fects have been recently reviewed.2–4 Selective CB1 receptor antag-
onists are under development for treatment of obesity.5,6 CB1
receptors are found primarily in the brain, whereas CB2 receptors
are found predominantly in the immune cells and tissues.7–9 CB1
receptors are also found in human epidermal keratinocytes10,11
and known to modify the proliferation and differentiation of the
transformed keratinocytes.12,13
However; no report has been yet published for the role of com-
pound 1 as a hair growth stimulator. Interestingly, in a report it
has been demonstrated that the endocannabinoid N-arachidono-
ylethanolamide as well as exocannabinoid
D
9-tetrahydrocannab-
inol dose dependently inhibited hair shaft elongation and these
effects were inhibited by a selective CB1 receptor antagonist.15
Thus, CB1 receptor antagonists could prove to be an interesting
therapeutic tool to counteract hair loss and clinically manage un-
wanted hair loss as a life style drug. In continuation of our cannab-
inoid research,16 we synthesized few thienyl substituted pyrazole-
Rimonabant 1 (Fig. 1) is a potent CB1 receptor antagonist
and has been approved in Europe as antiobesity drug.14
O
N
R3
NH
O
N
R2
NH
N
q
N
N
ZRC Communication # 234.
Cl
S
Cl
Cl
R1
* Corresponding author. Tel: +91 2717 250801; fax: +91 2717 250606.
E-mail addresses: brijeshsrivastava@zyduscadila.com, bksri2000@yahoo.com
(B.K. Srivastava).
Cl
1
Cl
2-11
Present address: Department of Chemistry, The University of Warwick, United
Kingdom.
à
Present address: Department of Chemistry, University of Cambridge, United
Kingdom.
Figure 1.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.03.046

B. K. Srivastava et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2546–2550
2547
O
The target compounds 2–11 were screened in vitro in CHOK1
cells stably expressing human CB1 receptor using cAMP functional
assay and functional activity determined which was expressed as
EC50. The in vitro CB1 receptor data (Table 1) revealed that the
unsubstituted thienyl derivative 2 had 5.5-fold less CB1 activity
than rimonabant 1. The chloro thienyl derivative 3 was observed
to be 2.4-fold less active in CB1 receptor activity when compared
to compound 1.
R1
O
a
S
b
OC2H5
R1
R1
16
S
S
O
20
O
Li
1
12 R1= -H
13 R1= -Cl
14
15 R1= -I
1
R = -H
R = -H
21 R1= -Cl
17 R1= -Cl
22 R1= -Br
1
18 R1= -Br
19
R = -Br
1
1
23
R = -I
R = -I
c
O
N
O
O
The bromo thienyl derivative 4 and iodo thienyl derivative
5 exhibited 1.6-and 1.3-fold less CB1 activity respectively when
compared to compound 1. Replacement of the piperidinyl
group of 3 by pyrrolidinyl in 6 elicited decreased activity. Fur-
ther substitution of homopiperidinyl 7 showed even lower CB1
OEt
Cl
OEt
Br
OEt
N
g
N
f
N
N
N
S
S
S
Cl
Cl
R1
R1
R1
Cl
Cl
Cl
24 R1= -H
34 R1= -Cl
32 R1= -Cl
1
1
1
25
35
R = -Cl
R = -Br
33
R = -Br
26 R1= -Br
27 R1= -I
Table 1
In vitro hCB1 and hCB2 functional assay for assessing cAMP activity for 5-thienyl
pyrazole-3-carboxamide derivatives 2–11
d
O
d
R3
NH
O
O
R3
O
R2
OH
R2
OH
NH
e
e
N
N
N
N
N
N
N
N
S
S
Cl
Cl
S
R1
R1
Cl
S
R1
Cl
R1
Cl
Cl
Cl
Cl
2
11
28 R1= -H
-
36 R1= -Cl
37 R1= -Br
2-11
1
29
R = -Cl
30 R1= -Br
31 R1= -I
Compd
R1
R2
R3
hCB1 (cAMP)a,b
EC50 M)
hCB2 (cAMP)a,c
EC50 M)
(
l
(l
Scheme 1. Reagents and conditions: (a) (CH3CH2CO)2O, BF3ꢀEt2O, 118–120 °C,
30 min, 62–78%; (b) C6H10O4, LHMDS (1.06 M soln. in THF), Et2O, ꢁ78 °C, 20–22 h,
56–64%; (c) 2,4-Cl2C6H4NHNH2ꢀHCl, C2H5OH, 0–5 °C, 1 h, IPAꢀHCl, 75–78 °C, 20–
22 h: (d) KOH aq, CH3OH, H2O, 65–67 °C, 2 h; (e) R3NH2, EDCꢀHCl, HOBtꢀH2O, TEA,
dry CH2Cl2, 30–45 min; (f) NBS, (C6H5CO)2O2, CCl4, 72–74 °C, 4 h; (g) CuBr, CH3Li
(1.6 M soln. in diethylether), Et2O, ꢁ78 °C, 2 h.
3
–Cl
–Me
0.58 0.10
0.40 0.01
0.32 0.05
1.00 0.10
1.10 0.09
0.69 0.09
0.80 0.05
0.54 0.03
0.51 0.05
1.33 0.50
0.24 0.01
23.67 1.00
23.21 2.30
29.44 2.55
20.92 1.85
12.81 1.50
7.43 0.55
15.66 2.38
25.93 3.55
19.54 1.25
7.55 0.3
N
N
4
5
–Br
–I
–Me
–Me
–Me
–Me
–Me
–Me
–Et
N
N
N
N
N
N
N
N
3-carboxamide derivatives 2–11 where the 5th aryl group of rimo-
nabant has been bioisosterically replaced by thienyl group (Fig. 1)
and evaluated them for their cannabinoid receptor selectivity, anti-
obesity effect and selected compound for hair growth stimulator
property in rodent models.16j
The preparation of thienyl pyrazole-3-carboxamides 2–11 are
outlined in the Scheme 1 and were synthesized in a conventional
method as reported in literature.17–19 The thienyl derivatives 12–
15 were procured from Sigma Aldrich and ketones 16–19 were
synthesized as per the literature procedure.20 The ketones were
reacted with diethyl oxalate in the presence of lithium bis (tri-
methylsilyl) amide to afford corresponding lithium salts 20–23.
These lithium salts were reacted with 2,4-dichlorophenylhydra-
zine hydrochloride under acidic conditions to give thienyl substi-
tuted 1H-pyrazole-3-carboxylic acid ethyl esters 24–27. The
synthesis of acids 28–31, 36 and 37 involved usual basic hydro-
lysis of corresponding ester 24–27, 34 and 35.
The thienyl pyrazole-3-carboxamide analogs 2–11 were pre-
pared21 by condensing the corresponding acids 28–31, 36 and 37
with cyclic amines R3–NH2 under usual peptide bond formation
chemistry using [1-(3-dimethylaminopropyl)-3-ethyl carbodiim-
ide] hydrochloride and 1-hydroxybenzotriazole hydrate. The syn-
thesis of 4-bromomethyl ester analog 32 and 33 involved the
bromination using N-bromosuccinamide of ester 25 and 26. The
methylation of 32 and 33 was achieved using methyllithium cata-
lyzed by cuprous bromide as per the reported procedure21 to give
34 and 35.
6
–Cl
–Cl
–Cl
–Cl
–Cl
–Br
H
7
8
O
9
10
11
2
–Et
–Me
1
31.21 3.21
a
Values indicate mean SD of at least three independent experiments performed
in duplicate.
b,c
cAMP assay was carried out in Chinese Hamster Ovarian cells stably expressing
human hCB1 and hCB2 receptor, respectively.

2548
B. K. Srivastava et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2546–2550
activity than 3 and 6. Morpholine derivative 8 exhibited medi-
ocre CB1 receptor activity. The presence of more bulky bicyclic
amine 9 revived the CB1 activity up to some extent as com-
pared to compounds 6 and 7. Interestingly the chloro thienyl
derivative with ethyl side chain 10 showed better CB1 receptor
activity.
derivative 9, all showed lesser efficacy as compared to com-
pound 3 as well as compound 1 against sucrose solution con-
sumption (Table 2). The bromo thienyl substituted with ethyl
Table 4
However, bromo thienyl derivative with ethyl chain on the
position 4 of the pyrazole 11 exhibited nearly similar activity
as that exhibited by compound 3. The same set of compounds
was also evaluated for their hCB2 functional activity (Table 1).
It is clear that compounds 2–11 behave as weaker CB2R antago-
nist in cAMP assay. The CB1R agonists are reported to promote
the sucrose consumption in rodents22 and the selective CB1R
antagonists reduce sucrose feeding and drinking in rodents.23
Compounds 2–11 were further evaluated for their consumption
of 5% sucrose solution in obese Zucker rats, which have elevated
hypothalamic levels of the endocannabinoid as compared to lean
rats.24,25
The thienyl derivative 2, moderately inhibited the consump-
tion of sucrose solution as compared to compound 1 (Table 2).
The chloro thienyl derivative 3, which structurally mimics to
rimonabant, exhibited inhibition of sucrose solution comparable
to compound 1. The bromo thienyl derivative 4 and iodo thienyl
derivative 5 exhibited lower suppression of sucrose solution con-
sumption as compared to compound 3, however, the iodo thie-
nyl derivative 5 was found to be slightly superior to 1 in the
sucrose solution intake assay. Pyrrolidinyl derivative 6, homo-
piperidinyl derivative 7, morpholinyl derivative 8 and bicyclic
Mean pharmacokinetic parameter of 3 and 1 in fasted female Zucker fa/fa rats after
oral dose of 30 mg/kga
Compd
Tmax (h)
Cmax
(
lg/mL)
T1/2 (h)
AUC(0–1) (h lg/mL)
3
1
1.4 0.7
2.6 1.3
0.52 0.07
1.92 0.31
20.78 1.07
26.55 7.23
12.41 4.54
41.20 3.65
a
Values indicate mean SD for n = 6 rats.
Table 5
Tissue and plasma distribution of compounds 3 and 1 in fasted female Zucker fa/fa rat
at 3 h after oral dose of 30 mg/kga
Compd
Drug concentration
White adipose tissue
g/mL g/g
Brain
Plasma
lg/mL
lg/mL
l
g/g
l
l
3
1
0.21 0.18
0.15 0.01
0.64 0.55
0.45 0.03
0.98 0.40
1.40 0.22
2.97 1.19
4.25 0.66
0.85 0.06
0.40 0.04
a
Values indicate mean SEM for n = 6 rats.
37.5
Vehicle Control
Compd 1 (10 mg/kg, p.o.)
Compd 3 (10 mg/kg,p.o.)
35.0
Table 2
*
In vivo efficacy of 5-thienyl pyrazole-3-carboxamide derivatives 2–11 in 5% sucrose
solution intake model at single dose of 10 mg/kg in female Zucker fa/fa rats
*
*
32.5
*
*
Compd
5% Sucrose solution
% Inhibition
versus control
*
intake in 4 h in grama
30.0
27.5
Control
2
3
4
5
6
7
8
41.8 3.6
36.6 4.1
21.7 3.6
26.0 4.8
24.2 1.5
27.4 2.8
33.4 3.1
28.6 2.4
30.8 1.8
28.7 1.2
25.4 0.9
12.4 3.1
48.0 1.2
37.8 4.1*
42.10 0.6
34.3 1.3
20.1 1.7
31.5 1.2
26.3 0.9
31.3 0.8
39.2 0.6*
40.1 10.2
0
7
14
21
28
Day
Figure 2. The effect of compounds 1 and 3 on bodyweight in high fat diet-induced
obese C57BL/6J mice. P <0.05 when compared with the vehicle-treated control
group, repeat measure ANOVA followed by Dunnett’s test. Mean SEM for n = 8
*
9
rats.
10
11
1
*
25.0 4.3
100
90
a
Values indicate mean SEM for n = 6 rats in 4 h.
*
p <0.05, when compared with the control group, one way ANOVA followed by
Dunnett’s multiple comparison test.
Vehicle Control
80
Compound 1 (10mg/kg,p.o.)
70
Compound 3 (10 mg/kg,p.o.)
Table 3
60
Effect of compound 3 on CB1 agonist WIN-55212-2 (1 mg/kg, iv) induced mouse
*
tetrad modela
50
*
Compd 3
Change in
Analgesic
Catalepsyc (%
immobility on (No. of square
ring for 300 s) crossed in 300 s)
Locomotor activityd
(mg/kg, po) body temp. effectb
40
(°C)
(% MPE)
30
0 (Control)
1
3
5
4.79 0.27
88.75 2.42
95.53 7.86
20.67 3.38
69.8 5.40*
109.2 6.23*
126.5 8.37*
171.4 6.38*
2.56 0.40* 34.84 13.03* 80.73 2.35
20
1.92 0.24* 12.28 3.87*
0.23 0.09* 4.12 1.52*
0.23 0.07* 4.35 1.35*
73.13 5.50
58.13 4.33*
41.80 3.31*
10
10
a
Values indicate mean SEM for n = 6.
% MPE on hot plate.
% immobility.
0
b
c
Figure 3. The effect of compounds 1 and 3 on food intake in high fat diet-induced
obese C57BL/6J mice. P <0.05 when compared with the vehicle-treated control
d
*
No of squares crossed in 5 min.
*
P <0.05, significant differences with WIN 55212-2-treated control group.
group, One way ANOVA followed by Dunnett’s test. Mean SEM for n = 8 rats.

B. K. Srivastava et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2546–2550
2549
Figure 4. The long term (28 days) effect of control, compounds 3 and 1 (10 mg/kg) on hair growth in C57BL/6J mice: (a) high fat fed mouse as control; (b) compound 3
(10 mg/kg) repeat dose treatment in high fat fed mouse; (c) compound 1 (10 mg/kg) repeat dose treatment in high fat fed mouse.
Table 6
chain 11, showed significant suppression of sucrose solution as
The effect of compounds 1 and 3 on the hair growth on male C57BL/6J mice after 28th
day of dosing (n = 8 mice)
compared to corresponding chloro thienyl derivative 10 and
compound 1. Depending upon the in vitro hCB1 activity and pro-
Compd
Area (cm2) (mean SEM)a
nounced in vivo efficacy shown by compound 3, the effect of
compound 3 was evaluated on CB1 agonist WIN-55212-2 in-
duced hypothermia, analgesia, locomotor activity and catalepsy
in male Swiss Albino mice to further confirm its CB1 antagonism
(Table 3).26,27 Compound 3 showed dose dependent CB1 antago-
nism in this model. The pharmacokinetics parameters of com-
pound 3 were also evaluated in fasted female Zucker fa/fa rats
and compared with compound 1 (Table 4). The AUC (0–1) for
compound 3 was found to be inferior to compound 1. The tissue
and plasma distribution of compound 3 (Table 5); when com-
pared to compound 1, revealed higher drug concentration in
Treatment day 0
Treatment day 28
Control
3
1
0.297 0.021
0.292 0.024
0.256 0.074
0.346 0.079
0.011 0.023*
0.156 0.068
a
The bald area where hair growth or pigmentation has not appeared.
P <0.05, ANOVA followed by Dunnets multiple comparison test, when compared
with the vehicle-treated control group.
*
Herein, we have described compound 3 with antiobesity effect
through CB1 receptor antagonism, which structurally mimics the
rimonabant 1. Additionally, compound 3 was also efficacious in
diet-induced obese (C57BL/6J) mice, showing reduction in overall
body weight with interesting activity as a hair growth stimulator.
However, no any such hair growth stimulation was observed after
the topical application of either of compounds 3 and 1. Notably, no
report has been yet published for compound 1 as a hair growth
stimulator. Thus, this class of compounds needs further attention
as a hair growth stimulator.
the brain (0.21 0.18
compound 1(0.15 0.01
compound 3 was found to be slightly less in white adipose tis-
sues (0.98 0.40 g/mL) as compared to compound
(1.40 0.22 g/mL).
lg/mL) for compound 3 as compared to
lg/mL). However, the concentration of
l
1
l
Since, the chloro thienyl derivative 3 exhibited a significant
potency and efficacy it was subsequently taken for 28 days
chronic oral study, once daily at the dose of 10 mg/kg in
C57BL/6J mice of 6–8 weeks age with diet-induced obesity.
The diet-induced obesity in C57BL/6J mice is a well-known
model for obesity that resembles the clinical obesity in humans
and the relative potency of CB1 receptor antagonists is also
evaluated by various in vivo effects in C57BL/6J mice.28 Thus,
compounds 3 and 1 were studied in C57BL/6J mice. For all
in vivo experiments, compounds were suspended with 0.01%
Tween 80 plus 5% DMSO in saline (NaCl 0.9%) for intravenous
administration (particularly for the CB1 agonist WIN-55212-2)
or with 0.5% carboxymethylcellulose sodium salt in distilled
water for oral route. The test compounds were administered
at the dose of 10 mg/kg. All the compounds were administered
by oral route in a volume of 2 mL/kg body weight for rats and
10 mL/kg body weight for mice. WIN-55212-2 was injected
Acknowledgement
We are thankful to both the reviewers for number of valuable
suggestions, the management of Zydus Group for the encourage-
ment including Dr. B. B. Lohray and Dr. V. B. Lohray, analytical
department for analytical support, Mr. Amol Dhawas, Mr. Pravin
Kadam for synthesizing some of the intermediates, Mr. Sandeep
Shegade and Mr. Pankaj Makadia for the help in the preparation
of the manuscript.
Supplementary data
intravenous at
a dose of 1 mg/kg in mice in a volume of
10 mL/kg body weight.
Supplementary data (biological assays) associated with this
article can be found, in the online version, at doi:10.1016/
j.bmcl.2009.03.046.
Compound 3 significantly reduced the body weight gain and
food intake as compared to control (Figs. 2 and 3). The C57BL/
6J mice when fed on high fat diet for eight weeks displayed
significant alopecia (loss of hair on dorsal side, Fig. 4). These
C57BL/6J mice were divided into three groups and each group
was treated for a period of 28 days. Interestingly, compound
3 affected hair growth significantly and the bald area reduced
to 0.011 cm2 as compared to rimonabant, which showed bald
area 0.156 cm2 where hair growth has not appeared (Table 6,
Fig. 4).
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