Structure-activity relationship studies of novel pyrazole and imidazole carboxamides as cannabinoid-1 (CB1) antagonists

Article abstract of DOI:10.1016/j.bmcl.2011.06.017

The synthesis and biological evaluation of novel pyrazole and imidazole carboxamides as CB1 antagonists are described. As a part of eastern amide SAR, various chemically diverse motifs were introduced on rimonabant template. The central pyrazole core was

Full text of DOI:10.1016/j.bmcl.2011.06.017

Bioorganic & Medicinal Chemistry Letters 21 (2011) 4913–4918
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Structure–activity relationship studies of novel pyrazole and imidazole
carboxamides as cannabinoid-1 (CB1) antagonists q
⇑
Pradip K. Sasmal , Rashmi Talwar, J. Swetha, D. Balasubrahmanyam, B. Venkatesham, Khaji Abdul Rawoof,
B. Neelima Devi, Vikram P. Jadhav, Sanjoy K. Khan, Priya Mohan, D. Srinivasa Reddy,
Vijay Kumar Nyavanandi, Srinivas Nanduri, K. Shiva Kumar, M. Kannan, P. Srinivas, Prabhakar Nadipalli,
Hira Chaudhury, V. J. Sebastian
Discovery Research, Dr. Reddy’s Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500049, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis and biological evaluation of novel pyrazole and imidazole carboxamides as CB1 antagonists
are described. As a part of eastern amide SAR, various chemically diverse motifs were introduced on rimo-
nabant template. The central pyrazole core was also replaced with its conformationally constrained motif
and imidazole moieties. In general, a range of modifications were well tolerated. Several molecules with
low- and sub-nanomolar potencies were identified as potent CB1 receptor antagonists. The in vivo proof
of principle for weight loss is demonstrated with a lead compound in DIO mice model.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 22 February 2011
Revised 27 May 2011
Accepted 6 June 2011
Available online 7 July 2011
Keywords:
Cannabinoid 1 (CB1) receptor
CB1 antagonists
Pyrazole and imidazole carboxamides
Obesity
DIO mice model
The prevalence of obesity is rapidly increasing globally and no
satisfactorily safe and effective obesity drugs are available at the
moment. Recent studies have shown that impaired handling of
cellular energy homeostasis is closely associated with metabolic
syndrome including obesity, type 2 diabetes and related diseases.
The endocannabinoid system (ECS), and specifically the cannabi-
noid type 1 (CB1) receptor, plays a pivotal role in energy homeosta-
sis.1–3 As such, stimulation of the ECS promotes food intake and
energy storage and may be chronically overactive in obese sub-
jects.4–7 CB1 receptor-deficient mice are resistant to diet-induced
obesity even though their total caloric intake is similar to that of
wild-type littermates.8 In contrast, blockade of the CB1 receptor
in the central nervous system decreases food intake and increases
energy expenditure, leading to a reduction in body weight.9–12
Such an approach is particularly interesting since it not only causes
weight loss but also reverses the metabolic effects of obesity such
as insulin resistance and hyperlipidemia.13 Besides obesity, block-
ing CB1 receptor may have potential in the treatment of a number
of diseases such as neuroinflammatory disorders,14 cognitive
disorders,15 septic shock,15 psychosis,15,16 addiction,17 and gastro-
intestinal disorders.18 Another cannabinoid receptor, CB2 is related
to immune regulation and neurodegeneration.19 Therefore, the
CB2/CB1 selectivity should be taken into consideration for new
drug development of antiobesity agent. Significant efforts around
the globe led to the identification of several potent and selective
CB1 antagonists which were tested in clinical trials. Amongst these
rimonabant (1)20 (Fig. 1) was initially approved by EMEA for the
treatment of obesity but unfortunately this was withdrawn from
O
N
N
NH
N
N
N
O
N
R
NH
N
N
Cl
Cl
N
1
(rimonabant)
Cl
Cl
Cl
O
Cl
O
N
NC
Cl
N
H
3a
3b
: R = H
: R = Me
q
DRL Publication No. 728.
Corresponding author at present address: Dr. Reddy’s Laboratories Ltd, Inno-
CF3
⇑
2 (taranabant)
vation Plaza, Bachupally, Hyderabad 500090, India. Tel.: +91 40 4434 6865; fax: +91
40 4434 6125.
E-mail addresses: sasmalpk@yahoo.co.in, pradipks@drreddys.com (P.K. Sasmal).
Figure 1. Structures of CB1 antagonists.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.06.017

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P. K. Sasmal et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4913–4918
the market due to various psychiatric events. For the similar rea-
son, the development of another CB1 antagonist taranabant (2)21
was suspended from clinical trial.
Treatment of VIII with various haloketones afforded targets
17–20. Hydrolysis of 20 produced 21. Compounds 22–26 were syn-
thesized following routes as outlined in Scheme 4. The pyrazole
acid was first converted to amide IX which after four steps protocol
viz., hydrolysis of ester, Weinreb amide formation, Grignard reac-
tion and bromination produced bromo ketone X. Coupling of X
with various partners afforded the target compounds 22–26.
The synthesis of oxadiazole compounds 27–37 is outlined in
Scheme 5. Upon treatment with hydroxylamine, the cyano inter-
mediates VII were converted to N-hydroxyamidines XI which after
reaction with acetic anhydride furnished 5-methyl-1,2,4-oxadiaz-
ole derivative 27. The corresponding trifluoromethyl analogs 28
and 30–32 were prepared by the treatment of XI with trifluoroace-
tic anhydride under refluxing conditions. The isomeric 1,3,4-oxadi-
azole derivative 29 was synthesized from VII via two steps
protocols viz., tetrazole formation from cyano compound followed
by treatment of XII with trifluoroacetic anhydride. Compounds 33
and 35 were synthesized from 28 and 31 respectively by NBS med-
iated bromination followed by AgNO3 mediated hydrolysis.
However, despite consecutive failures of leading CB1 receptor
antagonists, works continue to identify novel peripherally re-
stricted CB1 antagonists22 that limit BBB penetration so that they
do not induce serious psychiatric disorders. To test this hypothesis,
recently 7TM Pharma is evaluating their peripherally restricted
CB1 antagonist TM-3883723 (structure undisclosed) in human. In
our previous communication,24 we disclosed N2-methylated tetra-
zole derivatives including compounds 3a and 3b as potent CB1
antagonists. We report herein SAR studies on novel eastern amides
along with the central pyrazole core modifications to imidazoles
and conformationally constrained tricyclic pyrazoles to identify
lead compounds.
The target compounds (Tables 1–4) were synthesized as
outlined in Schemes 1–6. The synthesis of 2-(1-methyl-1H-tetra-
zol-5-yl)propan-2-amine (III) was commenced with 2-amino-2-
methylpropanenitrile (Scheme 1). The alkylation of tetrazole I25
led to the formation of both II and IIa.26 Hydrogenolysis of II gave
the crucial intermediate III, coupling of which with various pyra-
zole acids IV24,27 furnished compounds 4–14.
Table 2
The constrained analogs 15 and 16 were synthesized following
Scheme 2. The tetrahydrobenzoannulenone derivatives V were first
converted to tetrahydrobenzocycloheptapyrazole carboxylic acid
derivatives VI which after subsequent coupling with III afforded
the desired compounds. Synthesis of compounds 17–21 is men-
tioned in Scheme 3. The coupling of 5-(4-chlorophenyl)-1-(2,4-
dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (IVa)
with aminonitrile under EDC/HOBt conditions furnished interme-
diate VII which was subsequently converted to thioamide VIII.
Rat CB1 binding affinities of compounds 17–29
O
N
R
NH
N
Cl
Cl
Cl
a
Compound
R
rCB1_IC50 (nM)
Table 1
N
N
Rat CB1 binding affinities of compounds 1–16
17
15
2
S
CF3
N
N
O
18
19
20
R2
NH
N
N
S
N
N
N
R1
22
Cl
CO2Et
CO2Et
S
N
Cl
10
S
Compound
R1
R2
rCB1_IC50 (nM)
a
CO2H
N
b
21
22
1
2
3a
3b
4
5
6
7
8
18b
0.3b
88
S
N
12
S
39
Cl
Cl
Br
Me
Et
Et
Me
Et
Et
Et
Et
Et
Et
145
0.5
0.1
1.1
22
N
S
N
23
24
121
11
N
N
N
N
N
OSO2nPr
CN
9
OMe
CO2Et
CO2H
OH
OCH2COOEt
OCH2COOH
5
25
26
27
88
63
33
10
11
12
13
14
15
16
17
Cl
c
d
e
N
N
N
CF3
Et
>1000f
31
g
N
O
a
Data are reported as the mean for n = 2 measurements and SD is generally
N
28
29
3
6
within 20% of the average.
N
CF3
b
O
N N
See Ref. 30 for comparison with literature.
50% binding at 1 lM.
23% binding at 100 nM.
32% binding at 100 nM.
c
d
e
f
CF3
O
a
25% binding at 1
lM
As in Table 1.
50% binding at 1 lM.
g
b
38% binding at 100 nM.

P. K. Sasmal et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4913–4918
4915
Table 3
a
N
N
Rat CB1 binding affinities of compounds 30–37
CbzHN
CbzHN
CN
CbzHN
+
N
N
N
N
N
N
I
N
II
N
R3
IIa
R2
CF3
N
O
N
R1
O
N
NH
O
N
b
R2
OH
N
Cl
Cl
N
N
c
R1
H2N
+
4-9
Cl
N
Cl
III
IVa-f
R1
R2
R3
rCB1_IC50 (nM)
a
Cl
1 = Cl, R2 = Me;
1 = OSO2nPr, R2 = Me;
Compound
1 = Cl, R2 = Et;
R
1 = Br, R2 = Et;
1
a:
d:
b:
R
c:
R
R
28
30
31
32
33
34
35
36
37
Me
Me
Me
Me
CH2OH
CH2OMe
CH2OH
CO2H
Me
Et
Me
Me
3
6
0.1
0.8
0.4
4
e:
f:
R
1 = CN, R2 = Et;
R
= OMe, R2 = Et
–CH2CH2–
–CH2CH2CH2–
Me
Me
–CH2CH2–
d
f
e
8
9
10
12
11
Me
Me
g
h
0.1
13
14
b
–CH2CH2–
–CH2CH2–
CO2Et
1
Scheme 1. Reagents and conditions: (a) (i) NaN3, DMF, NH4Cl, 120 °C, 16 h; (ii) MeI,
K2CO3, DMF, rt, 2 h, 26% for II and 36% for IIa over two steps; (b) Pd(OH)2/C, EtOAc,
a
As in Table 1.
b
44% and 66% binding at 100 nM and 1 lM, respectively.
H2 (balloon), rt, 14 h, 92%; (c) EDCÁHCl, HOBt, Et3N, CH2Cl2, rt, 10 h, 68–83%; (d) HCl
(g), EtOH, 0 °C, 1 h then rt, 40 h, 43%; (e) LiOH, EtOH/THF/H2O (1:1:1), rt, 4 h, 79%;
(f) BBr3, CH2Cl2, 0 °C to rt, 30 min, 63%; (g) K2CO3, DMF, bromoethyl acetate, 60 °C,
3 h, 42%; (h) LiOH, THF/H2O (1:1), rt, 4 h, 74%.
Table 4
Rat CB1 binding affinities of compounds 38–42
O
R
NH
CO2Et
A
NHNH2
·HCl
Cl
a
O
+
Cl
Cl
Li
O
O
X
X
V
X
Cl
b
(X = Cl, OMe)
N
a
Compound
A
R
rCB1_IC50 (nM)
N
N
O
O
N
NH
OH
N
N
N
N
N
b
38
c
N
N
N
N
N
Cl
Cl
N
N
X
X
N
N
39
40
41
36
3
N
N
15:
16: X = OMe
X = Cl
VI
Cl
Cl
CF3
CF3
N
N
N
N
N
O
Scheme 2. Reagents and conditions: (a) LiHMDS, ether, À78 °C, (CO2Et)2, rt, 14 h,
95%; (b) (i) EtOH, reflux, 16 h; (ii) HOAc, reflux, 12 h; (iii) KOH, MeOH, reflux, 3 h,
28% over three steps; (c) III, EDCÁHCl, HOBt, Et3N, CH2Cl2, rt, 10 h, 62–69%.
N
N
30
13
O
N
N
N
O
N
42
N
CF3
R2
R2
O
N
R1
R1
NH2
a
As in Table 1.
42% binding at 100 nM.
O
N
O
N
OH
CN
b
N
H
N
H
S
a
b
Ar1
N
Ar1
Ar1
N
N
VII
VIII
Ar2
Ar2
Ar2
Compound 34 was made by the treatment of methanol on bromo
intermediate derived from 28. The RuCl3–NaIO4 mediated oxida-
tion of 35 led to the corresponding carboxylic acid 36 which was
converted to ester 37.
The synthesis of compounds 38–42 were accomplished from
imidazole carboxylic acids XIII28 and XIV29 by standard protocols
as illustrated in Scheme 6.
IVa
Ar1 = 4-chlorophenyl
Ar2 = 2,4-dichlorophenyl
(R1 = R2 = Me)
c
f
e
d
g
21
20
19
18
17
Scheme 3. Reagents and conditions: (a) aminonitrile, EDCÁHCl, HOBt, Et3N, CH2Cl2,
rt, 10 h, 73–88%; (b) H2S, EtOH, NH4OH, À10 °C to rt, 10 h, 80%; (c) chloroacetone,
EtOH, reflux, 16 h, 74%; (d) (i) 3-bromo-1,1,1-trifluoropropan-2-one, EtOH, reflux,
16 h; (ii) PTSA, benzene, reflux, 30 min, 35% (two steps); (e) ethyl 2-chloro-3-
oxobutanoate, EtOH, reflux, 16 h, 46%; (f) ethyl 4-chloro-3-oxobutanoate, EtOH,
reflux, 16 h, 41%; (g) LiOH, THF/H2O (1:1), rt, 16 h, 95%.
The target compounds were evaluated in vitro in a rat CB1 bind-
ing assay24 and results are shown in Tables 1–4. Initially, the
N2-methylated tetrazoles of 3a and 3b were replaced with N1-
methylated tetrazoles. As mentioned in Table 1, compound 4
showed little reduction in rCB1 potency compared to 3a whereas

4916
P. K. Sasmal et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4913–4918
Br
compound 5 showed very good rCB1 binding affinity with IC50
0.5 nM compare to the potency of 3b. In general, the replacement
of p-Cl with other functionalities (Br, CN, OSO2Pr, OMe and CO2Et)
is well tolerated with the most potency of IC50 0.1 nM displayed by
bromo anlog 6 whereas the hydrogen bond donors (COOH and OH)
are detrimental to potency. The phenoxyacetate derivative 13 has
shown reduction in potency whereas the corresponding acid 14
has lost all its potency. Extending the pyrazole ethyl group to its
constrained counterpart tetrahydrobenzocycloheptapyrazole has
shown reduction in potency (5 vs 15) and further loss in potency
was observed when chloro was replaced with methoxy group (5
vs 9 and 15 vs 16).
O
N
O
N
O
OH
CO2Me
b
N
H
N
H
O
a
Ar1
N
N
Ar1
Ar1
N
IX
N
X
Ar2
Ar2
Ar2
IVa
c
g
f
e
d
22
26
25
24
23
As a part of SAR studies on eastern amide part, the tetrazole
moiety was replaced with various monocyclic and bicyclic hereto-
cycles and the results are displayed in Table 2. In general the wide
range of variations is accepted in this region though the hydrogen
bond donor as in 21 is not tolerated. The replacement of methyl
group with more lipophilic trifluoromethyl group has shown to
boost potency (17 vs 18 and 27 vs 28). The 1,3,4-oxadiazole deriv-
ative 29 has shown twofold loss in potency compared to its iso-
meric 1,2,4-oxadiazole derivative 28.
Scheme 4. Reagents and conditions: (a) (i) SOCl2, EtOH, reflux, 2 h; (ii) methyl 2-
amino-2-methylpropanoate hydrochloride, Et3N, CH2Cl2, 0 °C to rt, 14 h, 95% over
two steps; (b) (i) LiOH, THF/H2O (1:1), rt, 16 h, 93%; (ii) N,O-dimethylhydroxyl-
amine hydrochloride, Et3N, BOP, CH2Cl2, rt, 16 h, 40%; (iii) MeMgCl (3 M in THF),
THF, À78 °C, 2 h, then warming to rt, 2 h, 53%; (iv) Br2, CHCl3, 0 °C to rt, 14 h, 60%;
(c) thioacetamide, EtOH, reflux, 16 h, 46%; (d) 2-aminopyrimidine, EtOH, reflux,
16 h, 31%; (e) 2-aminothiazole, EtOH, reflux, 16 h, 35%; (f) 5-chloropyridin-2-amine,
EtOH, reflux, 16 h, 38%; (g) 5-(trifluoromethyl)pyridin-2-amine, EtOH, reflux, 16 h,
32%.
Considering various properties (c Log P, tPSA, solubility, etc.),
oxadiazoles were preferred over thiazoles for additional SAR in
the eastern part of this scaffold. Further SAR was focused on com-
pound 28 by replacing gem-dimethyl group with ethyl-methyl,
cyclopropyl and cyclobutyl groups and the results are disclosed
in Table 3. The cyclopropyl analog 31 has shown very high rCB1
affinity with IC50 of 0.1 nM. Replacement of the 4-methyl group
of pyrazole with more polar hydroxymethyl functionality as in
compound 33 and 35 displayed also low-nanomolar potency of
IC50 0.4 and 0.1 nM, respectively. The corresponding carboxylic
acid of 35 as in 36 was completely detrimental to CB1 whereas
the carbethoxy group as in 37 displayed potency of 1 nM.
The effect of replacing the pyrazole core with imidazole is pre-
sented in Table 4. The combination of imidazole core with eastern
tetrazole has shown significant reduction in rCB1 potency (39 vs 5)
though as observed before the switching methyl to ethyl at C5 of
imidazole has displayed significant improvement in potency (38
vs 39). Compared to tetrazole counterpart 39, as expected the oxa-
diazole derivative 40 has shown 12-fold improvement in potency
displaying rCB1 IC50 of 3 nM. The isomeric imidazole core as in
41 and 42 has shown to be non-optimal in this scenario.
R2
R1
N
O
N
O
N
N
N
CN
N
H
N
H
HN
XII
e
d
29
Ar1
Ar1
(R1 = R2 = Me)
N
N
VII
Ar2
Ar2
a
R2
R1
NH2
b
O
N
H
27
NOH
c
28, 30-32
N
Ar1
XI
N
Ar2
f, g
f, h
28
33
35
28
34
f, g
i
j
31
36
37
Scheme 5. Reagents and conditions: (a) hydroxylamine hydrochloride, K2CO3,
EtOH, reflux, 5 h, 60–75%; (b) acetic anhydride, 120 °C, 4 h, 58%; (c) trifluoroacetic
anhydride, reflux, 6 h, 48%; (d) NaN3, DMF, NH4Cl, 120 °C, 16 h, 90%; (e) trifluoro-
acetic anhydride, rt, 48 h, 21%; (f) NBS, benzoyl peroxide, CCl4, reflux, 5 h, 80%; (g)
AgNO3, acetone/H2O (7:3), 60 °C, 16 h, 53%; (h) MeOH, rt, 16 h, 63%; (i) RuCl3, NaIO4,
CCl4/MeCN/H2O (1:1:1); 0 °C to rt, 4 h, 36%; (j) (i) SOCl2, CHCl3, reflux, 1 h; (ii) EtOH,
rt, 1 h, 77% over two steps.
As discussed above a number of compounds with low nanomo-
lar binding affinity for CB1 have been identified. Select compounds
were tested for hCB2 receptor affinity studies and also assessed for
its central pharmacodynamic effect in the hypothermia model31
Table 5
Profile of select CB1 antagonist
O
Compound hCB2 affinity (% binding
at 1 M)
% Inhibition of
hypothermiaa
hERG_IC50
(lM)
R
OH
l
a
b, c
1
5
6
29
31
33
35
34b
99c
96
83
97
97
97
99
2.79d
38-39
40
N
N
Ar1
XIII
e
16
27
64
49
34
18
(R = Et)
(R = Me, Et)
22.7
ndf
Ar2
>30
>30
nd
l
l
Mg
Mh
O
O
CN
c
N
H
OH
b
41
42
N
N
d
Ar1
Ar1
N
Ar2
N
a
% Inhibition of WIN-55212 induced hypothermia at 30 min in SAM after com-
pound administration (10 mg/kg po).
Ar2
b
XV
XIV
hCB2_IC50 1.98 lM.
Dose 3 mg/kg po.
Reported value, see Ref. 33.
c
d
e
f
Scheme 6. Reagents and conditions: (a) III, EDCÁHCl, HOBt, Et3N, CH2Cl2, rt, 10 h,
60–67%; (b) 2-amino-2-methylpropanenitrile, EDCÁHCl, HOBt, Et3N, CH2Cl2, rt, 10 h,
75–86%; (c) (i) hydroxylamine hydrochloride, K2CO3, EtOH, reflux, 5 h, 60–68%; (ii)
trifluoroacetic anhydride, reflux, 6 h, 49–53%; (d) (i) NaN3, DMF, NH4Cl, 120 °C, 16 h,
98%; (ii) trifluoroacetic anhydride, rt, 48 h, 30%.
59.7% inhibition at 10
Not determined.
lM and precipitation at higher concentration.
g
h
7.2% inhibition at 30
lM.
38.9% inhibition at 30
l
M.

P. K. Sasmal et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4913–4918
4917
pyrazoles were also tested for rCB1 receptor affinity. In general, a
range of modifications were well tolerated. Several molecules were
identified with low and sub-nanomolar potency as CB1 antago-
nists. The representative molecule 31 displaying excellent potency
for rCB1 and high selectivity over both hCB2 and hERG showed sig-
nificant anti-obesity effect in a DIO mice model after chronic treat-
ment for 15 days. This effect of 31 might come from the peripheral
mode of action along with some contribution of central effect. Be-
sides obesity, the disclosed CB1 ligands might find their application
in pharmacological intervention of other diseases involving CB1
signaling pathways.37
Acknowledgments
We thank Professor Javed Iqbal and Dr. Ranjan Chakrabarti for
their continuous support and encouragement. The support of the
analytical department of Discovery Research is highly appreciated.
Supplementary data
Figure 2. Effect on acute food intake after single dose oral administration of
rimonabant (A: 10 mg/kg dose) and 31 (B: 10 mg/kg dose and C: 30 mg/kg dose) to
SAM versus vehicle control animals.
Supplementary data (synthetic procedures and characterization
data of all compounds 4–42) associated with this article can be
found, in the online version, at doi:10.1016/j.bmcl.2011.06.017.
and the results are summarized in Table 5. All of these compounds
have shown decent selectivity over hCB2 and very good inhibition
of CB1 agonist (WIN-55212) induced hypothermia in Swiss Albino
Mice (SAM) model. Few of them were also tested in patch clamp
assay32 to measure their potential to block hERG potassium chan-
nel. Amongst these compound 31 was found to be highly selective
over hERG (Table 5).
Compound 31 has shown dose dependant reduction in acute
food intake (Fig. 2) when tested at 10 and 30 mg/kg po in SAM
model. Rimonabant at a dose of 10 mg/kg po showed better effect
compared to the highest tested dose of 30 mg/kg po of compound
31 suggesting that rimonabant might be having more pronounced
central effect compared to more polar compound 31.34 Compound
31, showing good oral PK profile,35 was evaluated further in a diet-
induced obesity (DIO) mouse model using C57BL/6J mice. On oral
administration, compound 31 (10 mg/kg, q.d.)36 showed steady
loss of body weight culminating in a statistically significant weight
loss of 11% on day 15 as shown in Figure 3.
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Figure 3. Effect on body weight after subchronic oral administration of 31 (N
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36. q.d. stands for Latin word quaque die (every day).
lg h/mL, Cmax:
l
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