1,2,3-Triazole derivatives as new cannabinoid CB1 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2008.11.029

This letter reports the new entry of novel 1,2,3-triazole derivatives as CB1 receptor antagonists. The design, synthesis and biological evaluation of N1 and N2 substituted 1,2,3-trizoles are described. The N2 substituted, symmetrical 1,2,3-triazoles are m

Full text of DOI:10.1016/j.bmcl.2008.11.029

Bioorganic & Medicinal Chemistry Letters 19 (2009) 1022–1025
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
1,2,3-Triazole derivatives as new cannabinoid CB1 receptor antagonists
a
a
a
b
b,
*
Duen-Ren Hou a, , Safiul Alam , Ting-Chun Kuan , Mani Ramanathan , Tsung-Pang Lin , Ming-Shiu Hung
*
a Department of Chemistry, National Central University, 300 Jhong-Da Road, Jhongli City, Taoyuan, Taiwan
b Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
This letter reports the new entry of novel 1,2,3-triazole derivatives as CB1 receptor antagonists. The
design, synthesis and biological evaluation of N1 and N2 substituted 1,2,3-trizoles are described. The
N2 substituted, symmetrical 1,2,3-triazoles are more potent ligands than the unsymmetrical analogues.
The in vitro activity of these triazoles is further improved by inserting a methylene group between the
central core and the carbonyl side chain. The most potent antagonists prepared in this series
(IC50 < 20 nM) are the triazoles containing benzyl amides. These triazoles also show excellent selectivity
Received 24 September 2008
Revised 5 November 2008
Accepted 11 November 2008
Available online 14 November 2008
Keywords:
Cannabinoid
Obesity
between CB1 and CB2 receptors (IC50 > 10
lM for CB2; CB2/CB1 > 1000).
Ó 2008 Elsevier Ltd. All rights reserved.
Triazole
Obesity caused by an imbalance between food intake and en-
ergy expenditure,1 is a significant risk factor for cardiovascular dis-
ease and diabetes, and associated with significantly reduced life
longevity.2 The World Health Organization (WHO) declared that
obesity has become a global epidemic, posing a serious threat to
public health.3 The short-term diet or exercise is not effective as
most obese patients readily regain their lost weight thereafter.
Therefore, the medical treatment of obesity is an attractive ap-
proach.4 In this respect, cannabinoid-1 receptor (CB1R) and its
endogenous ligands (agonists), the endocannabinoids,5 have been
found to be involved in the control of weight via a dual mechanism
of food intake modification and the regulation of energy homeosta-
sis.6 Indeed, the biological effects of the CB1 receptors, which are
mainly located within the central nervous system, can be mediated
through exposure to agonists or antagonists (inverse agonists).7
Blocking the effects of the endogenous cannabinoids has become
a therapeutic avenue to treat obesity.8 The other known cannabi-
noid receptor (CB2R), is predominantly found in the immune sys-
tem and related to immune regulation.7 Therefore, good CB1/CB2
selectivity is a desired feature for the development of new anti-
obesity drug.9
Cl
Cl
O
N
N
HN
N
Cl
Rimonabant
(SR141716A)
Figure 1.
(MK-0364)13 have been reported to be in various phases of clinical
trials.7,9,14
In addition to the pyrazole core10 of SR141716A, derivatives of
other five membered heterocycles, such as pyrrole,15 thiophene,16
thiazole,17 imidazole,18,19 oxazole,18a and 1,2,4-triazole19,20 are also
known as the CB1 receptor antagonists. However, the derivatives
of 1,2,3-triazole have not been explored in this context. Herein,
we report our study on the design, synthesis and biological evalu-
ation of 1,2,3-triazoles as new CB1 receptor antagonists. Later, we
also notice that these triazoles possess excellent selectivity toward
to CB1 and CB2 receptors.
The most clinically advanced CB1 receptor antagonist, Rimona-
bant (SR141716A) launched by Sanofi-Aventis, binds to the human
CB1 receptor with 5.6 0.5 nM (Ki) affinity (Fig. 1).10a,10b Later,
many small molecule CB1 antagonists with diverse chemical struc-
tures have been prepared and reviewed.11 For example, Ibipina-
bant (SLV319),12 Otenabant (CP-945,598) and Taranabant
We started our study with the synthesis of 4,5-diaryl-N1-
substituted-1,2,3-triazoles 1 by the Ru-catalyzed cyclization reac-
tion21 of diaryl acetylenes22 and azides (Scheme 1). However, this
Ru-catalyzed reaction for the ortho-substituted diarylacetylenes is
very sluggish.23
We found that these 1-substituted triazoles are poor CB1 antag-
onists (Table 1, vide infra). Therefore, 2-substituted 4,5-diaryl-
1,2,3-triazoles were assembled by two strategies (Schemes 2 and
3). The 1,3-dipolar cycloaddition reaction of diarylacetylenes with
sodium azide provided the 4,5-diaryl-1,2,3-triazoles, 2–4. The fol-
* Corresponding authors. Tel.: +886 3 4279442; fax: +886 3 4227664.
E-mail address: drhou@ncu.edu.tw (D.-R. Hou).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.11.029

D.-R. Hou et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1022–1025
1023
R2
N
N
R1
N
NH
N3CH2COR
+
N
NCH2COR
a
a
Cl
Cl
R1
Cl
R2
R1 = R2 = Cl, 2
Cl
Cl
Cl
Cl
Cl
1a, R = OnBu
R
R
1 = Cl, R2 = H, 3
1 = R2 = H, 4
1b, R = N(CH2)5
NHR
N
Scheme 1. Reagents and conditions: (a) RuCpCl(PPh3)3, benzene, reflux, 75–80%.
O
N
b
N
Cl
2
5c, R = Bn
5d, R = Cy
5e, R = adamantyl
Table 1
Ligand binding assays of 1,2,3-triazoles25
Entry Compound
IC50 (hCB1, nM)a
EC50 (hCB1,
nM)b
IC50 (hCB2)a
M)
Cl
Cl
Cl
(
l
1
2
3
4
5
6
7
8
1a
1b
5c
5d
5e
6c
6d
6e
7d
7e
8a
8b
11
9a
9b
9c
13c
9d
9f
13f
9g
13g
9h
9i
(64.1)c
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
NHR
N
(33.0)c
O
(23.8)c
b
N
(29.2)c
N
Cl
6c, R = Bn
6d, R = Cy
6e, R = adamantyl
3
4
4496.8 871.1 (78.9)c
(18.6)c
(30.5)c
(34.5)c
Cl
Cl
(19.9)c
NHR
N
9
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
(19.7)c
(46.1)c
b
N
(55.7)c
N
(14.3)c
7d, R = Cy
7e, R = adamantyl
1173.2 263.4
168.9 32.2
66.9 8.9
203.5 78.1
144.4 110.0
19.3 3.5
262.2 183.7
11.6 3.4
449.2 67.9
25.7 2.9
81.9 44.2
48.9 12.0
64.8 10.5
22.6 8.8
251.1 88.1
15.0 1.8
122.0 32.1
87.0 17.0
216.3 60.7
203.6 112.3
23.5 11.2
256.1 98.7
50.7 11.8
235.2 28.8
35.1 22.2
56.2 8.1
12.2 5.4
17.8 6.7
22.0 6.1
136.2 17.6
18.2 9.5
5.9 0.8
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
1.9 0.1
Cl
Cl
Scheme 2. Reagents and conditions: (a) NaN3, DMF, 170 °C, 3–4 h, 75–88%; (b)
isocyanate, DMAP, THF, reflux, 1–2 h, 20–90%.
CH2COX
N
N
a
N
N
NH
Ar
N
NCH2COX
N
N
+
9j
9k
9l
Ar
Ar
Ar
Ar
Ar
X = OnBu, 9a
X = OnBu, 8a
Ar = 2,4-Cl2C6H3
9m
SR141716A
2
X = N(CH2)5, 9b
X = N(CH2), 8b
a
Displacement of specific [3H]-CP55940 binding in HEK 293 cells stably trans-
Scheme 3. Reagents and conditions: (a) BrCH2CO2nBu or BrCH2CON(CH2)5, NaH,
Bu4NI, THF, rt, 1 h. 8a:9a = 1:4 (63%); 8b:9b = 1:5 (66%).
fected with human CB1 receptor or human CB2 receptor.
b
Functional activity (EC50) determined by inhibition of Eu-GTP binding to hCB1
transfected HEK 293 membrane.
c
Percent inhibition at 10 lM.
we noticed the series of the three triazoles 5e, 6e and 7e, all with
a sterically bulky adamantyl group, but 5e clearly showed better
potency than the other two (Table 1, entries 5, 8 and 10). On the
other hand, the series of 5d, 6d and 7d, all with the less bulky
cyclohexyl group, and the pairs of 5c and 6c, both with a benzyl
group, show much smaller difference in CB1 binding assay (Table
1, entries 4, 7 and 9; entries 3 and 6). A reasonable conjecture for
these observations is that the ortho-chlorines and the hindered
adamantly group in 5e force the carbonyl group twisting away
from the plane of triazole (Fig. 2).
This result prompted us to modify our design to increase the
rotational freedom of the carbonyl group. Thus, triazoles 9 and
13, with an additional methylene group between the triazole and
the carbonyl moiety, were synthesized. This new design greatly in-
creased their efficacy to the CB1 receptor. For example, around
three order increase in the ligand binding ability was observed
(5c versus 9c and 5d versus 9d), and the IC50 and EC50 values of
these triazoles consistently fall into nanomolar range (entries
14–28).
lowing coupling reactions using various isocyanates generated the
ureas 5–7 with good yields (Scheme 2). Here, we found that the
acylation only occurred at N-2 position according to the analysis
of 1H- and 13C-NMR.24
Alternatively, alkylation of compound 2 with bromoacetate or
bromoacetamide gave the mixture of 1-and 2-substituted triazoles
(8 and 9, respectively), which are separable by column chromatog-
raphy (Scheme 3). The two regioisomer of 8 and 9 was unmistak-
ably assigned by the 1H and 13C NMR spectroscopies. Later, we
adopted phenyl bromoacetate (10) as the alkylation reagent to pre-
pare the 2-(phenoxycarbonyl)methyl triazoles 11 and 12 as the
convenient precursors to various amides (9 and 13, Scheme 4).
The results of the displacement ligand binding assay25 using the
1,2,3-triazoles and SR141716A are summarized in Table 1. Com-
pounds 1 and 8 showed that the 1-substituted triazoles are poor li-
gands for CB1 receptor (Table 1, entries 1–2, 11–12). However, the
triazoles with 2-carbamoyl group (5c–d, 6c–d and 7d, entries 3–4,
6–7 and 9) provide even lower bioactivity. We were puzzled by
this result at first: although 6d and SR141716A are structurally
similar, they have very different affinity to CB1 receptor. Later,
Among the triazoles screened, symmetrical triazoles 9 with 4,5-
bis-(2,4-dichlorophenyl) substituents are more potent than the
unsymmetrical 4-(2,4-dichlorophenyl)-5-(4-chlorophenyl) ana-

1024
D.-R. Hou et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1022–1025
ity of CB1 over CB2 receptor. These feature should merit further
studies, such as in vivo assays, on 1,2,3-triazoles as CB1
antagonists.
CH2CO2Ph
O
N
Br
N
N
Cl
OPh
10
2, 3
R = Cl, 11
R = H, 12
NaH, Bu4NI
65-70%
Acknowledgments
Cl
R
Cl
This research was supported by the National Science Council
(NSC 95-2323-B-007-005, NSC 96-2323-B-007-001 and NSC 95-
2133-M-008-007-MY3), and National Health Research Institutes
(NHRI), Taiwan, ROC. We are grateful to Ms. Ping-Yu Lin at the
Institute of Chemistry, Academia Sinica, Ms. Wen-Chi Hsiao at
NHRI, and Valuable Instrument Center in National Central Univer-
sity for obtaining mass analysis.
9c, X = NHBn
9d, X = NHCy
9f, X = NHCH2(
9g, X = NHCH2(
9h, X = NHCH2(
o
-FC6H4)
p-FC6H4)
CH2COX
N
m
-FC6H4)
-OMeC6H4)
-ClC6H4)
N
N
a
Cl
9i, X = NHCH2(
9j, X = NHCH2(
p
o
11
12
9k, X = NHCH2(p-ClC6H4)
9l, X = NHCH2(2,5-F2C6H3)
Cl
9m, X = NHC6H5
Cl
Cl
Supplementary data
CH2COX
Supplementary data associated with this article can be found, in
the online version, at 10.1016/j.bmcl.2008.11.029.
N
N
N
13c, X = NHBn
a
Cl
13f, X = NHCH2(
o
-FC6H4)
13g, X = NHCH2(
p-FC6H4)
References and notes
Cl
Cl
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Cl
Cl
O
O
N
N
N
N
N
N
N
N
H
H
Cl
Cl
Cl
7e; more planar
5e
Figure 2. Twist of the carbonyl group away from the plane of triazole due to the
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or other amides (9b, 9d, and 9m) prepared. Indeed, halogenated
benzyl amides (9f and 9g) show the best potency (IC50 < 20 nM).
These triazoles were further screened toward CB2 receptor, and
the results showed that they have very low affinity to CB2R. Such
huge CB1/CB2 selectivity is rather unusual among the reported
antagonists.7,26 However, we do not know the reasons for such dis-
crimination at this moment.
Comparing with other heterocycles as the central unit of CB1
antagonists, the number of substituents for 1,2,3-triazole is limited
to three, due to the low valence number of nitrogen (there are four
substituents in pyrazole, for example). The few substituents ease
the steric repulsions around the central core and lead to strong
conjugation between the carbonyl group and the 1,2,3-triazole of
ureas 5–7, thus enhanced the double bond character in the bond-
ing of N-2 and the carbon. The key receptor–ligand interaction is
proposed to be the hydrogen bond between the carbonyl group
and the Lys192-Asp366 residue of the CB1 receptor.12c,14a,27 Thus,
the rigid conformation in these ureas (5–7) holds back the impor-
tant hydrogen bond for the ligand–receptor interaction. On the
other hand, the disruption of conjugation by inserting a methylene
group not only changes the distance, but also allows the orienta-
tion of the carbonyl group more suitable for the key hydrogen
bonding; therefore, better potency.
In summary, we have reported the 1,2,3-triazoles as effec-
tive, new CB1 antagonists. These compounds exhibit high
level in vitro activity for CB1 receptor as well as good selectiv-

D.-R. Hou et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1022–1025
1025
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20. (a) Jagerovic, N.; Hernandez-Folgado, L.; Alkorta, I.; Goya, P.; Martin, M. I.;
Dannert, M. T.; Alsasua, A.; Frigola, J.; Cuberes, M. R.; Dordal, A.; Holenz, J. Eur. J.
Med. Chem. 2006, 41, 114; (b) Jagerovic, N.; Hernandez-Folgado, L.; Alkorta, I.;
Goya, P.; Navarro, M.; Serrano, A.; de Fonseca, F. R.; Dannert, M. T.; Alsasua, A.;
Suardiaz, M.; Pascual, D.; Martin, M. I. J. Med. Chem. 2004, 47, 2939; (c) Pavon, F.
J.; Bilbao, A.; Hernandez-Folgado, L.; Cippitelli, A.; Jagerovic, N.; Abellan, G.;
25. Please see the supporting information for the detailed procedures.
26. The reported CB1/CB2 selectivity of Rimonabant is ꢀ143, Ref. 12b. Current
studies on this issue, see: (a) Tuccinardi, T.; Ferrarini, P. L.; Manera, C.; Ortore,
G.; Saccomanni, G.; Martinelli, A. J. Med. Chem. 2006, 49, 984; (b) Lange, J. H. M.;
Kruse, C. G.; Van Vliet, B. J. WO2007138050, 2007.
27. The ligand binding models for Rimonabant and SLV319 in the CB1 receptor
have been reported, which show the hydrogen bonding acceptor, that is,
carbonyl or sulfonyl group, is not located on the same plane of the central core;
see Refs. 12c,14a.