Novel 3,4-diarylpyrazolines as potent cannabinoid CB1 receptor antagonists with lower lipophilicity

Article abstract of DOI:10.1016/j.bmcl.2005.07.054

Novel 3,4-diarylpyrazolines 1 as potent CB₁ receptor antagonists with lipophilicity lower than that of SLV319 are described. The key change is the replacement of the arylsulfonyl group in the original series by a dialkylaminosulfonyl moiety. Th

Full text of DOI:10.1016/j.bmcl.2005.07.054

Bioorganic & Medicinal Chemistry Letters 15 (2005) 4794–4798
Novel 3,4-diarylpyrazolines as potent cannabinoid CB1
receptor antagonists with lower lipophilicity
Jos H. M. Lange,* Herman H. van Stuivenberg, Willem Veerman, Henri C. Wals,
Bob Stork, Hein K. A. C. Coolen, Andrew C. McCreary, Tiny J. P. Adolfs and
Chris G. Kruse
Solvay Pharmaceuticals, Research Laboratories, C. J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands
Received 12 April 2005; revised 18 June 2005; accepted 19 July 2005
Available online 1 September 2005
Abstract—Novel 3,4-diarylpyrazolines 1 as potent CB1 receptor antagonists with lipophilicity lower than that of SLV319 are
described. The key change is the replacement of the arylsulfonyl group in the original series by a dialkylaminosulfonyl moiety.
The absolute configuration (4S) of eutomer 24 was established by X-ray diffraction analysis and 24 showed a close molecular
fit with rimonabant in a CB1 receptor-based model. Compound 17 exhibited the highest CB1 receptor affinity (Ki = 24 nM) in this
series, as well as very potent CB1 antagonistic activity (pA2 = 8.8) and a high CB1/CB2 subtype selectivity (ꢀ147-fold).
ꢀ 2005 Elsevier Ltd. All rights reserved.
Cannabinoids have been used as medicinal agents for
centuries.1,2 However, only within the past 10 years
has research in the cannabinoid area revealed vital infor-
mation about CB receptors and their (endogenous) ago-
nists. The discovery and subsequent cloning3,4 of two
subtypes of cannabinoid receptors (CB1 and CB2) have
enabled the development of CB receptor screening as-
says. Recent data suggest that there may be a third can-
nabinoid receptor5,6 (CB3). Wide distribution of the CB1
receptors in the brain and their apparent role in media-
tion of neurotransmission7,8 make the CB1 receptor an
interesting molecular target for CNS-directed drug dis-
covery in the areas of both psychiatric and neurological
disorders.9,10 Several reviews provide a comprehensive
overview11,12 of the current status in the fast-moving
cannabinoid research area including CB1 receptor
antagonists.13–19
Recently, we disclosed27 the CB1 receptor antagonists
SLV319 and SLV326. Both compounds exhibit high
CB1/CB2 subtype selectivities and are orally active in
CB1 receptor-mediated pharmacological in vivo models.
Cl
R4
X
R5
O
N
N
N
N
N
N
H
H
H
N
N
N
O
O
S
R3
N
N
N
S
O
O
Cl
1
NR R2
Cl
.HCl
Cl
R
Rimonabant
SLV319 (R = Cl)
1
SLV326 (R = CF3)
The invention of SR141716A (rimonabant) by Sanofi-
Synthelabo20 as a CB1/CB2 subtype selective and orally
active CB1 receptor antagonist has stimulated the search
for novel pyrazoles21–23 and bioisosteres thereof24–26 as
cannabinoid CB1 receptor antagonists. Rimonabant is
in Phase III clinical development for the treatment of
obesity and the facilitation of smoking cessation.
In general, the known cannabinoid CB1 receptor ligands
are lipophilic compounds,28,29 which limit their water
solubility and may require sophisticated formulation
methodology. In this paper, the design and synthesis
of less lipophilic30,31 structural analogues of SLV319
and SLV326 are described. It was envisaged that
replacement of the arylsulfonyl group in the original ser-
ies by a dialkylaminosulfonyl moiety would result in
compounds of general formula 1 with lower lipophilicity
and retained cannabinoid CB1 antagonistic activity.
*
Corresponding author. Fax: +31 29 4477138; e-mail: jos.lange@
solvay.com
0960-894X/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.07.054

J. H. M. Lange et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4794–4798
4795
O
The novel CB1 antagonists of general formula 1 were
prepared via synthesis routes A–D.
N
S
R1R2N
C
S
O
b
c
O
O
N
SK
NH2
Route A constitutes the coupling of 3,4-diarylpyrazo-
line32 2 with chlorosulfonylisocyanate, followed by
nucleophilic attack of dimethylamine to produce the
intermediate 3 in 58% yield (Scheme 1). Chlorination of
3 and subsequent reaction with methylamine gave com-
pound 4. Although this route seemed to be straightfor-
ward and the chlorination/amination sequence worked
quite well in the synthesis of SLV319,27 the conversion
of 3 into 4 gave a disappointingly low yield of 18%.
S
R1R2N
a
S
R1R2N
7
O
SK
O
O
N
S
5
6
S
R1R2N
O
S
8
Scheme 2. Reagents and conditions: (a) CS2, KOH, DMF, rt, 4 h; (b)
diphosgene, CH2Cl2, rt, 20 h; (c) CH3I, DMF, 0 ꢁC, 2 h.
An alternative approach started from aminosulfona-
mides33 5, which were converted into the corresponding
dithioimidocarbamates 6 in yields ranging from 71 to
95% and subsequently reacted with diphosgene (Scheme
2). The isothiocyanates 7 were formed in 55–86% yield
and reacted with pyrazoline 2 to furnish the intermedi-
ates 9 in 22–90% yield. The target compounds 11–17
were obtained from 9 by amination in the presence of
HgCl2 in 38–89% yield (Scheme 3, route B).
Cl
Cl
Cl
b
a
N
N
N
Route B
N
N
N
H
NHR3
S
HN
S
N
2
O
O
O
S O
NR1R2
NR1R2
In route C, the intermediate 9 was S-alkylated34 with
methyl iodide to afford 10 in 78–95% yield. Subsequent
nucleophilic attack by an amine R3NH2 gave the target
compounds 19–22 in 81–95% yield (Scheme 3). Analo-
gously, compound 18 was easily prepared from 3-(4-
chlorophenyl)-4-(3-pyridyl)-4,5-dihydro-(1H)-pyrazole.
Target compound 23 was synthesized via a slightly mod-
ified route (Scheme 3, Route D). The pyrazoline 2 was
reacted with 8 (which was obtained from 6 by double
S-methylation (Scheme 2)) to give intermediate 10 in
78% yield, which was reacted with methylamine to give
23 in 95% yield.
11-17
9
e
Route D
c
Route C
Cl
Cl
d
N
N
N
N
NHR3
SCH3
N
S
N
O
O
NR1R2
O
S O
NR1R2
Since the 3,4-diarylpyrazoline moiety contains a chiral
centre at its 4-position, the prepared target compounds
4 and 11–23 are racemates. It was reported27 that the
interaction of the structurally related SLV319 with the
CB1 receptor is highly stereoselective. Furthermore, it
is interesting to note that both compound 21 and rimo-
nabant contain a piperidin-1-yl moiety, which is antici-
pated to bind in the same region of the CB1 receptor.
To investigate further the stereochemical requirements
for binding to the CB1 receptor in this pyrazoline series,
the racemic 21 was resolved by applying chiral prepara-
tive HPLC (stationary phase: Chiralpak AD (20 lm);
10
19-23
Scheme 3. Reagents and conditions: (a) 7, CH2Cl2, rt, 2 h; (b) R3NH2,
HgCl2, CH3CN, rt, 4 h; (c) CH3I, Et3N, acetone, rt, 16 h; (d) R3NH2,
MeOH, rt, 2 h; (e) 8, pyridine 100 ꢁC, 40 h.
mobile phase: CH3OH/0.1% diethylamine) to furnish
the optically pure enantiomers (ꢁ)-2435 and (+)-25.
An X-ray diffraction analysis of 24 (which was crystal-
lized from absolute ethanol) revealed36 the 4S configura-
tion at its C4 pyrazoline ring atom. A stereoview of the
X-ray diffraction result is shown in Figure 1.
Cl
Cl
Cl
The prepared set comprising of 16 target compounds for
pharmacological evaluation is given in Table 1.
a, b
Route A
c, d
N
N
N
N
N
N
NHCH3
H
O
N
S O
N(CH3)2
The CB1 receptor affinities of the key compounds 4 and
11–25 were assessed in CB1 and CB2 receptor binding
studies27 (displacement of the specific binding of
[3H]CP-55,940 in CHO human CB1 or CB2 receptor
transfected cells). CB1 receptor antagonistic activities
were determined in a functional cell assay27 (blockade
of CP-55,940 induced arachidonic acid release in CHO
human CB1 receptor transfected cells). CB1 and CB2
HN
S O
O
O
N(CH3)2
3
4
2
Scheme 1. Reagents and conditions: (a) ClSO2N@C@O, CH2Cl2,
0 ꢁC, 2 h; (b) (CH3)2NH, 0 ꢁC, 2 h; (c) PCl5, chlorobenzene, reflux, 1 h;
(d) CH3NH2, CH2Cl2, rt, 2 h.

4796
J. H. M. Lange et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4794–4798
Figure 1. Stereoview of the X-ray diffraction result of 24.
Table 1. Structural formula of prepared CB1 receptor antagonists 4 and 11–25 and pharmacological in vitro results
Cl
X
N
N
NHR3
N
O
S O
NR1R2
R1
R2
R3
CB1 rb
CB2 rb
CB1 funct
a,b
a,b
a,b
Compound
X
Rimonabant
SLV319
25.0 15 (11.5)15
7.8 1.4
223 103
30 14
1580 150 (1640)15
7493 126
3835 1015
3270 1208
1126 237
1871 1061
1601 577
1032 401
2584 787
3526 1015
9077 923
2755 1148
2864 1080
1321 264
5372 1392
n.d.c
8.6 0.1
9.9 0.6
8.3 0.3
8.6 0.2
8.3 0.3
8.2 0.3
7.6 0.2
8.9 0.2
8.4 0.1
8.8 0.2
7.5 0.3
8.7 0.1
8.5 0.3
8.7 0.3
8.0 0.2
8.1 0.2
8.7 0.2
7.5 0.1
4
11
C
C
C
C
C
C
C
C
N
C
C
C
C
C
C
C
CH3
C2H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C2H5
i-C3H7
C2H5
12
13
32 12
117 81
231 66
155 69
125 54
24 14
14
15
(CH2)4
(CH2)6
(CH2)7
16
17
(CH2)2S(CH2)2
18
19
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
141 48
60 20
i-C3H7
C2H5
CH3
20
21
209 113
152 68
75 36
(CH2)5
22
23
(CH2)2O(CH2)2
(CH2)2S(O2)(CH2)2
(CH2)5
CH3
CH3
832 168
58 19
763 148
(S)-(ꢁ)-24
(R)-(+)-25
CH3
CH3
3495 968
n.d.c
(CH2)5
a CB1 rb, Displacement of specific CP-55,940 binding in CHO cells stably transfected with human CB1 receptor, expressed as Ki SEM (nM); CB2 rb
,
displacement of specific CP-55,940 binding in CHO cells stably transfected with human CB2 receptor, expressed as Ki SEM (nM); CB1 funct, CB1
functional cell assay; [3H]arachidonic acid release in CHO cells, expressed as pA2 SEM values.
b All Ki and pA2 values are mean values from at least three independent experiments.
c n.d., not determined.
receptor binding results are expressed as Ki values. The
CB1 antagonistic potencies of the compounds are ex-
pressed as pA2 values.
The CB1 receptor binding data of the target compounds
4 and 11–13 revealed that their affinities depend on the
NR1R2 substitution pattern. N,N-Diethyl and N-meth-
yl-N-isopropyl substitution gave rise to strongly binding
compounds. The target compounds 14–17 and 21–23
wherein the substituents R1 and R2 together with the at-
tached nitrogen atom form a heterocyclic ring all elicited
The pharmacological results of the target compounds 4
and 11–25 and the reference compounds rimonabant
and SLV319 are given in Table 1.

J. H. M. Lange et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4794–4798
4797
Table 2. Pharmacological in vivo results and logP of key compounds
CB1 receptor affinity. The thiomorpholine analogue 17
displayed the highest affinity, whereas its SO2 congener
23 was found to be considerably less active. The S-enan-
tiomer 24 elicited a 13-fold higher affinity than its mirror
image 25 for the CB1 receptor, which is in line with ear-
lier reported results in the original27 pyrazoline series
wherein SLV319 (which has the S configuration) showed
an approximately 100-fold higher CB1 receptor affinity
than the corresponding R enantiomer.
a
b
Compound
CBBP
CBTEMP
PGPc
logPd
Rimonabant
SLV319
3.2
5.5
3
3
1.2
1.4
1.5
3.4
1.8
1.4
5.5
5.1
4.8
3.2
3.8
4.8
11
18
20
3
>30
27
8
-
22
(S)-(ꢁ)-24
3
10
a Antagonism of CP-55,940 induced hypotension in rat expressed as
ED50 (mg/kg po administration).
b Antagonism of WIN 55,212-2 induced hypothermia in mice expressed
Interestingly, the pyridyl analogue 18 has a substantially
lower CB1 receptor binding affinity than its phenyl-
substituted counterpart 11.
as least effective dose (LED, mg/kg po administration).
c P-glycoprotein-based membrane transport factor, expressed as the
ratio of the bottom to top transport and top to bottom transport.
d LogP determination using a validated reverse-phase HPLC method.
Variation in R3 (compounds 11, 19 and 20) showed that
the methyl group is superior to larger alkyl groups.
The reported model for the binding of rimonabant in the
CB1 receptor,38 based on the 2.8-A X-ray structure of
˚
39
In general, the compounds in this series elicited consid-
erable CB1/CB2 receptor subtype selectivities. Com-
pound 17 showed the highest CB1 binding affinity and
was also found to be the most selective. Its selectivity
(ꢀ147-fold) is comparable to the reported20 selectivity
of SanofiÕs frontrunner rimonabant (ꢀ143-fold).
bovine rhodopsin (Rho), was reconstructed. The origi-
nal template was modified to the putative inactive R-
state. The optimal receptor-based alignment of rimona-
bant27 in this model was used as the starting point for
aligning the minimized energy conformation of 24 with
SLV319. The result is shown in Figure 2. The molecular
fit of 24 and SLV319 revealed a high degree of overlap in
this protein-based receptor model with comparable
modes of interaction with the crucial Asp366-Lys192
salt bridge that has been reported38 to govern CB1 in-
verse agonistic activity. Further comparison with rimo-
nabant (Fig. 3) reveals a closer overlap with the
The results from the functional arachidonic acid release-
based assay clearly revealed the strong CB1 antagonistic
properties of our target compounds. The azepanyl deriv-
ative 15 exhibited the strongest antagonistic potency
(pA2 = 8.9) in this series. The antagonistic potency of
the eutomer 24 was found to be considerably higher
than its mirror image 25, which is in agreement with
the observed CB1 receptor affinity data.
Tyr275
Asp366-Lys192
Trp255
The in vivo activity of the key dihydropyrazoles 11, 18,
22 and 24 was investigated in two mechanistic pharma-
cological models, viz. a CB1 agonist (CP-55,940) in-
duced hypotension27 rat model and a CB1 agonist
(WIN-55,212-2) induced hypothermia27 mouse model,
and compared with the known selective CB1 receptor
antagonists SLV31927 and rimonabant. The logP value
of the compounds was determined by a validated HPLC
method.27 The P-glycoprotein transport factor37 of the
compounds was also determined in vitro. The results
are given in Table 2. They reveal that compounds 11,
22 and 24 elicited in vivo activities after oral administra-
tion in both the hypotension rat and hypothermia
mouse models that are in line with their in vitro CB1
activities.
Val196
Phe278
Trp279
Phe170
Leu387
Met384
Ser383
Phe200
Trp356
Figure 2. Alignment of SLV319 and 24 in the CB1 receptor binding
site.
Tyr275
Asp366-Lys192
Trp255
The pyridyl analogue 18 was found to be inactive in the
hypotension test, which is in line with its relatively low
potency in our in vitro functional assay (Table 1). More-
over, 18 was identified as a P-glycoprotein substrate
in vitro, which generally results in reduced CNS penetra-
bility. The other compounds in this series lacked this
undesirable property. This is in proper agreement with
their in vivo activities in our (CNS-mediated) hypother-
mia mouse model.
Val196
Phe170
Leu387
Phe278
Trp279
Met384
Ser383
The obtained logP values of compounds 11, 18, 22 and
24 are all lower than those of rimonabant and SLV319
(Table 2). Compound 18 displayed the lowest logP
value due to the presence of its 3-pyridyl moiety.
Trp356
Phe200
Figure 3. Alignment of rimonabant, SLV319 and 24 in the CB1
receptor binding site.

4798
J. H. M. Lange et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4794–4798
22. Meschler, J. P.; Kraichely, D. M.; Wilken, G. H.; Howlett,
A. C. Biochem. Pharmacol. 2000, 60, 1315.
23. Katoch-Rouse, R.; Pavlova, O. A.; Caulder, T.; Hoffman,
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exception of the 4-methyl group that is present in rimo-
nabant and is lacking in both SLV319 and 24. Further-
more, the amidine NHCH3 moiety that is present in
both SLV319 and 24 clearly has no counterpart in this
molecular fit with rimonabant.
24. Dyck, B.; Goodfellow, V. S.; Phillips, T.; Grey, J.;
Haddach, M.; Rowbottom, M.; Naeve, G. S.; Brown,
B.; Saunders, J. Bioorg. Med. Chem. Lett. 2004, 14, 1151.
25. Lange, J. H. M.; van Stuivenberg, H. H.; Coolen, H. K. A.
C.; Adolfs, T. J. P.; McCreary, A. C.; Keizer, H. G.; Wals,
H. C.; Veerman, V.; Borst, A. J. M.; De Looff, W.;
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In conclusion, a series of novel 3,4-diarylpyrazolines
with lower lipophilicity than the parent compounds
SLV319, SLV326 and rimonabant was identified in vitro
as potent and CB1/2 subtype selective CB1 receptor
antagonists. Representative compounds shared favour-
able activities in vivo after oral administration.
Acknowledgments
27. Lange, J. H. M.; Coolen, H. K. A. C.; van Stuivenberg, H.
H.; Dijksman, J. A. R.; Herremans, A. H. J.; Ronken, E.;
Keizer, H. G.; Tipker, K.; McCreary, A. C.; Veerman, V.;
Wals, H. C.; Stork, S.; Verveer, P. C.; den Hartog, A. P.;
de Jong, N. M. J.; Adolfs, T. J. P.; Hoogendoorn, J.;
Kruse, C. G. J. Med. Chem. 2004, 47, 627.
28. Cannabinoid Receptors; Pertwee, R. G., Ed.; Academic
Press: London, 1995.
29. Stoit, A. R.; Lange, J. H. M.; Den Hartog, A. P.; Ronken,
E.; Tipker, K.; Van Stuivenberg, H. H.; Dijksman, J. A.
R.; Wals, H. C.; Kruse, C. G. Chem. Pharm. Bull. 2002,
50, 1109.
Dr. Mia Pras-Raves is acknowledged for supplying the
X-ray diffraction data. Mr. Jan Hoogendoorn is
acknowledged for the chiral preparative HPLC separa-
tion of 21. Crystallographic analyses and the structure
determination of 24 were performed by Dr. H. Kooij-
man and Dr. A. L. Spek, Bijvoet Centre for Biomolecu-
lar Research, Utrecht University, Utrecht, The
Netherlands.
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˚
wavelength: 0.71073 A, X-ray exposure time: 6.6 h, crystal
size: 0.10 · 0.25 · 0.35 mm, crystal system: orthorhombic,
space group: P212121, unit cell dimensions: a = 9.0320;
˚
b = 10.9733;
c = 22.475 A,
calculated
density:
1.372 g cmꢁ3, completeness: 99.9%, total number of reflec-
tions: 65,533, number of unique reflections: 5109, number
of refined parameters: 359. Flack x-parameter: 0.02.
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