Sulfonamide derivatives as new potent and selective CB2 cannabinoid receptor agonists

Article abstract of DOI:10.1016/j.bmcl.2007.07.005

A novel series of sulfonamide derivatives 3, the CB₂ receptor agonists, was synthesized and evaluated for activity against the human CB₂ receptor. We first identified sulfonamide 3a, which was obtained by random screening of our in-h

Full text of DOI:10.1016/j.bmcl.2007.07.005

Bioorganic & Medicinal Chemistry Letters 17 (2007) 5133–5135
Sulfonamide derivatives as new potent and selective
CB2 cannabinoid receptor agonists
Hiroshi Ohta,a,* Tomoko Ishizaka,a Mitsukane Yoshinaga,a Aki Morita,b
Yasumitsu Tomishima,b Yoshihisa Todab and Shuji Saitoa
aMedicinal Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku,
Saitama-shi, Saitama 331-9530, Japan
bMolecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho,
Kita-ku, Saitama-shi, Saitama 331-9530, Japan
Received 4 June 2007; revised 26 June 2007; accepted 2 July 2007
Available online 10 July 2007
Abstract—A novel series of sulfonamide derivatives 3, the CB2 receptor agonists, was synthesized and evaluated for activity against
the human CB2 receptor. We first identified sulfonamide 3a, which was obtained by random screening of our in-house chemical
library as a moderately active (CB2 IC50 = 340 nM) CB2 receptor agonist. We then attempted to test its analogues to identify com-
pounds with a high affinity for the CB2 receptor. One of these, compound 3f, exhibited high affinity for the human CB2 receptor
(IC50 = 16 nM) and high selectivity for CB2 over CB1 (CB1 IC50/CB2IC50 = 106), and behaved as a full CB2 receptor agonist in
the [35S]GTPcS binding assay (CB2 EC50 = 7.2 nM, Emax = 100%).
Ó 2007 Elsevier Ltd. All rights reserved.
Cannabis sativa L. (marijuana) has been used for its
psychoactive and medicinal properties since times
immemorial, and delta9-tetrahydrocannabinol (delta9-
THC) was isolated as its major psychoactive compo-
nent in the 1960s.1 THC and its analogues are classified
as cannabinoids, and possess numerous biological
properties, including analgesic, antiemetic, anti-inflam-
matory, anticonvulsive, and anticancer effects.2 Signifi-
cant advances have been made in the understanding of
the manner in which cannabinoids interact with biolog-
ical systems, after the discovery of the CB1 and CB2
receptors.3,4 The CB1 receptor is expressed primarily
in the CNS and activates the psychotropic effects of
marijuana. The CB2 receptor is expressed in immune-
related tissues and cells, such as the spleen, tonsils,
and thymus, natural killer cells, T cells, and B cells.5–7
It has been suggested that the immunomodulatory effects
of the cannabinoid present in marijuana are mediated via
the CB2 receptor. Recent studies have indicated that the
CB2 receptor may be involved in the control of peripheral
pain,8,9 inflammation,10 and cancer development.11 The
receptor has also been suggested to have an antifibrogen-
ic role in the liver12 and to act as a regulator of microglial
cell migration in the brain.13,14 It is considered that the
development of a highly selective CB2 receptor ligand is
important for an understanding of the physiological ef-
fects of cannabinoids, such as their immunosuppressive,
anti-inflammatory, and antinociceptive activities. How-
ever, there are a few compounds, such as aminopyrimi-
dine15 (GW842166X, CB2 EC50 = 50 nM, CB1 EC50
>
30,000 nM) and 3-carbonylindole16 (A-0796260, CB2
IC50 = 0.77 nM, CB1 IC50 = 330 nM), that are selective
for the CB2 receptor (Fig. 1).
In this paper, we report the identification of novel, selec-
tive, and potent CB2 receptor agonists. Sulfonamide 3a
was identified as one of the hits by our high-throughput
screening and showed moderate binding affinity for the
CB2 receptor (IC50 = 340 nM). Compound 3a was found
to be an agonist of the CB2 receptor as confirmed by the
human [35S]GTPcS binding assay (EC50 = 110 nM,
Emax = 110%). This compound has attractive attributes,
including a low molecular weight and various sites in the
molecule that render themselves to structural modifica-
tion for optimization. We, therefore, tried exploring its
analogues to identify compounds with a high affinity
for the CB2 receptor.
Keywords: Cannabinoid; CB2 receptor; Sulfonamide derivatives; SAR.
*
Corresponding author. Tel.: +81 48 663 1111; fax: +81 48 652
7254; e-mail: hiroshi.ohta@po.rd.taisho.co.jp
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.07.005

5134
H. Ohta et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5133–5135
OH
group based on the presence of the double bond of
anandamide,18 an endogenous ligand of the cannabinoid
receptor. Replacing the methyl group at 3a with an allyl
group markedly increased the binding affinity of the
compound for the CB2 receptor (3a vs 3b), therefore,
we investigated its analogues (3c–e). Substitution with
bulky alkenyl groups, such as the prenyl group, resulted
in a lowering of the affinity for the CB2 receptor as com-
pared with that of the straight-chain alkenyl compound
(3c vs 3b). Compound 3e (R = propargyl) exhibited
about threefold lower affinity for the CB2 receptor than
compound 3b (R = allyl). The results of structural trans-
formations indicated that the most suitable group for
this site was a cyclopropylmethyl group (3d), which
was used as an alternative to the allyl group. Compound
3d demonstrated a significant increase, by about five-
fold, of the affinity for the CB2 receptor over that of
3a. These findings suggest that the improved affinity
associated with the introduction of the allyl and cyclo-
propylmethyl groups may depend on the donor–accep-
tor interaction with the p electron between these
functional groups and the CB2 receptor, and that the
sterically acceptable space on R for interaction with
the CB2 receptor is narrow.
OH
OH
O
HO
O
Delta 9-THC
CP-55940
CF3
O
O
Cl
O
N
N
N
H
N
N
H
N
Cl
GW842166X
A-796260
O
OH
N
H
Anandamide
Figure 1. Structure of delta9-THC, CP-55940, GW842166X, A-
796260, and anandamide.
The synthetic chemistry for the preparation of 3a–g is
outlined in Scheme 1. Sulfonamides 3a–g were synthe-
sized from 2-aminothiazole (1), a commercially available
compound (Fluorochem Ltd). Compound 1 was treated
with aryl sulfonyl chlorides under basic conditions, fol-
lowed by treatment with alkyl halides in the presence of
sodium hydride, to obtain sulfonamides 3a–g (the proce-
dure for synthesis of compound 3f is described in detail
in the note).17
Next, modification focused on the phenyl group in 3d.
Substitution of the phenyl group of 3d with a 2-naphthyl
group (3g) decreased the affinity for the CB2 receptor by
about sevenfold. However, replacement of the phenyl
group of 3d with a 1-naphthyl group (3f) resulted in a
significant increase in the affinity for the CB2 receptor
(3f vs 3d). These results suggest that the conformation
of the aromatic ring is important to obtain a high affin-
ity for the CB2 receptor. Furthermore, 3f exhibited a
high selectivity for the CB2 receptor (CB1 IC50/CB2
IC50 = 106) and was found to be a full CB2 receptor ago-
nist (CB2 EC50 = 7.2 nM, Emax = 100%).
Compound 3a, which was identified by our high-
throughput screening, exhibited moderate affinity for
the CB2 receptor (IC50 = 340 nM) and no affinity for
the CB1 receptor (IC50 > 50,000 nM). These findings
encouraged us to use sulfonamide 3a to seek a new type
of selective CB2 receptor ligand (Table 1). First, we
modified the methyl group at the position-3 of the
thiazole ring to clarify the effects of substituents on the
CB2 receptor activity. We designed 3b with an allyl
In this paper, we have reported the synthesis and SAR
of novel CB2 receptor ligands. The SAR study showed
Table 1. Pharmacological profile of sulfonamide derivatives
R
N
N
S
S
Ar
O
O
Compound
Ar
R
Binding affinity
a
IC50 (nM)
Agonist activity
b
CB2 EC50 (nM)
c
Emax (%)
CB2
CB1
3a
3b
3c
3d
3e
3f
Ph
Ph
Me
340
75
>50,000
—
110
—
110
—
CH2–CH@CH2
CH2–CH@CMe2
CH2–(Cyclopropyl)
CH2–CCH
Ph
Ph
170
65
—
—
—
—
—
—
Ph
1-Nap
2-Nap
210
16
—
—
—
CH2–(Cyclopropyl)
CH2–(Cyclopropyl)
1700
—
7.2
—
100
—
3g
490
CP-55,940 Ref. 19
0.82
2.1
0.86
100
a Evaluated on the basis of [3H]-CP-55,940 binding to membranes of Chinese hamster ovary (CHO) cells expressing the human CB2 or CB1 receptor.
b Evaluated by using a functional assay based on [35S]GTPcS binding to membranes of CHO cells expressing the human CB2 receptor.
c Compared to the maximal response to CP-55,940, a full agonist of the human CB2 receptor.

H. Ohta et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5133–5135
5135
R
N
N
S
N
S
a
b
NH2
NH
Ar
N
Ar
S
S
S
O
O
O
O
1
2
3
Scheme 1. Reagents and conditions: (a) ArSO2Cl, cat. DMAP, pyridine, rt; (b) RX, cat. NaI, NaH, DMF, rt.
15. Giblin, G.; O’Shaughnessy, C.; Naylor, A.; Mitchell,
W. L.; Eatherton, A.; Jandu, K.; Slingsby, B.; Sweet-
ing, J.; Wall, I.; Goldsmith, P.; Brown, A. J.; Haslam,
C.; Wilson, A.; Whittington, N. C.; Green, R.
Abstracts of Papers, 229th National Meeting of the
American Chemical Society, San Diego, CA, Mar. 13–
17, 2005; American Chemical Society: Washington,
DC, 2005; MEDI 5; Eatherton, A. J.; Giblin, G. M.
P.; Green, R. H.; Mitchell, W. L.; Naylor, A.;
Rawlings, D. A.; Slingsby, B. P.; Whittington, A. R.
WO2004/018433.
that the functional group at position-3 of the thiazole
ring and the Ar group of sulfonamide greatly affected
the CB2 receptor affinity. These studies led to compound
3f, which combines good potency with a high selectivity
for the CB2 receptor. We believe that SAR studies will
provide new opportunities to explore newer CB2 recep-
tor ligands with improved features.
Supplementary data
16. Meyer, M.; Hsieh, G.; Pai, M.; Zhu, C.; Chandran, P.;
Honore, P.; Dart, M.; Frost, J.; Daza, T.; Grayson, G.;
Mukherjee, S.; Fan, Y.; Yao, B. Abstracts of Papers, 16th
Annual Symposium on the Cannabinoids, Tihany, Hun-
gary, Jun. 24–28, 2006; International Cannabinoid
Research Society, Burington,VT, 2006; p 147; Pace, J.
M.; Tietje, K.; Dart, M. J.; Meyer, M. D. WO2006/
069196.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.bmcl.2007.07.005.
References and notes
17. Typical procedure; synthesis of N-[5-tert-butyl-3-(cyclopro-
pylmethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]naphthalene-
1-sulfonamide (3f). To a mixture of 1 (0.12 g, 0.70 mmol),
4-dimethylaminopyridine (0.010 g, 0.082 mmol), and pyri-
dine (1.5 ml) was added 1-naphthalenesulfonylchloride
(0.19 g), and the mixture was stirred overnight. To the
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filtered and recrystallized from chloroform/hexane to give
0.22 g (yield; 88%) of 2f as a pale pink powder. To a mixture
of 2f (0.20 g, 0.55 mmol) and sodium iodide (0.010 g
0.068 mmol) in DMF (1.5 ml) was added sodium hydride
(0.024 g, 0.67 mmol), and the mixture was stirred for
15 min. To the reaction mixture was added (bromometh-
yl)cyclopropane (0.11 g, 0.83 mmol), and the reaction
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ethyl acetate. The organic layer was washed with brine,
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0.85–1.08 (m, 1H), 1.33 (s, 9H), 2.24 (s, 3H), 3.80 (d,
J = 7.0 Hz, 2H), 7.42–7.69 (m, 3H), 7.82–8.03 (m, 2H),
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