Development of Quinazoline/Pyrimidine-2,4(1H,3H)-diones as Agonists of Cannabinoid Receptor Type 2

Article abstract of DOI:10.1021/acsmedchemlett.7b00007

Starting from a prototypical structure 1, we describe our efforts to design and obtain novel quinazoline/pyrimidine-2,4(1H,3H)-diones with high CB2 agonist potency and selectivity as well as improved physicochemical characteristics, mainly hydrophilicity. The most potent and selective CB2 agonists, 8 and 36, in this series were also endowed with lower logP values than that of GW842166X and lead compound 1. These derivatives appear to be promising lead compounds for the development of future CB2 agonists.

Full text of DOI:10.1021/acsmedchemlett.7b00007

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Development of Quinazoline/Pyrimidine-2,4(1H,3H)-
diones as Agonists of Cannabinoid Receptor Type 2
Hai-Yan Qian, Zhi-Long Wang, You-Lu Pan, Li-li Chen, Xin Xie, and Jian-Zhong Chen
ACS Med. Chem. Lett., Just Accepted Manuscript • Publication Date (Web): 01 May 2017
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Development of Quinazoline/Pyrimidine-2,4(1H,3H)-diones as
Agonists of Cannabinoid Receptor Type 2
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HaiꢀYan Qian,†,§ ZhiꢀLong Wang,‡,§ YouꢀLu Pan,† LiꢀLi Chen,† Xin Xie,‡,* and JianꢀZhong Chen†,*
†College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, P. R. China
‡CAS Key Laboratory of Receptor Research, National Center for Drug Screening, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, Shanghai 201203, P. R. China
KEYWORDS: Cannabinoid receptors, CB2 agonist, structure-activity relationship, molecular modeling
ABSTRACT: Starting from
a prototypical structure 1, we describe our efforts to design and obtain novel
quinazoline/pyrimidineꢀ2,4(1H,3H)ꢀdiones with high CB2 agonist potency and selectivity as well as improved physicochemical
characteristics, mainly hydrophilicity. The most potent and selective CB2 agonists, 8 and 36, in this series were also endowed with
lower logP values than that of GW842166X and lead compound 1. These derivatives appear to be promising lead compounds for
the development of future CB2 agonists.
Cannabinoids target two
G
proteinꢀcoupled receptors,
cannabinoid receptor type 1 (CB1) and cannabinoid receptor type
2 (CB2).1 A number of ligands have been developed for CB1 or
CB2, with several compounds proceeding to clinical trials. CB1
antagonist SR141617A (Figure S1) was approved as an
antiꢀobesity drug in Europe in 20062 but was withdrawn from the
market two years later due to serious central nervous system (CNS)
side effects associated with CB1 inhibition. In contrast, CB2 has
been proposed to be a potential drug target to treat pain and
immuneꢀrelated diseases without CNS problems. Several CB2
ligands, such as JWHꢀ133,3 HUꢀ308,4 and AM12415 (Figure S1),
were developed based on traditional cannabinoids. Other
structurally diverse CB2 ligands have also been reported, among
which Sꢀ7774696 and GW842166X7 (Figure S1) have been tested
in clinical trials for the treatment of atopic dermatitis and pain
associated with osteoarthritis and rheumatoid arthritis,
respectively. However, GW842166X turned out to lack efficacy in
subjects.8 Although many CB2 ligands have been discovered,9ꢀ11
no compound has completed clinical development and reached the
market. One major issue could be inadequate drugꢀlikeness, which
decreases clinical performance.12 The ClogP value of
GW842166X exceeds 4. Hence, reducing the logP value without
compromising activity may be a strategy to obtain promising CB2
ligands. Ellsworth et al. have described their efforts to improve the
pharmacokinetic properties within their chemical series via
reductions in logP.13
Recently, a series of quinoloneꢀ2,4(1H,3H)ꢀdiones has been
reported to be CB2 ligands by our group.14 Compound 1 (Figure
1), a potent CB2 agonist, has been demonstrated to alleviate
clinical symptoms of experimental autoimmune encephalomyelitis
and protect the CNS from immune damage. Interestingly, the
introduction of substituents at the C7 position of the nucleus
reversed the functional profile, as exemplified by compound 2,
which is actually an antagonist of CB2 (Figure 1). Despite their
good potency and selectivity for CB2, this class of molecules has
drawbacks, including the difficult separation of the two
E/Zꢀisomers and their high lipophilicity.
Figure 1. Lead compounds 1 and 2 and diagram for the
agonists while retaining CB2 bioactivity and selectivity, starting
from structure 1. First, to reduce the lipophilicity, the nucleus in 1
was replaced as shown in quinazolineꢀ2,4(1H,3H)ꢀdione (general
structure I) and pyrimidineꢀ2,4(1H,3H)ꢀdione (general structure II,
Figure 1). Second, to address the difficult separation of the
E/Zꢀisomers, the enamine moiety was replaced by an acetamide
link based on the interaction patterns between the designed
compounds and CB2 predicted by molecular simulations
(described in the Supporting Information).
The CB1 and CB2 bioactivities (EC50 values) of target
compounds 3ꢀ40 (Tables 1ꢀ2) were determined by wholeꢀcell
calcium mobilization assays.15 GW842166X was synthesized
based on the reported method16 and used as the reference standard
for a CB2 agonist; several standard cannabinoids were tested for
further validation of the bioassays (details in the Supporting
Information). Most of the compounds displayed full or partial
CB2 agonist activities without activating or inhibiting CB1 (Table
S1). Some compounds exhibited higher CB2 agonist potency than
GW842166X and lead compound 1. The EC50 values (CB2
agonist) of compounds 7, 8, and 11 were below 30 nM, and their
Herein, we describe our efforts to obtain new CB2ꢀselective
1
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Emax values were between 77% and 99%. Compound 8, with more
5, with nꢀbutyl and nꢀpentyl groups at R1, respectively, showed
1
2
3
4
5
6
7
8
than 715ꢀfold selectivity against CB1,was 25ꢀtimes more potent
than GW842166X. Encouragingly, the CB2ꢀselective agonist 8
was slightly more potent on CB2 than CP55940, a dual agonist of
CB1 and CB2. Compounds 7 and 11 displayed full agonist
activity on CB2, with EC50 values of 23.53 ± 4.85 nM and 27.69 ±
6.28 nM, respectively, similar to the CB2 activity of CP55940.
Notably, among the pyrimidineꢀ2,4(1H,3H)ꢀdiones, 36 had both
the highest CB2 potency and CB2 selectivity. Generally, this class
of ligands showed lower efficacy on CB2 than the
quinazolineꢀ2,4(1H,3H)ꢀdiones.
To evalute the drugꢀlike physicochemical properties of the
designed compounds, their ClogPs were calculated using
XꢀlogP.17 Most quinazoline/pyrimidineꢀ2,4(1H,3H)ꢀdiones have
an MW of approximately 350 and a ClogP near 3.00. For example,
compounds 7, 8, 14, and 36 presented ClogP values of 2.76, 3.30,
2.61, and 2.73, respectively, which were significantly lower than
that of the lead compound 1 (ClogP = 4.65) and GW841266X
(ClogP = 4.13). The experimental logP values of GW842166X, 1,
8, and 36 were also measured at 4.27, 4.35, 2.56, and 2.24,
respectively, using the method described in the Supporting
Information. Through structural optimization, we developed novel
CB2ꢀselective agonists with high potency and selectivity as well
as more appropriate logP values compared to both GW842166X
and lead compound 1.
more than 10ꢀfold higher CB2 agonist activity than 3, with a
shorter nꢀpropyl at R1. Among the C5ꢀsubstituted compounds,
compound 8, with an nꢀpentyl group at R1, exhibited the best CB2
agonist activity, but truncating the nꢀpentyl group (6) or replacing
the saturated carbon chain of R1 with a cyclopropylmethyl group
(12) or an unsaturated alkyl chain (14) led to a decrease in the
CB2 agonist activity. The EC50 values increased for the R2
8ꢀmethyl derivatives bearing the following R1 moieties in
increasing order: nꢀpentyl (11), nꢀbutyl (10), butꢀ3ꢀenꢀ1ꢀyl (15),
cyclopropylmethyl (13), and nꢀpropyl (9). These results suggested
that the nꢀpentyl group of R1 was best for generating CB2 agonists.
The essential length of the R1 straight chain could be determined
from its interaction with the narrow hydrophobic cavity
surrounded by W172, Y190, and W194 in CB2, as observed from
molecular simulations (Figure S3). Moreover, the R2 5ꢀmethyl
9
10
11
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derivatives 6ꢀ8 and R2 8ꢀmethyl analogues 9ꢀ11 demonstrated
higher potency for CB2 than compounds 3-5, which lacked an R2
substituent. When the C5 position was substituted with a methoxy
group (25), the potency dramatically decreased compared to that
of 8. Similarly, compound 11, with an R2 8ꢀmethyl group,
displayed higher CB2 agonist activity than the corresponding
8ꢀchloride (28) or 8ꢀmethoxy (29) analogue. Therefore, for the R2
positon of quinazolineꢀ2,4(1H,3H)ꢀdiones, 5/8ꢀmethyl groups
were found to be most beneficial to the CB2 agonist activity and
selectivity. In addition, an R2 5ꢀmethyl group was slightly
perferable to an 8ꢀmethyl group based on comparison of the
activities of 6 vs 9, 7 vs 10, and 8 vs 11.
As listed in Table 1, the structureꢀactivity relationships (SARs)
related
to
various R1 and
R2 groups on the
quinazolineꢀ2,4(1H,3H)ꢀdiones were explored. Compounds 4 and
Table 1. Effects of Different Functional Groups on Quinazoline-2,4(1H,3H)-diones on the Activity Profiles
a
b
CB1 EC50
(nM)
CB2 EC50
CB2 Emax
Cmpd
R1
R2
R3
SI c
(95% CI, nM) (% of control)
nꢀpropyl
nꢀbutyl
nꢀpentyl
nꢀpropyl
nꢀbutyl
nꢀpentyl
nꢀpropyl
nꢀbutyl
H
H
H
5ꢀCH3
5ꢀCH3
5ꢀCH3
8ꢀCH3
8ꢀCH3
8ꢀCH3
tꢀbutyl
tꢀbutyl
tꢀbutyl
tꢀbutyl
tꢀbutyl
tꢀbutyl
tꢀbutyl
tꢀbutyl
tꢀbutyl
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
1420 ± 258
75 ± 11
101 ± 4
80 ± 3
113 ± 4
98 ± 8
>7
>89
3
4
5
6
7
8
9
10
11
111.9 ± 28.3
86.51 ± 25.22
113.3 ± 10.6
23.53 ± 4.85
13.99 ± 5.36
406.9 ± 96.16
38.22 ± 10.73
27.69 ± 6.28
>116
>88
>425
>715
>25
77 ± 8
121 ± 10
102 ± 2
99 ± 11
>262
>361
nꢀpentyl
5ꢀCH3
8ꢀCH3
tꢀbutyl
tꢀbutyl
>10000
>10000
68.33 ± 6.10
308.8 ± 110.7
106 ± 3
110 ± 5
>146
>32
12
13
5ꢀCH3
8ꢀCH3
H
H
H
H
H
5ꢀCH3
5ꢀCH3
5ꢀCl
tꢀbutyl
tꢀbutyl
nꢀbutyl
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
30.02 ± 8.40
46.79 ± 7.69
99.57 ± 24.22
78.59 ± 16.73
370.2 ± 118.3
213.7 ± 56.35
743.2 ± 307.8
>10000
467.6 ± 83.2
394.9 ± 126.0
147.4 ± 11.8
>10000
1250 ± 610
>10000
>10000
52.71 ± 12.52
>10000
103 ± 6
90 ± 6
78 ± 3
81 ± 1
65 ± 8
58 ± 4
NDd
83 ± 3
56 ± 3
30 ± 4
ND
88 ± 5
ND
ND
118 ± 4
ND
97 ± 2
100 ± 8
>214
>100
>127
>27
>47
>13
ND
>21
>25
>68
ND
>8
ND
ND
>190
ND
>29
1
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
nꢀpentyl
nꢀpentyl
nꢀpentyl
nꢀpentyl
nꢀpentyl
nꢀpentyl
nꢀpentyl
nꢀpentyl
nꢀpentyl
nꢀpentyl
nꢀpentyl
nꢀpentyl
nꢀpentyl
nꢀpentyl
iꢀbutyl
iꢀpropyl
cyclopropyl
cyclohexyl
nꢀbutyl
cyclohexyl
nꢀbutyl
cyclohexyl
tꢀbutyl
nꢀbutyl
5ꢀCl
5ꢀOCH3
5ꢀOCH3
5ꢀOCH3
8ꢀCl
cyclohexyl
tꢀbutyl
tꢀbutyl
8ꢀOCH3
GW842166X
CP55940
342.8 ± 46.63
28.62 ± 6.42
aAssay protocols are provided in the Supporting Information. EC50 values were obtained from an 8ꢀpoint experiment with three
replicates. CI, confidence interval. bEmax values displayed as the means ± SEM are relative (%) to the maximal effect of CP55940. cSI:
2
selectivity index for CB2, SI = EC (CB1)/EC (CB2). dND = not determined.
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Table 2. Effects of Different Functional Groups on Pyrimidine-2,4(1H,3H)-diones on the Activity Profiles
1
2
3
4
5
6
7
8
9
a
b
CB1 EC50
(nM)
CB2 EC50
CB2 Emax
Cmpd
R1
R2
R3
SI c
(95% CI, nM)
(% of control)
nꢀbutyl
nꢀpentyl
nꢀhexyl
nꢀpentyl
nꢀpentyl
nꢀpentyl
nꢀpentyl
nꢀpentyl
H
H
H
H
H
Cl
Br
I
tꢀbutyl
tꢀbutyl
tꢀbutyl
nꢀbutyl
cyclohexyl
tꢀbutyl
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
NDd
72 ± 3
65 ± 10
ND
ND
>13
>13
ND
30
31
32
33
34
35
36
37
722.1 ± 27.7
766.8 ± 92.8
>10000
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
>10000
ND
ND
226.8 ± 43.8
48.74 ± 7.88
178.2 ± 51.3
65 ± 2
74 ± 2
78 ± 11
>44
>205
>56
tꢀbutyl
tꢀbutyl
nꢀpentyl
nꢀpentyl
tꢀbutyl
>10000
269.5 ± 31.7
71 ± 2
>37
38
phenyl
tꢀbutyl
tꢀbutyl
>10000
>10000
>10000
>10000
ND
ND
ND
ND
39
40
nꢀpentyl mꢀCH3ꢀphenyl
aAssay protocols are provided in the Supporting Information. EC50 values were obtained from an 8ꢀpoint experiment with three
replicates. CI, confidence interval. Emax displayed as the means ± SEM are relative (%) to the maximal effect of CP55940. SI:
b
c
selectivity index for CB2, SI = EC50(CB1)/EC50(CB2). dND = not determined.
Next, SAR studies of the R3 substituents in
groups performed better in terms of both potency and selectivity.
Compound 8 exhibited the highest CB2 agonist activity without
CB1 potency. In addition, structural optimizations around the
pyrimidineꢀ2,4(1H,3H)ꢀdione scaffold, especially at the C5
position, led to the highly potent and selective CB2 agonist 36.
Most importantly, the lipophilicity of target compounds 8 (logP =
2.56) and 36 (logP = 2.24) were significantly improved compared
to that of the known CB2 agonist GW842166X (logP = 4.27) and
lead 1 (logP = 4.35). The presented data offer an attractive starting
point for further optimization.
quinazolineꢀ2,4(1H,3H)ꢀdiones were conducted with a fixed
nꢀpentyl group at R1. The R3 nꢀbutyl derivative 16 maintained
similar CB2 agonist activity to that of 5 with an tꢀbutyl group at
R3. However, when other hydrophobic groups, such as isobutyl
(17), isopropyl (18), and cyclopropyl (19), were introduced as the
R3 moiety, significant decreases in potency were observed in
comparison with the potency of 5. Compound 20 with an R3
cyclohexyl group lost all CB2 agonist activity. Intriguingly,
replacing the R3 tꢀbutyl group of 8 with an nꢀbutyl (21) or
cyclohexyl (22) group was proved to be exceedingly detrimental
to the CB2 agonist activity. In fact, our modeling results predicted
that the R3 tꢀbutyl group of 8 makes favorable contact with the
aromatic side chains of F91 and F94 (Figure S3B). As indicated
by the SAR results for the quinazolineꢀ2,4(1H,3H)ꢀdiones, R1
nꢀpentyl, R2 5/8ꢀmethyl, and R3 tꢀbutyl groups are optimal for
CB2 agonist activity in this series.
For the pyrimidineꢀ2,4(1H,3H)ꢀdiones (Table 2), R1 nꢀpentyl
and nꢀhexyl groups contributed similarly to the CB2 agonist
activity (31 vs 32), while an nꢀbutyl at R1 was competely
detrimental, as reflected by compound 30. Herein, we selected the
an R1 nꢀpentyl group for further structural modification.
Replacement of the R3 tꢀbutyl group (31) with an nꢀbutyl (33) or
cyclohexyl (34) moiety completely lost the CB2 agonist activity.
Consequently, the tꢀbutyl group was identified as a desirable R3
moiety in pyrimidineꢀ2,4(1H,3H)ꢀdiones. Based on 31,
compounds 35ꢀ40 with various R2 groups were obtained. Three
halogen derivatives with 5ꢀchloro (35), 5ꢀbromo (36), and 5ꢀiodo
(37) groups displayed improved CB2 agonist activities and
selectivities compared with 31, of which 36 was the most potent.
In addition, introducing an R2 cyclopropyl group resulted in
compound 38, with a 6ꢀfold decreased CB2 agonist activity
compared with that of 36. Significantly, compounds 39 and 40,
with phenyl and m-CH3ꢀphenyl groups at R2, respectively, lacked
any CB2 activity. Thus, an R2 5ꢀbromo group is optimal for highly
potent CB2 agonist activity of pyrimidineꢀ2,4(1H,3H)ꢀdiones.
In summary, starting from lead compound 1, extensive SARs of
novel quinazoline/pyrimidineꢀ2,4(1H,3H)ꢀdiones were developed.
Our optimization efforts led to potent and selective CB2 agonists
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Molecular simulations to predict the interaction patterns of the
designed compounds binding to the CB2 receptor, synthetic
procedures for target compounds 3-40, analytical and spectral
characterization data of the target compounds, logP measurements
of compounds GW842166X, 1, 8, and 36 in octanol/water, and
biological assays information.
AUTHOR INFORMATION
Corresponding Author
* X.X.: eꢀmail, xxie@simm.ac.cn; phone/fax, 86ꢀ21ꢀ50801313.
* J.ꢀZ.C.: eꢀmail, chjz@zju.edu.cn; phone/fax, 86ꢀ571ꢀ88208659.
Author Contributions
§ These authors (H.ꢀY.Q. and Z.ꢀL.W.) contributed equally to this
work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This project was supported by grants from the National Natural
Science Foundation of China (30973637, 81425024, and
81473135), the Ministry of Science and Technology
with
more
suitable
logP
values.
Among
the
quinazolineꢀ2,4(1H,3H)ꢀdiones 3-29, compounds with 5/8ꢀmethyl
3
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(2014CB541906), and the Zhejiang Technology Office (Qianjiang
Talents Project 2010R10048).
9. Aghazadeh Tabrizi, M.; Baraldi, P. G.; Borea, P. A.; Varani,
1
2
3
4
5
6
7
8
K. Medicinal chemistry, pharmacology, and potential
therapeutic benefits of cannabinoid CB2 receptor agonists.
Chem. Rev. 2016, 116, 519ꢀ560.
ABBREVIATIONS
10. Muccioli, G.; Lambert, D. Current knowledge on the
antagonists and inverse agonists of cannabinoid receptors.
Curr. Med. Chem. 2005, 12, 1361ꢀ1394.
11. Riether, D. Selective cannabinoid receptor 2 modulators: a
patent review 2009ꢀpresent. Expert Opin. Ther. Pat. 2012, 22,
495ꢀ510.
12. Mugnaini, C.; Brizzi, A.; Ligresti, A.; Allarà, M.; Lamponi,
S.; Vacondio, F.; Silva, C.; Mor, M.; Di Marzo, V.; Corelli, F.
Investigations on the 4ꢀquinoloneꢀ3ꢀcarboxylic acid motif. 7.
CB1, cannabinoid receptor type 1; CB2, cannabinoid receptor type
2; CNS, central nervous system; SAR, structureꢀactivity
relationship
REFERENCES
1. Howlett, A. B., F.; Bonner, T.; Cabral, G.; Casellas, P.;
Devane, W.; Felder, C.; Herkenham, M.; Mackie, K.; Martin,
B. International Union of Pharmacology. XXVII.
Classification of cannabinoid receptors. Pharmacol. Rev.
2002, 54, 161ꢀ202.
2. Henness, S.; Robinson, D. M.; LysengꢀWilliamson, K. A.
Rimonabant. Drugs 2006, 66, 2109ꢀ2119.
3. Huffman, J. W.; Liddle, J.; Yu, S.; Aung, M. M.; Abood, M.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Synthesis
and
pharmacological
evaluation
of
4ꢀquinoloneꢀ3ꢀcarboxamides
and
4ꢀhydroxyꢀ2ꢀquinoloneꢀ3ꢀcarboxamides as high affinity
cannabinoid receptor 2 (CB2R) ligands with improved
aqueous solubility J. Med. Chem. 2016, 59, 1052ꢀ1067.
13. Ellsworth, B. A.; Sher, P. M.; Wu, X.; Wu, G.; Sulsky, R. B.;
Gu, Z.; Murugesan, N.; Zhu, Y.; Yu, G.; Sitkoff, D. F.;
Carlson, K. E.; Kang, L.; Yang, Y.; Lee, N.; Baska, R. A.;
Keim, W. J.; Cullen, M. J.; Azzara, A. V.; Zuvich, E.;
Thomas, M. A.; Rohrbach, K. W.; Devenny, J. J.; Godonis, H.
E.; Harvey, S. J.; Murphy, B. J.; Everlof, G. G.; Stetsko, P. I.;
Gudmundsson, O.; Johnghar, S.; Ranasinghe, A.; Behnia, K.;
Pelleymounter, M. A.; Ewing, W. R. Reductions in log P
improved protein binding and clearance predictions enabling
the prospective design of cannabinoid receptor (CB1)
antagonists with desired pharmacokinetic properties. J. Med.
Chem. 2013, 56, 9586ꢀ9600.
E.;
Wiley,
J.
L.;
Martin,
B.
R.
related
3ꢀ(1',1'ꢀdimethylbutyl)ꢀ1ꢀdeoxyꢀꢁ8ꢀTHC
and
compounds: synthesis of selective ligands for the CB2
receptor. Bioorg. Med. Chem. Lett. 1999, 7, 2905ꢀ2914.
4. Hanuš, L.; Breuer, A.; Tchilibon, S.; Shiloah, S.; Goldenberg,
D.; Horowitz, M.; Pertwee, R. G.; Ross, R. A.; Mechoulam,
R.; Fride, E. HUꢀ308: a specific agonist for CB2, a peripheral
cannabinoid receptor. Proc. Natl. Acad. Sci. USA 1999, 96,
14228ꢀ14233.
5. Ibrahim, M. M.; Deng, H.; Zvonok, A.; Cockayne, D. A.;
Kwan, J.; Mata, H. P.; Vanderah, T. W.; Lai, J.; Porreca, F.;
Makriyannis, A. Activation of CB2 cannabinoid receptors by
AM1241 inhibits experimental neuropathic pain: pain
inhibition by receptors not present in the CNS. Proc. Natl.
Acad. Sci. USA 2003, 100, 10529ꢀ10533.
6. A randomized, doubleꢀblind study to evaluate the safety and
efficacy of 2 doses of Sꢀ777469 in patients with atopic
dermatitis. https://clinicaltrials.gov/ct2/show/NCT00703573.
7. Giblin, G. M. P.; O'Shaughnessy, C. T.; Naylor, A.; Mitchell,
W. L.; Eatherton, A. J.; Slingsby, B. P.; Rawlings, D. A.;
Goldsmith, P.; Brown, A. J.; Haslam, C. P.; Clayton, N. M.;
Wilson, A. W.; Chessell, I. P.; Wittington, A. R.; Green, R.
14. Han, S.; Zhang, F.ꢀF.; Qian, H.ꢀY.; Chen, L.ꢀL.; Pu, J.ꢀB.;
Xie,
X.;
Chen,
J.ꢀZ.
Development
of
quinolineꢀ2,4(1H,3H)ꢀdiones as potent and selective ligands
of the cannabinoid type 2 receptor. J. Med. Chem. 2015, 58,
5751ꢀ5769.
15. Zhu, T.; Fang, L.ꢀY.; Xie, X. Development of a universal
highthroughput calcium assay for Gꢀproteinꢀcoupled
receptors with promiscuous Gꢀprotein Gα15/16. Acta
Pharmacol. Sin. 2008, 29, 507ꢀ516.
16. Giblin, G. M.; O'Shaughnessy, C. T.; Naylor, A.; Mitchell, W.
L.; Eatherton, A. J.; Slingsby, B. P.; Rawlings, D. A.;
Goldsmith, P.; Brown, A. J.; Haslam, C. P. Discovery of
2ꢀ[(2,4ꢀdichlorophenyl)amino]ꢀNꢀ[(tetrahydroꢀ2Hꢀpyranꢀ4ꢀyl
Discovery
of
2ꢀ[(2,4ꢀdichlorophenyl)amino]ꢀNꢀ[(tetrahydroꢀ2Hꢀpyranꢀ4ꢀyl
)methyl]ꢀ4ꢀ(trifluoromethyl)ꢀ5ꢀpyrimidinecarboxamide,
selective CB2 receptor agonist for the treatment of
inflammatory pain. J. Med. Chem. 2007, 50, 2597ꢀ2600.
8. Ostenfeld, T.; Price, J.; Albanese, M.; Bullman, J.; Guillard,
F.; Meyer, I.; Leeson, R.; Costantin, C.; Ziviani, L.; Nocini, P.
F.; Milleri, S. A randomized, controlled study to investigate
the analgesic efficacy of single doses of the cannabinoid
receptorꢀ2 agonist GW842166, ibuprofen or placebo in
patients with acute pain following third molar tooth
extraction. Clin. J. Pain 2011, 27, 668ꢀ676.
a
)methyl]ꢀ4ꢀ(trifluoromethyl)ꢀ5ꢀpyrimidinecarboxamide,
a
selective CB2 receptor agonist for the treatment of
inflammatory pain. J. Med. Chem. 2007, 50, 2597ꢀ2600.
17. Cheng, T.; Zhao, Y.; Li, X.; Lin, F.; Xu, Y.; Zhang, X.; Li,
Y.; Wang, R.; Lai, L. Computation of octanolꢀwater partition
coefficients by guiding an additive model with knowledge. J.
Chem. Inf. Model. 2007, 47, 2140ꢀ2148.
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