Synthesis and SAR of novel imidazoles as potent and selective cannabinoid CB2 receptor antagonists with high binding efficiencies

Article abstract of DOI:10.1016/j.bmcl.2009.12.032

The synthesis and structure-activity relationship studies of imidazoles are described. The target compounds 6-20 represent a novel chemotype of potent and CB₂/CB₁ selective cannabinoid CB₂ receptor antagonists/inverse agonists with very high binding efficiencies in combination with favourable log P and calculated polar surface area values. Compound 12 exhibited the highest CB₂ receptor affinity (K_i = 1.03 nM) in this series, as well as the highest CB₂/CB₁ subtype selectivity (>9708-fold).

Full text of DOI:10.1016/j.bmcl.2009.12.032

Bioorganic & Medicinal Chemistry Letters 20 (2010) 1084–1089
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and SAR of novel imidazoles as potent and selective cannabinoid
CB2 receptor antagonists with high binding efficiencies
*
Jos H. M. Lange , Martina A. W. van der Neut, Henri C. Wals, Gijs D. Kuil, Alice J. M. Borst, Arie Mulder,
Arnold P. den Hartog, Hicham Zilaout, Wouter Goutier, Herman H. van Stuivenberg, Bernard J. van Vliet
Solvay Pharmaceuticals, Research Laboratories, C. J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis and structure–activity relationship studies of imidazoles are described. The target com-
pounds 6–20 represent a novel chemotype of potent and CB2/CB1 selective cannabinoid CB2 receptor
antagonists/inverse agonists with very high binding efficiencies in combination with favourable log P
and calculated polar surface area values. Compound 12 exhibited the highest CB2 receptor affinity
(Ki = 1.03 nM) in this series, as well as the highest CB2/CB1 subtype selectivity (>9708-fold).
Ó 2009 Elsevier Ltd. All rights reserved.
Received 10 November 2009
Revised 4 December 2009
Accepted 6 December 2009
Available online 11 December 2009
Keywords:
Binding efficiency index
Ligand efficiency
Cannabinoid CB2 receptor
Inverse agonist
Polar surface area
Lipophilicity
Subtype selectivity
Ligand-lipophilicity efficiency
Lipophilic efficiency
The cannabinoid CB2 receptor was cloned1 in 1993 and is almost
exclusively expressed in cells of the immune system, spleen, pan-
creas, tonsils and thymus.2 Under certain circumstances the CB2
receptor is also expressed3,4 in astrocytes, microglia and the brain-
stem.5 CB2 receptor ligands have potential in the therapeutic treat-
ment of several diseases6 such as inflammation, multiple sclerosis,
neuropathic pain,7 immune regulation,8 osteoporosis and certain
types of cancer. Recently, CB2 receptor inverse agonists were also
shown to block9 leucocyte recruitment in vivo.
Cl
O
O
O
O
O
N
N
H
N
N
H
O
N
H
O
SR144528 (1)
JTE-907 (2)
The amino acid sequence of the CB2 receptor has an overall
identity1 of 44% with the CB1 receptor. Their homology in the GPCR
transmembrane domain amounts to 68%, thereby providing good
prospects for the design of CB subtype selective ligands. Intense re-
search efforts have indeed led to the discovery of subtype selective
human cannabinoid CB1 receptor antagonists/inverse agonists,10
selective CB2 receptor agonists such as JWH133,11 HU-308,12
L759656,13 AM-1241,14 A-796260 and A-83633915 as well as selec-
tive CB2 receptor antagonists/inverse agonists from different
chemical series such as the pyrazolecarboxamide16,17 SR144528
(1), the 2-oxoquinoline18 JTE-907 (2) and the triarylbissulfone19
SCH-356036 (3).
NH
Cl
S
O
O
F
S
O
O
S
O
O
SCH-356036 (3)
Several reviews described20–25 the medicinal chemistry of CB2
receptor ligands. Although many efforts have concentrated on
the modelling of the CB2 receptor and their ligands20 as well as
on receptor mutations,26 it can be concluded that the design of no-
vel CB2 selective antagonists or agonists by CB2 receptor modelling
or virtual screening is still a challenging task.27–30 It is interesting
* Corresponding author. Tel.: +31 (0)294 479731; fax: +31 (0)294 477138.
E-mail address: jos.lange@solvay.com (J.H.M. Lange).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.12.032

J. H. M. Lange et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1084–1089
1085
to note that both the selective CB1 receptor antagonist rimona-
O
O
bant31 and the selective CB2 receptor antagonist 1 contain a 5-aryl-
pyrazole-3-carboxamide scaffold. This intriguing observation
prompted us to start CB2 receptor antagonist design efforts based
on our32 CB1 antagonistic 1,2-diarylimidazoles 4 which can be con-
sidered as bioisosters of rimonabant (Scheme 1). The preference for
the imidazoles as a starting point for the design of CB2 selective
antagonists was fuelled by the generally observed31,32 slightly
higher CB2 receptor affinities in the 1,2-diarylimidazole series as
compared to the corresponding 1,5-diarylpyrazoles.
O
OEt
N
H
N
N
OEt
b
N
a
N
N
N
H
21
22
6
Scheme 2. Reagents and conditions: (a) C6H5B(OH)2, CuI, EtOH/H2O, reflux, 60 h
(26%); (b) (À)-cis-myrtanylamine, Al(CH3)3, CH2Cl2, 35 °C, 16 h (65%).
It was noted that the 1-arylmethyl moiety of 1 adds significant
molecular weight and lipophilicity33 to the molecule. Since, we
were particularly interested in novel CB2 receptor antagonist
chemotypes with high ligand efficiencies34 and favourable log P
values, attention was given to the chemotype 5 wherein the large
arylmethyl group of 1 is replaced by a considerably smaller substi-
tuent35 R1 at the corresponding imidazole 2-position. Removal of
the original 2-aryl moiety in 4 was furthermore anticipated to have
a detrimental effect on the CB1 activity of the compounds, based on
our extensive CB1 SAR knowledge, thereby increasing CB2/CB1 sub-
type selectivity36,37 In addition, the carboxamide N-piperidinyl
substituent in 4 was replaced by a lipophilic substituent compara-
ble to the trimethylbicyclo[2.2.1]heptane group in 1.
In concreto, these design considerations led to a series of fifteen
novel imidazole derivatives 6–20. The synthesis of compound 6 is
depicted in Scheme 2. The commercially available ester 21 was re-
acted with benzeneboronic acid in the presence of a catalytic
amount of CuI to afford 22 in a modest yield. Weinreb amidation38
of 22 with (À)-cis-myrtanylamine gave the imidazole 6 in 65%
yield.
under basic conditions to the carboxylic acid 42, which was then
amidated with 1-adamantamineÁHCl to provide target compound
14. Compound 41 was converted in a straightforward Weinreb
amidation38 to 15.
The synthesis of the imidazoles 16–18 is depicted in Scheme 5.
The ester intermediate 43 was prepared from the corresponding
nitroacrylate analogously40 to the method described in Scheme 4.
Ester hydrolysis of 43, followed by amidation with 1-adamanta-
mineÁHCl led to the carboxamide 44. Subsequent regioselective
lithiation of 44 with the strong non-nucleophilic base LDA, fol-
lowed by treatment with an electrophile led to the target com-
pounds 16–18 in reasonable yields. It is interesting to note that
this strategy provides a nice alternative for the synthesis of 4-
alkylated imidazoles such as 8 and 12. Compounds 8 and 12 were
obtained from 44 via the reaction with CH3I and C2H5I in 70% and
41% yields, respectively.
The 2,5-dichloroimidazole derivative 19 was prepared as shown
in Scheme 6. The dicarboxylic acid 45 was mono-decarboxylated in
acetic anhydride and subsequently esterified with sulfuric acid in
ethanol to 46. N-Arylation with benzeneboronic acid in the pres-
ence of CuCl gave a regioisomeric mixture from which 47 was sep-
arated by flash chromatography. Basic hydrolysis of the ester group
and subsequent amidation with adamantamineÁHCl afforded 48.
Prolonged chlorination41 of 48 with N-chlorosuccinimide eventu-
ally led to the incorporation of two chloro atoms at the imidazole
nucleus and thereby produced the target compound 19.
The synthesis of the imidazoles 7–13 is depicted in Scheme 3.
The commercially available oxo-esters 23–25 were reacted with
NaNO2 to furnish the oximes 26–28. Subsequent catalytic reduc-
tive acetylation with acetic anhydride afforded the crude com-
pounds 29–31 which were cycloaromatized with aniline in
butyronitrile in the presence of trifluoroacetic acid to the imida-
zoles 32–34. This sequence of reactions constitutes a powerful
route to the synthesis of 1-aryl-2,5-dialkylimidazole-4-carboxyl-
ates. It is interesting to note that our optimized reaction conditions
led to considerable higher yields as well as less by-product forma-
tion as compared with the original procedure39 which consisted of
heating in xylene. Ester hydrolysis of 32–34 delivered the corre-
sponding acids 35–37 in quantitative yield. The target compounds
7–13 were obtained from 35–37 via amidation reactions in the
presence of a coupling reagent (either HBTU or CIP) in yields rang-
ing from 60–72%.
The cyclohexylimidazole analogue 20 was prepared according
to Scheme 7. The nitroacrylate40 49 was reacted with cyclohexyl-
amine to produce the corresponding cyclohexylamino derivative
50 in low yield. Subsequent cycloaromatization under reductive
conditions with triethylorthoacetate gave the imidazole ester 51
which was efficiently converted via a Weinreb amidation38 with
1-adamantamineÁHCl to 20.
The target compounds 14 and 15 were prepared40 according to
Scheme 4. The nitroacrylates 38 and 39 were cycloaromatized un-
der reductive conditions with triethylorthopropionate to the 2-
ethylimidazoles 40 and 41, respectively. Ester 40 was hydrolyzed
The pharmacological data of the reference compounds 1–3 and
target compounds 6–20 are depicted in Table 1. The observed order
of CB2 receptor affinities and CB1/CB2 receptor subtype selectivities
of the reference compounds 1–3 matches the reported data.16,18,19
O
N
N
O
Cl
O
H
N
N
lipophilic
substituent
N
N
N
N
H
N
H
Cl
R1
Ar1
N
N
Ar
Ar
Cl
Rimonabant
4
5 Ar = Aryl
R1 = H, Me, Et
Scheme 1. Design concept of novel imidazoles 5 as selective cannabinoid CB2 receptor antagonists from CB1 receptor antagonists 4.

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J. H. M. Lange et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1084–1089
O
O
O
OMe
R
O
O
O
O
N
c
a
b
R
OMe
R
OMe
N
OMe
R
HN
N
OH
O
23 R = Me
24 R = Et
26 R = Me
27 R = Et
29 R = Me
30 R = Et
32 R = Me
33 R = Et
25 R = n-Bu
28 R = n-Bu
31 R = n-Bu
34 R = n-Bu
R1
O
O
Compound
7
R
NHR1
OH
Me
Me
Me
Me
Me
Et
cis-myrtanyl
N
N
d
e
32-34
R
R
8
N
adamantan-1-yl
N
adamantan-2-yl
9
noradamantan-1-yl
o-(trifluoromethyl)benzyl
adamantan-1-yl
10
11
12
13
35 R = Me
36 R = Et
7-13
n-Bu
adamantan-1-yl
37 R = n-Bu
Scheme 3. Reagents and conditions: (a) NaNO2, H2O, 4 °C, 2 h; (b) H2, Pd/C, 1 atm, Ac2O, AcOH, rt, 20 h (50–65%); (c) C6H5NH2, TFA, butyronitrile, reflux, 45 min (40–51%); (d)
LiOH, H2O/THF, 70 °C, 16 h, followed by acidification with 1 N HCl, rt (93–100%); (e) R1NH2, HBTU or 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP), DIPEA,
CH3CN, rt, 16–40 h (60–72%).
O
O
N
OH
N
N
H
c
b
N
N
O
O
OEt
R1
NO2
NH
N
EtO
R1
a
N
42
14
d
O
N
40 R1 = H
41 R1 = Me
38 R1 = H
N
H
39 R1 = Me
N
15
Scheme 4. Reagents and conditions: (a) EtC(OEt)3, H2, Pd/C, 2.5 atm, 70 °C, 16 h (9–32%); (b) LiOH, H2O/THF, 70 °C, 16 h, followed by acidification with 1 N HCl, rt (100%); (c)
1-adamantamineÁHCl, CIP, DIPEA, CH2Cl2, rt, 16 h (52%); (d) 1-adamantamineÁHCl, Al(CH3)3, CH2Cl2, 35 °C, 16 h (63%).
In particular, the CB2 receptor affinity and CB1/CB2 receptor sub-
type selectivity data of Schering’s 3 are impressive. The CB2 recep-
tor binding data of our imidazoles 6–20 revealed that five of our
target compounds (8, 12, 14, 17 and 18) elicited more than
1000-fold CB1/CB2 receptor subtype selectivity values. Although
compound 12 showed a slightly lower CB2 receptor affinity as
compared with 3, its observed CB1/CB2 receptor subtype selectivity
was higher. Compounds 8, 12 and 14 combined a high CB2 receptor
affinity with a compact, low molecular weight chemical structure.
Compound 6 which lacks the 2-methyl group of 7 exhibited a nine-
fold lower CB2 receptor affinity. An analogous effect was observed
when comparing the CB2 receptor affinities of compounds 15 and
14. It can be concluded that the combination of a 1-aryl substituent
with a small alkyl substituent on both positions 2 and 5 of the
imidazole nucleus leads to very potent and selective CB2 receptor
ligands. The bulky 1-adamantyl group gives the best results in
our series of compounds since compound 8 showed a higher CB2
receptor affinity as compared with 7, 9, 10 and 11, respectively.
Replacement of the methyl group in 8 by a halogen substituent
or a methylsulfanyl group (16, 17, 18 and 19) led to lower CB2
receptor affinities. The replacement of the 5-methyl group in 8
by the larger n-butyl group (13) also resulted in a lower CB2 recep-

J. H. M. Lange et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1084–1089
1087
O
O
O
OEt
N
N
Compound
16
R
Reagent
N
N
N
H
H
c,d
a,b
Cl
To sCl
R
N
N
N
17
18
Br
(CBrF2)2
MeSSMe
SMe
44
16-18
43
Scheme 5. Reagents and conditions: (a) LiOH, H2O/THF, 70 °C, 16 h, followed by acidification with 1 N HCl, rt (100%); (b) 1-adamantamineÁHCl, HBTU, DIPEA, CH3CN, rt, 16 h
(70%); (c) excess LDA, THF, À70 °C, N2, 1 h; (d) reagent, THF, À70 °C to rt, N2, 12 h (28–50%).
O
O
O
O
O
OH
OH
OEt
c
OEt
d,e
N
N
N
N
N
N
N
H
H
a,b
f
Cl
N
H
Cl
N
H
N
N
N
O
45
46
47
48
19
Scheme 6. Reagents and conditions: (a) Ac2O, reflux, 5 h (73%); (b) H2SO4, EtOH, reflux, 36 h (71%); (c) C6H5B(OH)2, CuCl, EtOH/H2O, reflux, 100 h, (33%); (d) LiOH, H2O/THF,
60 °C, 16 h, followed by acidification with 1 N HCl, rt (82%); (e) 1-adamantamineÁHCl, HBTU, DIPEA, CH3CN, rt, 16 h (61%); (f) excess NCS, CHCl3, rt, 60 h (32%).
O
O
O
O
NO2
NH
OEt
N
EtO
N
N
H
NO2
OEt
b
a
c
EtO
N
N
49
50
51
20
Scheme 7. Reagents and conditions: (a) cyclohexylamine, EtOH, rt, 24 h (14%); (b) CH3C(OEt)3, H2, Pd/C, 4 atm, 73 °C, 24 h (58%); (c) 1-adamantamineÁHCl, Al(CH3)3,
ClCH2CH2Cl, 70 °C, 16 h (53%).
tor affinity. The presence of the lipophilic, non-aromatic cyclohexyl
group (20) instead of the phenyl moiety (8) at the 1-position of the
imidazole ring gave a sevenfold lower CB2 receptor affinity.
Compounds 1–3 have been reported16,18,19 to act as inverse ago-
nists44 at the constitutively active45 CB2 receptor. Our target com-
pounds also behave as potent CB2 receptor inverse agonists since
they were able to stimulate cAMP accumulation in a concentra-
tion-dependent manner (Table 1). In particular, compounds 8, 11
and 14 behaved as potent CB2 receptor inverse agonists. Unexpect-
edly, a modest pEC50 value (7.7 0.5) was initially observed for our
key compound 12. The assay incubation time turned out to be the
key factor here since after a prolonged incubation time (4 h) a
much higher pEC50 value (9.6 0.2) was found. Such an effect of
the incubation time on the observed CB2 inverse agonism was ab-
sent for the structural closely related 8 and 15 as well as for the po-
tent reference compound 3 (Table 1). However, 1 was also found
more active after a prolonged incubation period.
Furthermore, the reference compounds 1 (pA2 = 8.2 0.1), 2
(pA2 = 6.8 0.1), and 3 (pA2 = 9.0 0.4) were found to antagonize
the CB2 selective agonist JWH133 in a dose-dependent manner in
our human CB2 cAMP accumulation assay (20 min incubation
time), based on at least three independent experiments.43 The ob-
served order of the functional CB2 receptor antagonistic activities
of 1–3 is in line with their CB2 receptor affinities. Our novel imida-
zoles also functionally behaved as CB2 receptor antagonists, as
exemplified by 14 (pA2 = 8.3 0.4), and 19 (pA2 = 8.1 0.1). The
key compounds 8 (pA2 = 8.8 0.4) and 12 (pA2 = 9.0 0.2) were
also found very active as CB2 receptor antagonists after 4 h of incu-
bation in our cAMP accumulation assay.
The binding efficiency index (BEI) value has been suggested46 as
a better alternative for Hopkins’ ligand efficiency34 metric and
accurately reflects the efficiency of a given target-ligand binding
interaction. In order to compare their binding efficiencies, the BEI
values of the reference compounds 1–3 and the target compounds
6–20 were calculated (Table 2). From the BEI results of in particular
8, 12 and 14 it became clear that this new imidazole-scaffolded
chemotype incorporates a very efficient binding mode at the CB2
receptor. The BEI values of 8, 12 and 14 set a new standard in
the CB2 receptor antagonist/inverse agonist research area since
they are significantly higher than those of the known chemotypes
that are related to 1–3, respectively. It is interesting to note that 1–
3, which were discovered independently by different companies,
elicited comparable BEI values (ꢀ16–17) and that the BEI values
of 6–20 were all higher than those of 1–3. Accordingly, the
calculated ligand efficiency (LE) values of 1–3 were all lower than
0.40 whereas 7–12, 14–18 and 20 showed LE values of 0.40 or
higher.
Molecular weight and lipophilicity are key physicochemical
properties for drug candidates since it has been reported that the
mean molecular weight of orally administered drugs in develop-
ment decreases on passing through each of the different clinical
phases and that the most lipophilic compounds are being discon-

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J. H. M. Lange et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1084–1089
Table 1
Pharmacological data of reference compounds 1–3 and target compounds 6–20
Compound
Ki (CB2),a nM
Ki (CB1),b nM
CB2/CB1 ratio
>46
pEC50(CB2),c
1
1
1
2
2
21
3
>1000
7.4 0.4 (8.3 0.3)d
(7.6 0.1)16
(0.60 0.13)16
(1.99 0.94)18
130 630
(437 33)16
(50.3 8.37)18
3924 642
(2370 297)18
3538 638
(4378)19
30
<6.5
(35.9 7.32)18
0.8 0.3
3
3
4423
8.1 0.2 (8.3 0.3)d
(8.0)19
(1.0)19
6
175 77
>10,000
>57
6.8 0.2
7
8
9
20
5
3995 1173
4887 1796
3008 679
5444 433
1422 163
>10,000
1995
4152 2157
>1000
>10,000
>10,000
>10,000
>1000
200
1810
218
561
406
>9708
>102
2595
>79
>420
>1190
>1000
>20
7.5 0.7
2.7 0.9
13.8 4.9
9.7 5.5
3.5 2.2
1.03 0.20
9.8 5.7
1.6 0.8
12.7 3.2
23.8 3.9
8.4 2.1
10.0 2.9
50 13
9.1 0.2 (9.1 0.3)d
8.2 0.6
10
11
12
13
14
15
16
17
18
19
20
8.1 0.1
9.7 0.8
7.7 0.5 (9.6 0.2)d
8.3 0.2
8.8 0.8
7.9 0.1 (8.2 0.3)d
7.2 0.4
n.d.e
8.2 0.1
7.1 0.1
6.9 0.5
20.0 7.9
>10,000
>500
a
Displacement of specific CP-55,940 binding in CHO cells stably transfected with human CB2 receptor,42 expressed as Ki SEM (nM) The values represent the mean result
based on at least three independent experiments.
b
Displacement of specific CP-55,940 binding in CHO cells stably transfected with human CB1 receptor,42 expressed as Ki SEM (nM). The values represent the mean result
based on at least three independent experiments.
c
Functional hCB2 cAMP accumulation assay,43 expressed as pEC50 values (result after 20 min incubation time; see Supplementary data for detailed protocol). The values
represent the mean result based on at least three independent experiments.
d
Result after 4 h incubation time.
n.d.: Not determined.
e
Table 2
Calculated and experimental physicochemical parameters of compounds 1–3 and 6–20
BEIa
LEb
LLEc
A log P
Log PHPLC
cPSAe
d
Compound
Molecular weight
1
2
3
6
7
476
438
532
337
351
349
349
335
373
363
391
363
349
370
414
381
390
355
16
16
17
20
22
25
23
24
23
25
20
25
23
21
20
21
19
22
0.31
0.29
0.38
0.36
0.40
0.45
0.41
0.44
0.43
0.45
0.38
0.44
0.41
0.40
0.42
0.40
0.38
0.40
0.1
3.4
4.9
3.2
3.8
4.9
4.1
4.7
4.4
4.7
2.7
4.4
3.7
3.6
4.0
3.8
2.7
3.7
7.6
3.5
4.2
3.6
3.9
3.7
3.8
3.3
4.1
4.3
5.3
4.4
4.2
4.0
4.1
4.2
4.6
4.0
n.d.f
4.4g
1.8g
n.d.f
n.d.f
3.2h
n.d.f
n.d.f
n.d.f
3.5h
n.d.f
n.d.f
n.d.f
n.d.f
n.d.f
n.d.f
n.d.f
n.d.f
47
95
140
47
47
47
47
47
47
47
47
47
47
47
47
72
47
47
8
9
10
11
12
13
14
15
16
17
18
19
20
a
b
c
Binding efficiency index (BEI); BEI = pKi/(MW/1000).
Ligand efficiency index (LE); LE = À(RTlnKd)/N ꢁ 1.36 pKi/N, wherein N represents the number of non-hydrogen atoms.
ligand-lipophilicity efficiency (LLE); LLE = pKi À c log P ꢁ pKi À A log P.
Experimental log P value determined by a validated RP-HPLC method.42
Calculated polar surface area (Å2).
d
e
f
n.d.; not determined.
Determined at pH 7.
Determined at pH 11.
g
h
tinued from development.47 In addition, lipophilicity plays a role in
promoting binding to unwanted biological targets.48 In order to po-
sition these important key physicochemical properties of our imi-
dazoles 6–20 against the known CB2 antagonist reference
compounds 1–3, their A log P49 and molecular polar surface area
(PSA) values were calculated (Table 2). It can be concluded from
these lipophilicity results that Sanofi’s 1 has a very high lipophilicy
whereas all the other compounds from Table 2 show favourable
A log P values. Ligand-Lipophilicity Efficiency48,50 (LLE) (also re-
ferred to as Lipophilic Efficiency (LipE)) has recently been intro-
duced as
a parameter that combines both potency and
lipophilicity. The LLE value of 1 is very low due to its high lipophil-
icity. The LLE value of compound 8 equals the value of Schering’s 3.
Noteworthy, the A log P data for the imidazoles 8 and 12 are some-
what higher than the experimental data obtained from our vali-
dated RP-HPLC lipophilicity assay42 (Table 2.) The calculated

J. H. M. Lange et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1084–1089
1089
15. (a) Yao, B. B.; Hsieh, G. C.; Frost, J. M.; Fan, Y.; Garrison, T. R.; Daza, A. V.;
Grayson, G. K.; Zhu, C. Z.; Pai, M.; Chandran, P.; Salyers, A. K.; Wensink, E. J.;
Honore, P.; Sullivan, J. P.; Dart, M. J.; Meyer, M. D. Br. J. Pharmacol. 2008, 153,
390; (b) Yao, B. B.; Hsieh, G.; Daza, A. V.; Fan, Y.; Grayson, G. K.; Garrison, T. R.;
Kouhen, O. E.; Hooker, B. A.; Pai, M.; Wensink, E. J.; Salyers, A. K.; Chandran, P.;
Zhu, C. Z.; Zhong, C.; Ryther, K.; Gallagher, M. E.; Chin, C.-L.; Tovcimak, A. E.;
Hradil, V. P.; Fox, G. B.; Dart, M. J.; Honore, P.; Meyer, M. D.; Research, N. D. J.
Pharmacol. Exp. Ther. 2009, 328, 141.
16. Rinaldi-Carmona, M.; Barth, F.; Millan, J.; Derocq, J.-M.; Casellas, P.; Congy, C.;
Oustric, D.; Sarran, M.; Bouaboula, M.; Calandra, B.; Portier, M.; Shire, D.;
Brelière, J.-C.; Le Fur, G. J. Pharmacol. Exp. Ther. 1998, 284, 644.
17. Rinaldi-Carmona, M.; Barth, F.; Congy, C.; Martinez, S.; Oustric, D.; Pério, A.;
Poncelet, M.; Maruani, J.; Arnone, M.; Finance, O.; Soubrié, P.; Le Fur, G. J.
Pharmacol. Exp. Ther. 2004, 310, 905.
A log P result for 3 is also higher than its experimental log PHPLC
value.
Calculated PSA values have been shown to closely correlate
with drug transport properties, such as intestinal absorption or
blood-brain barrier penetration.51–53 Compounds having a PSA va-
lue >120 Å2 have generally been shown to have restricted oral bio-
availability. It is clear that Schering’s 3 does not comply with this
PSA threshold. The potent bissulfone 3 combines a high polarity
with a high molecular weight. The other compounds depicted in
Table 2 have low cPSA values, with the exception of JTE-907 which
exhibits an intermediate cPSA value of 95 Å2. Additional in vitro
permeability testing revealed that the compounds 8, 12 and 14
were not substrates of P-glycoprotein-mediated transport.54
Imidazole-4-carboxamides 6–20 were designed as a new chem-
otype of CB2 receptor antagonists. It was demonstrated herein that
these novel compounds 6–20 are potent and highly CB2/CB1 selec-
tive CB2 receptor antagonists/inverse agonists with very high bind-
ing efficiency index values, which exceeded the BEI values of the
CB2 reference compounds 1–3. Furthermore, the imidazoles 6–20
as a class exhibited both favourable A log P and calculated molec-
ular polar surface area values, which are major in silico indicators
for their pharmacokinetic properties.
18. Iwamura, H.; Suzuki, H.; Ueda, Y.; Kaya, T.; Inaba, T. J. Pharmacol. Exp. Ther.
2001, 296, 420.
19. Shankar, B. B.; Lavey, B. J.; Zhou, G.; Spitler, J. A.; Tong, L.; Rizvi, R.; Yang, D.-Y.;
Wolin, R.; Kozlowski, J. A.; Shih, N.-Y.; Wu, J.; Hipkin, R. W.; Gonsiorek, W.;
Lunn, C. A. Bioorg. Med. Chem. Lett. 2005, 15, 4417.
20. Raitio, K. H.; Salo, O. M. H.; Nevalainen, T.; Poso, A.; Jaervinen, T. Curr. Med.
Chem. 2005, 12, 1217.
21. Muccioli, G. G.; Lambert, D. M. Exp. Opin. Ther. Patents 2006, 16, 1405.
22. Högenauer, E. K. Exp. Opin. Ther. Patents 2007, 17, 1457.
23. Marriott, K.-S. C.; Huffman, J. W. Curr. Top. Med. Chem. 2008, 8, 187.
24. Worm, K.; Dolle, R. E. Curr. Pharm. Des. 2009, 15, 3345.
25. Thakur, G. A.; Tichkule, R.; Bajaj, S.; Makriyannis, A. Exp. Opin. Ther. Patents
2009, 19, 1647.
26. Poso, A.; Huffman, J. W. Br. J. Pharmacol. 2008, 153, 335.
27. Tuccinardi, T.; Ferrarini, P. L.; Manera, C.; Ortore, G.; Saccomanni, G.; Martinelli,
A. J. Med. Chem. 2006, 49, 984.
28. Chen, J.-Z.; Wang, J.; Xie, X.-Q. J. Chem. Inf. Model. 2007, 47, 1626.
29. Pei, Y.; Mercier, R. W.; Anday, J. K.; Thakur, G. A.; Zvonok, A. M.; Hurst, D.;
Reggio, P. H.; Janero, D. R.; Makriyannis, A. Chem. Biol. 2008, 15, 1207.
30. Tiburu, E. K.; Tyukhtenko, S.; Deshmukh, L.; Vinogradova, O.; Janero, D. R.;
Makriyannis, A. Biochem. Biophys. Res. Commun. 2009, 384, 243.
31. Lan, R.; Liu, Q.; Fan, P.; Lin, S.; Fernando, S. R.; McCallion, D.; Pertwee, R.;
Makriyannis, A. J. Med. Chem. 1999, 42, 769.
Acknowledgements
Jan Jeronimus and Hugo Morren are gratefully acknowledged
for supply of the analytical data. Dr. Chris Kruse is acknowledged
for his helpful suggestions.
32. 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, W.; Borst, A. J. M.; De Looff,
W.; Verveer, P. C.; Kruse, C. G. J. Med. Chem. 2005, 48, 1823.
33. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. W. Adv. Drug Delivery
Rev. 1997, 23, 3.
34. Hopkins, A. L.; Groom, C. R.; Alex, A. Drug Discovery Today 2004, 9, 430.
35. Verdonk, M. L.; Rees, D. C. ChemMedChem 2008, 3, 1179.
36. Lange, J. H. M.; Kruse, C. G. Curr. Opin. Drug Disc. Dev. 2004, 7, 498.
37. Lange, J. H. M.; Kruse, C. G. Chem. Rec. 2008, 8, 156.
38. Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982, 12, 989.
39. Haberhauer, G.; Rominger, F. Tetrahedron Lett. 2002, 43, 6335.
40. Gomez-Sanchez, A.; Hidalgo, F. J.; Chiara, J. L. J. Heterocycl. Chem. 1987, 24,
1757.
41. Bell, A. S.; Campbell, S. F.; Morris, D. S.; Roberts, D. A.; Stefaniak, M. H. J. Med.
Chem. 1989, 32, 1552.
Supplementary data
Supplementary data (selected analytical and synthesis data for
compounds 6–8, 12, 14 and 16–20. The protocol for the human
cannabinoid CB2 cAMP accumulation assay) associated with this
article can be found, in the online version, at doi:10.1016/
j.bmcl.2009.12.032.
References and notes
1. Munro, S.; Thomas, K. L.; Abu-Shaar, M. Nature 1993, 365, 61.
2. Klein, T. W.; Newton, C.; Friedman, H. Immunol. Today 1998, 19, 373.
3. Gong, J.-P.; Onaivi, E. S.; Ishiguro, H.; Liu, Q.-R.; Tagliaferro, P. A.; Brusco, A.;
Uhl, G. R. Brain Res. 2006, 1071, 10.
4. Svizenska, I.; Dubovy, P.; Sulcova, A. Pharmacol. Biochem. Behav. 2008, 90, 501.
5. van Sickle, M. D.; Duncan, M.; Kingsley, P. J.; Mouihate, A.; Urbani, P.; Mackie,
K.; Stella, N.; Makriyannis, A.; Piomelli, D.; Davison, J. S.; Marnett, L. J.; Di
Marzo, V.; Pitman, Q. J.; Patel, K. D.; Sharkey, K. A. Science 2005, 310, 329.
6. Klein, T. W.; Newton, C.; Larsen, K.; Lu, L.; Perkins, I.; Nong, L.; Friedman, H. J.
Leukocyte Biol. 2003, 74, 486.
7. Zhang, J.; Hoffert, C.; Vu, H. K.; Groblewski, T.; Ahmad, S.; O’Donnell, D. Eur. J.
Neurosci. 2003, 17, 2750.
8. Lunn, C. A.; Reich, E-P.; Fine, J. S.; Lavey, B.; Kozlowski, J. A.; Hipkin, R. W.;
Lundell, D. J.; Bober, L. A. Br. J. Pharmacol. 2008, 153, 226.
9. Lunn, C. A.; Fine, J. S.; Rojas-Triana, A.; Jackson, J. V.; Fan, X.; Kung, T. T.;
Gonsiorek, W.; Schwarz, M. A.; Lavey, B.; Kozlowski, J. A.; Narula, S. K.; Lundell,
D. J.; Hipkin, R. W.; Bober, L. A. J. Pharmacol. Exp. Ther. 2006, 316, 780.
10. Lange, J. H. M.; Kruse, C. G. Drug Discovery Today 2005, 10, 693.
11. Huffman, J. W.; Liddle, J.; Yu, S.; Aung, M. M.; Abood, M. E.; Wiley, J. L.; Martin,
B. R. Bioorg. Med. Chem. 1999, 7, 2905.
12. Hanus, L.; Breuer, A.; Tchilibon, S.; Shiloah, S.; Goldenberg, D.; Horowitz, M.;
Pertwee, R. G.; Ross, R. A.; Mechoulam, R.; Fride, E. Proc. Natl. Acad. Sci. U.S.A.
1999, 96, 14228.
42. 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, W.; Wals, H. C.; Stork, B.; 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.
43. Goutier, W.; Spaans, P. A.; van der Neut, M. A. W.; McCreary, A. C.; Reinders, J.
H. J. Neurosci. Methods, submitted for publication.
44. Kenakin, T. FASEB J. 2001, 15, 598.
45. Bond, R. A.; IJzerman, A. P. Trends Pharmacol. Sci. 2006, 27, 92.
46. Abad-Zapatero, C.; Metz, J. T. Drug Discovery Today 2005, 10, 464.
47. Wenlock, M. C.; Austin, R. P.; Barton, P.; Davis, A. M.; Leeson, P. D. J. Med. Chem.
2003, 46, 1250.
48. Leeson, P. D.; Springthorpe, B. Nat. Rev. Drug Disc. 2007, 6, 881.
49. Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J. J. Phys. Chem. A 1998, 102,
3762.
50. Ryckmans, T.; Edwards, M. P.; Horne, V. A.; Correia, A. M.; Owen, D. R.;
Thompson, L. R.; Tran, I.; Tutt, M. F.; Young, T. Bioorg. Med. Chem. Lett. 2009, 19,
4406.
51. Palm, K.; Stenberg, P.; Luthman, K.; Artursson, P. Pharm. Res. 1997, 14, 568.
52. Kelder, J.; Grootenhuis, P. D. J.; Bayada, D. M.; Delbressine, L. P. C.; Ploemen, J.-
P. Pharm. Res. 1999, 16, 1514.
53. Van de Waterbeemd, H.; Jones, B. C. Predicting Oral Absorption and
Bioavailability. In Progress in Medicinal Chemistry; King, F. D., Oxford, A. W.,
Eds.; Elsevier Science B.V.: Amsterdam, 2003; Vol. 41, pp 1–59.
54. Schinkel, A. H.; Wagenaar, E.; van Deemter, L.; Mol, C. A. A. M.; Borst, P. J. Clin.
Invest. 1995, 96, 1698.
13. Ross, R. A.; Brockie, H. C.; Stevenson, L. A.; Murphy, V. L.; Templeton, F.;
Makriyannis, A.; Pertwee, R. G. Br. J. Pharmacol. 1999, 126, 665.
14. Ibrahim, M. M.; Deng, H.; Zvonok, A.; Cockayne, D. A.; Kwan, J.; Mata, H. P.;
Vanderah, T. W.; Lai, J.; Porreca, F.; Makriyannis, A.; Malan, T. P., Jr. Proc. Natl.
Acad. Sci. U.S.A. 2003, 100, 10529.