5-Sulfonyl-benzimidazoles as selective CB2 agonists-Part 2

Article abstract of DOI:10.1016/j.bmcl.2011.10.091

In a previous communication, the SAR of a series of potent and selective 5-sulfonyl-benzimidazole CB2-receptor agonists was described. The lack of in vivo activity of compounds from this series was attributed to their poor solubility and metabolic stabili

Full text of DOI:10.1016/j.bmcl.2011.10.091

Bioorganic & Medicinal Chemistry Letters 22 (2012) 547–552
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
5-Sulfonyl-benzimidazoles as selective CB2 agonists-Part 2
Harrie J.M. Gijsen , Michel A.J. De Cleyn, Michel Surkyn, Guy R.E. Van Lommen , Bie M.P. Verbist à,
⇑
Marjoleen J.M.A. Nijsen §, Theo Meert, Jean Van Wauwe, Jeroen Aerssens
Janssen Research & Development, Turnhoutseweg 30, 2340 Beerse, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
In a previous communication, the SAR of a series of potent and selective 5-sulfonyl-benzimidazole CB2-
receptor agonists was described. The lack of in vivo activity of compounds from this series was attributed
to their poor solubility and metabolic stability. In this Letter, we report on the further optimization of this
series, leading to the relatively polar and peripherically acting CB2 agonists 41 and 49. Although both
compounds were not active in acute pain models, the less selective compound 41 displayed good, sus-
tained activity in a chronic model of neuropathic pain without the tolerance observed with morphine.
In addition, both 41 and 49 delayed the onset of clinical symptoms in an experimental model for Multiple
sclerosis.
Received 19 September 2011
Revised 24 October 2011
Accepted 26 October 2011
Available online 6 November 2011
Keywords:
Cannabinoid receptor
CB2 agonist
Ó 2011 Elsevier Ltd. All rights reserved.
Benzimidazole
The two known cannabinoid receptors CB1 and CB2 play a mod-
ulatory role in a complex array of biological processes.1 Activation
of both receptors has been associated with analgesic and anti-
inflammatory effects. However, while clear analgesic effects have
been observed for CB1-agonists, the reports on the in vivo effects
of CB2-agonists in animal pain2 and inflammation3 models are
far less conclusive.4 The undesirable psychotropic effects associ-
ated with activation of the CB1 receptor make the CB1 receptor a
less attractive drug target for pain indications. The CB2 receptor
does not carry this liability. It is mainly located in the periphery,
and its abundance in immune cells underlines the anti-inflamma-
tory potential.
Recently, we have reported on a series of 5-sulfonyl-benzimi-
dazoles as potent, highly selective, and peripherically restricted
CB2 agonists.5 One of the key compounds arising from this series
was compound 1 (Fig. 1), which combined selectivity with an
acceptable drug-like profile. Although this translated in a decent
pharmacokinetic profile, no analgesic effect could be demonstrated
in pain models. Achieving high compound levels over a prolonged
period of time proved to be difficult, which was attributed to the
suboptimal metabolic stability of 1, in combination with poor
solubility. In this Letter we describe the further optimization of
5-sulfonyl-benzimidazole CB2 agonists with improved metabolic
stability and solubility, which would allow us to investigate the po-
tential use of peripherically restricted CB2 agonists in animal
models.6
As reported by us previously,5 and confirmed by other groups
describing SAR on benzimidazole CB2 agonists,7 the t-butyl group
at the benzimidazole 2-position is optimal for achieving potency
as well as full agonistic efficacy. Therefore, our exploration focused
around further variation of the substituents at the benzimidazole
1- and 5-positions.
In 1, the introduction of an ortho-substituted pyridyl sulfone
substituent had resulted in an increased CB2/CB1 selectivity, as
well as an acceptable CYP-inhibition profile.5 Common approaches
to improve solubility include the introduction of additional hetero-
atoms, or increasing the number of rotatable bonds.8 We tried to
combine this via the introduction of heteroatom containing elon-
gated alkyl groups on the ortho pyridyl position (compounds 2–8,
Table 1).
Their synthesis is depicted in Scheme 1. Oxygen or nitrogen
linked alkyl substituents were easily introduced on fluoropyridyl
substituted 95 to give 2–5. Carbon linked alkyl groups were synthe-
sized via a selective Shonogashira reaction on 2,4-dichloropyridine
(10), followed by catalytic hydrogenation to give the 2-alkyl-4-
chloropyridines 12. These then underwent
a Buchwald type
O
O
hCB2 EC50
0.3nM
N
hCB1 EC50 1280 nM
N
metabolism (hLM, 15 min.) 48%
kinetic solubility (pH 7.4) <1 µM
N
S
O
O
⇑
Corresponding author. Tel.: +32 14 606830.
E-mail address: hgijsen@its.jnj.com (H.J.M. Gijsen).
1
Present affiliations: Galapagos.
Present affiliations: Ghent University.
Present affiliations: Abbott.
à
§
Figure 1. Structure and properties of previous lead and Pfizer analogue.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.10.091

548
H. J. M. Gijsen et al. / Bioorg. Med. Chem. Lett. 22 (2012) 547–552
Table 1
Elongated analogues of ethoxy substituted 1
O
R
N
N
hCB2 EC50 (nM)
hCB1 EC50 (nM)
% Metabolism in hLM (15 min)
N
S
O
O
Compound
R
1
0.3
0.8
1280
955
48
99
O
O
N
H
2
3
4
5
0.5
1.3
1.2
3850
804
100
53
O
O
O
O
3630
40
HO
O
O
6
7
1.1
5.6
>10000
>10000
93
86
AcNH
8
1.4
8320
44
AcNH
O
O
R
N
F
A
a
N
N
N
N
N
S
O
S
4-22%
O
O
O
n
9
2-5 A = O or NH
R
R
O
n
n
N
Cl
N
N
d, e
R
b
c
N
N
+
13-71%
40-63%
60%
Cl
Cl
Cl
HS
10
11
12
13
NH2
NHAc
n
R
O
O
O
for 14
n
n
N
N
N
N
N
g
f
N
N
N
N
S
S
O O
S
30-60%
72%
O
O
O O
15
7
n = 0
6
n = 1, R = OMe
8 n = 3
14 R = Phthalimide
Scheme 1. Reagents and conditions: (a) R-OH, NaH, dioxane;,or R-NH2, dioxane, 100 °C; (b) PdCl2(PPh3)2 (cat.), CuI, Et3N, 70 °C; (c) Pt/C 5% (cat.), H2, thiophene sol., Et3N,
MeOH; (d) Pd2dba3 (cat.), Xantphos, Cs2CO3, dioxane, 80–100 °C; (e) mCPBA, CHCl3; (f) hydrazine, EtOH; (g) AcCl, Et3N, CH2Cl2.
coupling with 13, whose synthesis has been described before.5
Subsequent oxidation gave sulfones 6 and 14. The latter were
deprotected and acetylated to give 7 and 8.
In general, the introduction of diversely substituted alkyl
groups was well tolerated, and maintained the potency and good
to excellent selectivity of 1 (Table 1).9 Unfortunately, the com-
pounds displayed a worse, or at best similar, metabolic stability
compared to 1. More unexpectedly, the solubility of these com-
pounds did not greatly improve either (data not shown).
but the tetrahydropyranyl ring is also a potential metabolic soft
spot. Earlier explorations had indicated a preference for lipophilic
groups at the benzimidazole 1-position to achieve high potency,
but this also resulted in low metabolic stability, as well as a re-
duced selectivity of CB2 versus CB1.5 Now, we replaced the tetra-
hydropyranyl moiety with more polar acylated piperidinyl and
tetrahydro-1,1-dioxo-thiopyranyl groups to improve both the met-
abolic stability and the solubility.
The synthesis of the target compounds is depicted in Schemes 2
and3. Introductionof a varietyof acylatedpiperidinylmethylgroups
was most easily achieved via a nucleophilic aromatic substitution
We then turned our attention to the benzimidazole-1-substitu-
ent. This had been shown to be crucial for achieving good potency,

H. J. M. Gijsen et al. / Bioorg. Med. Chem. Lett. 22 (2012) 547–552
549
Cl
Cl
Cl
a, b
c
alkyl
alkyl
HS
S
O O
S
O O
NO2
95-100%
60-100%
16
17
18
NBoc
NH2
19
NBoc
BocN
e
NH
NH
NH2
d
70-100%
alkyl
alkyl
S
O O
NO2
90-93%
S
O O
20
21
O
R
NH
N
f, g
h
N
N
N
alkyl
alkyl
50-80%
N
S
O O
S
O O
22
alkyl = CF3CH2CH2CH2: 23 - 28
Scheme 2. Reagents and conditions: (a) alkyl-halide, Cs2CO3, acetone; (b) mCPBA, CHCl3; (c) HNO3, H2SO4; (d) K2CO3, dioxane or iPrOH, 75–100 °C, 3–6 h; (e) H2, Pd/C (cat.)
MeOH; (f) PivCl, pyridine, CH2Cl2; (g) conc. HCl, HOAc, reflux, 3 h; (h) RCOCl or (RCO)2O, Et3N, CH2Cl2.
A
H
N
e
NO2
a, b
c, 82%
NO2
NH2
PMB
PMB
S
NH
S
NH
81%
12-73%
O
Cl
O
O
H
31
A
29
30
32 A = NBoc or S
d, 60-82%
A
A
A
A
g
i
h
N
N
N
N
N
N
N
PMB
R
R
80-100%
70%
30-90%
N
S
HS
S
S
O
O
33
35 A = S
36
37-49
A = SO2 or NCOR'
A = S
A = NH
A = S
A = NCOR'
A = NCOR'
f
82-100%
34 A = NCOR'
Scheme 3. Reagents and conditions: (a) PMBSH, KOH, EtOH, reflux, 2 h; (b) PivCl, pyridine, CH2Cl2; (c) Fe, aq HOAc, reflux, 4 h; (d) NaBH3CN, HOAc, CH2Cl2; (e) HOAc, reflux;
(f) (R’CO)2O, THF or (for R’ = COH) MeOCOH, reflux, 24 h. (g) TFA, MW 120 °C, 25–60 min; (h) R-halide, Cs2CO3, acetone or Pd2dba3 (cat.), Xantphos, Cs2CO3, dioxane, 80–
100 °C; (i) mCPBA, CHCl3.
with 19 on halobenzenes, activated by the para-sulfonyl and ortho-
nitro-groups such as in 18 (Scheme 2). Reduction of the nitro group
in 20 to aniline 21 was followed by pivaloylation to introduce the t-
butyl group. Subsequentcondensation tothe benzimidazole nucleus
under acidic conditions, with concomitant debocylation, led to 22.
Finally, acylation of 22 yielded compounds 23–28.
An alternative synthetic route allowed for a later introduction of
5-sulfonyl substituents, and is shown in Scheme 3. Starting from 5-
chloro-2-nitro-aniline 29, 4-methoxybenzylthiol (PMBSH) was
introduced as a protecting group via nucleophilic aromatic substi-
tution and subsequent reaction with pivaloylchloride gave 30.
Reduction of the nitro group was followed by reductive amination
with aldehyde 31 to introduce the desired benzimidazole-1-substi-
tuent. Condensation to the benzimidazole under acidic conditions
again resulted in debocylation, which allowed for subsequent
introduction of various acyl groups to give 34. Deprotection of
the para-methoxybenzyl group with TFA gave intermediates 35.
In the next steps the various 5-sulfonyl groups could be
introduced. Alkyl substituents were introduced via nucleophilic
substitution, (hetero)aromatic substituents were introduced via
Pd-catalyzed reactions.10 Finally, the sulfides 36 were oxidized to
the sulfones 37–49 using meta-chloroperoxybenzoic acid.
To investigate the change in properties by going from a
tetrahydropyranyl to acylated piperidinyl substituents, the

550
H. J. M. Gijsen et al. / Bioorg. Med. Chem. Lett. 22 (2012) 547–552
Table 2
Effect of N substitution on hCB2 agonist activity and selectivity
A
N
hCB2 EC50 (nM)
hCB1 EC50 (nM)
% Metabolism in hLM (15 min)
N
CF3
S
O
O
A
50
22
23
24
25
26
27
28
O
NH
NCOH
NCOCH3
NCOCH2CH3
NCOCF3
NCOOCH3
NCOCH2OCH3
1.1
240
2.4
13
19
23
320
>10000
5623
>10000
>10000
>10000
>10000
>10000
36
nd
17
17
4
20
54
nd
17
1585
Table 3
Variation of C-5- substitution with selected N-substituents
A
N
hCB2 EC50 (nM)
hCB1 EC50 (nM)
% Metabolism in hLM (15 min)
R
N
S
O
O
R
A
37
38
39
40
41
42
43
44
45
46
47
48
49
Ethyl
Ethyl
Ethyl
cPropylmethyl
cPropylmethyl
cPropylmethyl
cPentyl
Methoxyethyl
Hydroxypropyl
4-F-phenyl
NCOH
NCOCH3
SO2
NCOH
NCOCH3
SO2
NCOCH3
NCOCH3
NCOCH3
NCOCH3
NCOCH3
NCOH
23
8.4
28
>10000
>10000
>10000
2512
>10000
2676
>10000
>10000
>10000
>10000
>10000
321
7
13
nd
16
18
2
87
nd
nd
8
2.2
8.2
8.4
3.2
26
145
2.9
4.6
8.4
7.7
4-Pyridyl
2-Thiazolyl
2-Thiazolyl
29
nd
9
NCOCH3
3428
trifluorobutylsulfonyl group was selected as the benzimidazole
5-substituent (Table 2). As reported previously, this particular sub-
stituent had led to a potent, but moderately selective CB2 agonist
when combined with the tetrahydropyranylmethyl group at the 1-
position (compound 50).5 Replacement of the THP-group in this
compound, would allow us to determine the influence of this struc-
tural change at the 1-position on CB2/CB1 selectivity, in addition to
potency, metabolic stability, and solubility.
piperidinyl methyl 1-substituents with apolar 5-sulfonyl groups
such as in 23, 40, and 48 led to the most potent CB2 agonists in this
series, but also <10 lM CB1 agonism. Bis-sulfonyl containing com-
pounds 39 and 42 showed a comparable activity profile compared
to their acylpiperidinyl analogues, but suffered from low solubility.
Most compounds of interest were subsequently subjected to a
modified tetrad test in rats with doses up to 40 mg/kg (intraperito-
neal) for typical CNS mediated CB1 side-effects.11 In this test even
compounds displaying weak CB1 agonism are active. For example,
in this assay, 50 had a lowest active dose (LAD) for body tempera-
ture decrease at 10 mg/kg and flat body posture at 2.5 mg/kg. Of all
current compounds tested from Table 3, only compounds 46 and
48 were positive with a LAD of 10 mg/kg on all CB1 mediated
observations. While these effects can be explained for 48 based
on its limited CB2/CB1 selectivity, for 46 this is less obvious. Spe-
cies differences or increased brain penetration could offer a poten-
tial explanation, but this was not investigated.
Compounds 41 and 49 were selected for further in vivo profil-
ing, respectively as a highly selective and moderately selective
CB2 agonist, both without CB1 mediated side-effects up to
40 mg/kg.
Physicochemical and key in vitro and in vivo DMPK properties
for 41 and 49 are shown in Table 4. Compared to the high lipophil-
icity of most reported cannabinoid ligands, 41 and 49 are relatively
polar, with a LogP of 1.67 and 1.90, respectively. For formulation
purposes, a good solubility was observed for 41, but 49 was only
All the acylated piperidinyl analogues 23–28 displayed an im-
proved CB2/CB1 selectivity profile (Table 2), with EC50 values for
CB1 activation for most derivatives above 10 lmol. Metabolic sta-
bility and solubility (data not shown) were also improved for most
compounds. The non-acylated piperidinyl analogue 22 appeared to
have lost most of the CB2 activity. In comparison to 50, a drop in
potency was also observed for the acylated piperidinyl compounds,
but the 2–20 nM potency, in combination with the overall im-
proved properties, encouraged us to explore this variation further.
A set of analogues was prepared and tested containing formy-
lated and acetylated piperidinyl methyl N-substituents, combined
with various 5-sulfonyl groups. In addition, the tetrahydro-1,1-di-
oxo-thiopyranyl methyl group was investigated as a potential
alternative to the acyl piperidinyl methyl group (Table 3).
Apolar alkyl or (hetero)aryl sulfonyl substituents resulted in po-
tent and selective CB2 agonism. Introduction of more polar substit-
uents such as in 45, or an overall decreased lipophilicity as in 37,
39, or 44 led to a decrease in potency. The combination of N-formyl

H. J. M. Gijsen et al. / Bioorg. Med. Chem. Lett. 22 (2012) 547–552
551
Table 4
Physicochemical and key in vitro and in vivo DMPK properties for 41 and 49
O
O
N
N
N
N
N
N
S
N
S
O
S
O
O
O
41
49
LogP
TPSA
1.67
81
1.90
122
Solubility
(mg/mL)
1.5 (H2O)
25 (10% CD)
5% (h), 0% (r)
0.02 (H2O)
8 (20% CD)
12% (h), 0% (r),
6% (m), 0% (d)
Metabolic stabilitya
12% (m), 4% (d)
In vivo PKb
Rat
Dog
Rat
Dog
Cl (L/h/kg)
Vd (L/kg)
T1/2 (iv)
T1/2 (po)
Fabs
2.5
4.4
1.3 h
4 h
56%
0.18
0.8
1.9
3 h
3.2 h
86%
3.2
1.3
3.5 h
3.1 h
35%
0.05
0.7
3.7
4 h
5–19 h
100%
Brain/plasma
a
% Metabolism as measured after 60 min incubation at 5 lM with liver microsomes (h = human, r = rat, m = mouse, d = dog).
Rat (Sprague–Dawley): 2.5 mg/kg iv, 10 mg/kg po Dog (Beagle): 1 mg/kg iv, 5 mg/kg po.
b
Figure 3. Effect on EAE disease scores in mice after chronic treatment with 41 and
49.
Figures 2 and 3. In the chronic constriction injury (CCI) model of
neuropathic pain in rats,13 49 did reverse CCI induced cold allo-
dynia14 after daily subcutaneous (SC) administration of 40 mg/kg (
Fig. 2). This effect was maintained after 12 days of dosing, in con-
trast to treatment with morphine for which tolerance was observed
after 5–8 days of dosing. In the same test, no significant effect was
observed for the more CB2 selective 41 at doses of 10 and 40 mg/kg
SC. The activity observed for 49 can therefore not be attributed with
certainty to CB2 agonism. The activity could also be the result of the
weak CB1 activity of 49.4 Very low occupancy of CB1 receptors has
been shown to be sufficient to ellicit CB1-mediated effects,4a and
the current difference in activity for the highly CB2 selective 41 ver-
sus the less selective 49 could be in support of this.
In an experimental autoimmune encephalomyelitis (EAE) model
of multiple sclerosis (MS), chronic oral administration of 41 and 49
(40 mg/kg) in mice significantly delayed neurological signs in EAE (
Fig. 3).15 Since in this model for MS, both 41 and 49 are equally ac-
tive, this effect is more likely to be related to CB2 agonism, than the
effects observed in the CCI model. It should be noted that the delay
in neurological signs is only temporary. For an optimal approach to
treat MS, an increased brain penetration may be required.16
Despite the activity observed in both of these chronic models,
the limited analgesic and anti-inflammatory effects of both com-
pounds question the therapeutic usefulness of peripherically
Figure 2. Effect on CCI induced cold allodynia: lifting on a cold plate (0 °C for 4 min)
in CCI rats (n = 7) during chronic treatment with 42 versus morphine.13
soluble at 20 lg/mL in water. After addition of 20% cyclodextrin
(CD), formulations could be prepared of 49 with a concentration
up to 8 mg/mL. In all species tested, the compounds were found
to be metabolically stable in vitro.
For 41, in vivo plasma kinetics studies in rat and dog showed a
fairly high clearance and short half life in rat after iv dosing, but
the profile after oral dosing was acceptable with a half life of 4 h
and an absolute oral bioavailability (Fabs) of 56%. For 49, a similar
profile was observed in rat, with a slightly lower absolute oral
bioavailability of 35%. In a rat tissue distribution study, 41 and 49
gave a brain to plasma ratio of 0.18 and 0.05, respectively, indicat-
ing poor blood brain barrier penetration. For both compounds, an
overall improvement of the PK profile was observed in dogs.
Compounds 41 and 49 were then tested in a battery of analgesic
and anti-inflammatory models.12 Both 41 and 49 did not show
appreciable efficacy at 10 mg/kg in a number of acute nociception
models such as the hot plate, tail withdrawal reflex, or paw flick
tests. They were also ineffective in myco- and carrageenan-induced
thermal hyperalgesia. Significant effects were only observed after
chronic treatment, and some preliminary results are shown in

552
H. J. M. Gijsen et al. / Bioorg. Med. Chem. Lett. 22 (2012) 547–552
(b) Manley, P. J.; Zartman, A.; Paone, D. V.; Burgey, C. S.; Henze, D. A.; Della
Penna, K.; Desai, R.; Leitl, M. D.; Lemaire, W.; White, R. B.; Yeh, S.; Urban, M. O.;
Kane, S. A.; Hartman, G. D.; Bilodeau, M. T.; Trotter, B. W. Bioorg. Med. Chem.
Lett. 2011, 21, 2359.
restricted CB2 agonists. Recently, Pfizer has reported on the opti-
mization of the same series of 5-sulfonyl benzimidazole CB2-
agonists, leading to selective and brain penetrant CB2-agonist.7c
A direct comparison of the peripherically restricted 41 or 49 with
a brain penetrant analogue from the same series in relevant animal
models could offer further insight into the need for brain penetra-
tion in order to be efficacious.
5. Verbist, B. M. P.; De Cleyn, M. A. J.; Surkyn, M.; Fraiponts, E.; Aerssens, J.; Nijsen,
M. J. M. A.; Gijsen, H. J. M. Bioorg. Med. Chem. Lett. 2008, 18, 2574.
6. Thakur, G. A.; Tichkule, R.; Bajaj, S.; Makriyannis, A. Expert Opin. Ther. Pat. 2009,
19, 1647.
7. (a) Pagé, D.; Brochu, M.-C.; Yang, H.; Brown, W.; St.-Onge, S.; Martin, E.; Salois,
D. Lett. Drug Des. Discov. 2006, 3, 298; (b) 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; (c) Watson, C.; Owen, D. R.; Harding, D.;
Kon-I, K.; Lewis, M. L.; Mason, H. J.; Matsumizu, M.; Mukaiyama, T.; Rodriguez-
Lens, M.; Shima, A.; Takeuchi, M.; Tran, I.; Young, T. Bioorg. Med. Chem. Lett.
2011, 21, 4284.
Acknowledgement
We thank Erwin Fraiponts for the generation of the in vitro data.
8. Jain, N.; Yalkowsky, S. H. J. Pharm. Sci. 2001, 90, 234.
9. All compounds tested in this Letter were shown to be full CB2 agonists in our
assays. For experimental procedures of the assays, see the Supplementary data
of ref.5
10. Itoh, T.; Mase, T. Org. Lett. 2004, 24, 4587.
11. Pertwee, R. G. Br. J. Pharmacol. 1972, 46, 753.
12. Meert, T. F.; Vermeirsch, H. Pharmacol. Biochem. Be. 2005, 80, 309.
13. Bennett, G. J.; Xie, Y. K. Pain 1988, 33, 87.
14. Dowdall, T.; Robinson, I.; Meert, T. F. Pharmacol. Biochem. Be. 2005, 80, 93.
15. For experimental details, see Buntinx, M.; Hermans, B.; Goossens, J.; Moechars,
D.; Gilissen, R. A. H. J.; Doyon, J.; Boeckx, S.; Coesemans, E.; Van Lommen, G.;
Van Wauwe, J. P. J. Pharmacol. Exp. Ther. 2008, 327, 1.
References and notes
1. (a) Howlett, A. C.; Barth, F.; Bonner, T. I.; Cabral, G.; Casellas, P.; Devane, W. A.;
Felder, C. C.; Herkenham, M.; Mackie, K.; Martin, B. R.; Mechoulam, R.; Pertwee,
R. G. Pharmacol. Rev. 2002, 54, 161; (b) De Marzo, V. Nat. Rev. Drug Disc. 2008, 7,
438.
2. (a) Guindon, J.; Hohmann, A. G. Br. J. Pharmacol. 2008, 153, 319; (b) Beltramo,
M. Mini Rev. Med. Chem. 2009, 9, 11.
3. Whiteside, G. T.; Lee, G. P.; Valenzo, K. J. Curr. Med. Chem. 2007, 14, 917.
4. (a) Trotter, B. W.; Nanda, K. K.; Burgey, C. S.; Potteiger, C. M.; Deng, J. Z.; Green,
A. I.; Hartnett, J. C.; Kett, N. R.; Wu, Z.; Henze, D. A.; Della Penna, K.; Desai, R.;
Leitl, M. D.; Lemaire, W.; White, R. B.; Yeh, S.; Urban, M. O.; Kane, S. A.;
Hartman, G. D.; Bilodeau, M. T. Bioorg. Med. Chem. Lett. 2011, 21, 2354;
16. Docagne, F.; Mestre, L.; Loría, F.; Hernangómez, M.; Correa, F.; Guaza, C. Expert
Opin. Ther. Tar. 2008, 12, 185.