The design, synthesis and biological evaluation of novel URB602 analogues as potential monoacylglycerol lipase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2011.09.038

We have synthesised an extensive series of URB602 analogues as inhibitors of monoacylglycerol lipase (MAGL), which is the major enzyme responsible for metabolising the endocannabinoid 2-arachidonylglycerol. The recently identified crystal structure of MAG

Full text of DOI:10.1016/j.bmcl.2011.09.038

Bioorganic & Medicinal Chemistry Letters 21 (2011) 6782–6787
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The design, synthesis and biological evaluation of novel URB602 analogues
as potential monoacylglycerol lipase inhibitors
⇑
Monika Szabo, Mark Agostino, Daniel T. Malone, Elizabeth Yuriev, Ben Capuano
Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria 3052, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
We have synthesised an extensive series of URB602 analogues as inhibitors of monoacylglycerol lipase
(MAGL), which is the major enzyme responsible for metabolising the endocannabinoid 2-arachidonyl-
glycerol. The recently identified crystal structure of MAGL was used in the design strategy and revealed
three possible binding sites for URB602 and the proposed analogues. A test series of carbamate analogues
were docked into the identified sites to predict the most favourable binding location. The synthesised
analogues of URB602 explored the biological effects of isosteric replacement, ring size and substitution,
para substitution of the biphenyl moiety and the incorporation of a bicyclic element. The compounds
were tested for their ability to inhibit human MAGL. The carbamate analogue 16 displayed the most sig-
Received 8 August 2011
Revised 9 September 2011
Accepted 12 September 2011
Available online 18 September 2011
Keywords:
Endocannabinoid system
2-Arachidonylglycerol
Monoacylglycerol lipase
URB602
nificant inhibitory activity, reducing MAGL activity to 26% of controls at 100
parent compound URB602.
lM compared to 73% for the
Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
Structure–activity relationship
The endocannabinoid system (ECS) is a newly discovered phys-
iological drug target composed of receptors, endogenous ligands,
enzymes and accessory proteins. The ECS consists of two main
receptors, namely the CB1 receptor, which is predominately ex-
pressed on nerve terminals and modulates the inhibition of neuro-
transmitter release, and the CB2 receptor, which is mainly
associated with the modulation of cytokine release and migration
of immune cells.1
The two main endogenous ligands of the ECS are 2-arachidonyl-
glycerol (2-AG, 1) and anandamide (AEA, 2) (Fig. 1), which act as
agonists at CB1 and CB2 receptors.2 Unlike AEA, 2-AG is a full ago-
nist at these receptors.3 Monoacylglycerol lipase (MAGL) is the pri-
mary enzyme involved in the hydrolysis of 2-AG in the brain,
whereas AEA is predominately hydrolysed by fatty acid amide
hydrolase (FAAH).4,5 Research into 2-AG signalling has revealed
its role in inflammation, nociception and immune reactions.1,6
Additionally, MAGL inhibitors have been found to increase 2-AG
levels in the brain and spinal cord and also cause weakened
mechanical and cold allodynia via CB1 receptors, confirming their
ability to reduce neuropathic pain.7,8 Therefore MAGL inhibitors
provide an opportunity to investigate the role of 2-AG in various
cascades and complex pathways.
fects.9 The catalytic triad of MAGL was identified by site-directed
mutagenesis and is found in the active site (Ser122, Asp239 and
His269).10 Potent inhibitors of MAGL, such as JZL18411
(IC50 = 8 nM; 3) and Ly218324012 (IC50 = 20 nM; 4) (Fig. 1), act
via this catalytic triad to form a covalent bond with the serine res-
idue. However, both these inhibitors lack selectivity.13,14 Another
inhibitor, SAR629, (5), (Fig. 1) has been co-crystallised with MAGL
and appeared outside of the active site suggesting an alternative
mechanism of action.15
The N-aryl carbamate URB60216 (15c, Fig. 1) was discovered to
be a selective inhibitor of MAGL17 since it increases levels of 2-AG
without altering levels of AEA in both in vitro and in vivo models.
URB602 acts via a non-competitive mechanism, in which the activ-
ity can only partially be reversed; hence URB602 is also termed a
partially reversible inhibitor.18,19 Additionally, URB602 does not af-
fect the levels of other lipid metabolising enzymes in the ECS.18
The selectivity of URB602 makes it a suitable scaffold for designing
MAGL inhibitors and an important pharmacological tool for under-
standing the effects of 2-AG.
In this Letter, we have explored a variety of structural modifica-
tions of URB602 with the aim of producing a more potent inhibitor.
These structural modifications included isosteric replacement, ring
size and substitution, para substitution of the biphenyl moiety and
the incorporation of a bicyclic element (Fig. 2).
Selective inhibition of MAGL results in an increase of 2-AG con-
centration at ECS receptors. Thus, MAGL inhibition avoids the need
for direct activation of CB1 receptors, which is advantageous since
it may result in less psychoactive (and other unwanted) side ef-
To aid in the design and synthesis of URB602 analogues, we
docked the target carbamates and literature compounds into the
crystal structure of MAGL15 using the molecular modelling package
Glide.20,21 A total of 26 ligands, including literature compounds and
multiple carbamate analogues were docked (Supplementary data).
⇑
Corresponding author. Tel.: +61 3 9903 9556; fax: +61 3 9903 9581.
E-mail address: ben.capuano@monash.edu (B. Capuano).
0960-894X/$ - see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.09.038

M. Szabo et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6782–6787
6783
OH
O
O
OH
OH
N
H
O
2
1
O
O
O
O
O
N
N
OH
O2N
N
N
N
N
O
3
4
O
F
F
H
N
O
N
O
5
N
15c (URB602)
O
N
N
N
Figure 1. Chemical structures of the endocannabinoid ligands 2-AG (1), AEA (2), the potent covalent inhibitors of MAGL JZL184 (3), Ly2183240 (4), SAR629 (5) and the
selective non-covalent inhibitor URB602 (15c).
Isosteric Replacement
- Substitution
p
- O for N, O for S
- OH, Cl
Ring Size
H
- cyclobutyl to cyclooctyl
Ring Substitution
- (+)- & (-)-menthol
Bicyclics
N
O
O
-
norbornanyl
Isosteric Replacement
- O for N, O for S
Figure 2. Structural modifications to URB602.
Several of the carbamate compounds docked were synthesised, as
depicted in Scheme 1, whilst all other functional classes (urea,
thiourea, thiocarbamate and guanidine) were chosen for synthesis
for comparative purposes. The docking was performed to deter-
mine (i) how and where the compounds may be binding to MAGL
and (ii) which compounds may be better inhibitors.
results indicated that the most suitable binding site for URB602
carbamate analogues was the upper active site cavity (via a non-
covalent mechanism). The results showed that the p-OH substi-
tuted carbamate 16 produced the best Glide GScore value. A Glide
GScore of À6.643 was obtained for URB602, compared with À7.425
obtained for 16.
Prior to docking, SiteMap22,23 was used to identify possible sites/
cavities for docking. The top scoring site was a region in between the
two monomers, termed the ‘dimer site’ (Fig. 3a). The second and
third top scoring sites were the active site and the cavity in close
proximity to the active site (termed ‘upper active site’) on each of
the separate monomers (Fig. 3b). The residues Cys201 and Cys208,
found in the upper active site, have been identified as important
for MAGL function.15 King et al. also recognised this hydrophobic
pocket as a potential site for reversible inhibition of MAGL.24 The site
equivalent to the dimer site could not be identified by SiteMap when
using a single monomer. This suggested that the site may only be
operational when the enzyme is in its dimer form. Docking to this
site revealed that only six ligands were able to be accommodated
by this cavity, suggesting that ‘breathing’ between the two mono-
mers may be necessary for binding to occur at this site.
In the crystal structure of MAGL in complex with URB602, a
hydrogen bond exists between the amide hydrogen of Asn162 and
the oxygen atom adjacent to the carbonyl group of URB602. The
hydrogen bond with Asn162 was able to be replicated by the major-
ity of ligands in the compound library, as indicated by molecular
docking. The molecular docking experiments also suggested that
the ligands were likely to form hydrogen bonds with Ser165. We ex-
pected that the interactions between the ligands in the compound
library and the enzyme would predominantly be hydrophobic, since
the ligands are moderately lipophilic and the upper active site cavity
sits near the hydrophobic lid of MAGL. Residues Ala174, Gly220 and
Leu186 were consistently contacted by the majority of compounds
and are therefore likely to be the key residues involved in the non-
covalent binding of compounds to this site.
Docking to the upper active site suggested that 5- to 7-mem-
bered rings were the most preferable (Supplementary data). There-
fore, we decided to limit our synthetic efforts to only these ring
Covalent and non-covalent docking strategies were explored, to
each of the active site, upper active site and dimer site regions. Our

6784
M. Szabo et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6782–6787
HO
OH
Br
B
R
R
i)
+
NH2
10 (R = H)
NH2
11 (R = OH)
12
(R = Cl)
9
6
(R = H)
7 (R = OH)
8 (R = Cl)
ii) 10
13a-h
iii) 11-12
13c
iv) 10
14a-c
13a:
cyclobutanol
R
13b: cyclopentanol
13c: cyclohexanol
cycloheptanol
13d:
13e: cyclooctanol
13f: (-)-menthol
13g
: (+)-menthol
NH
NH
NH
13h: exo-norborneol
14a: cyclopentylamine
NH
O
O
R1
O
14b
: cyclohexylamine
R1
O
O
14c: cycloheptylamine
R1
15a-h
18a-c
R1 = cycloalkyl
16 (R = OH)
17
(R = Cl)
Scheme 1. Synthesis of carbamate and urea analogues of URB602. Reagents and conditions: (i) Pd(OAc)2 or Pd(PPh3)4, Na2CO3, methanol, reflux; (ii) CDI, DMAP, reflux 14 h
followed by cycloalkanol (13a–h), CH3CN, reflux, 24 h; (iii) CDI, DMAP, reflux, 14 h followed by cyclohexanol (13c), CH3CN, reflux, 24 h; (iv) CDI, TEA, reflux, 2 h, followed by
cycloalkylamine (14a–c), CH3CN, reflux, 4 h.
Figure 3. (a) Ribbon representation of MAGL. Dimer site indicated by Sitemap as the region between the two monomers (coloured red, blue and green). (b) Monomer B of
MAGL, with the upper active site indicated in yellow, with SAR629 non-covalently bound and the active site indicated in red, with SAR629 covalently bound to the enzyme.
sizes in making the urea, guanidine, thiocarbamate and thiourea
analogues of URB602. In addition to compound 16, we also decided
to synthesise the p-Cl substituted carbamate 17 for comparison of
the docking results with pharmacological data, as both compounds
docked in a very similar conformation and orientation (Fig. 1, Sup-
plementary data). However, 17 gave a lower Glide GScore (À6.563)
when compared with URB602 and 16.
ceeded as shown in Scheme 2 and used thiocarbonyldiimidazole
(TCDI) to generate the thioisocyanate intermediate 19. The forma-
tion of this intermediate was supported by 13C NMR spectroscopy,
with the presence of a carbon resonance at d 135.7 ppm corre-
sponding to the isothiocyanate functional group. Methanolic
ammonia was then added to furnish the thiourea product 20. For-
mation of the sulfonic acid derivative 21 was achieved by an oxida-
We envisaged the use of the Suzuki coupling reaction as integral
to the synthesis of the target compounds via the key biphenyl-
amine intermediates (10–12), involving phenylboronic acids 6–8,
3-bromoaniline 9 and a suitable palladium catalyst (Scheme 1).
These intermediates were isolated in good yield (50–76%). Com-
pounds 10–12 were reacted with carbonyldiimidazole (CDI) under
basic conditions to generate an activated carbamoyl imidazole
intermediate, upon which treatment with the designated cycloalk-
anol (13a–h) afforded the target carbamates (15a–h, 16, 17). The
urea analogues (18a–c) were synthesised by reacting 10 with CDI
and TEA followed by the addition of the appropriate cycloalkyl-
amine (14a–c). The synthesis of the guanidinum analogues pro-
tion reaction with hydrogen peroxide in the presence of a
molybdenum salt catalyst. The product was confirmed by LC–MS
exhibiting a peak at m/z = 277 and then reacted, without further
purification, to generate the guanidine analogues. These com-
pounds were converted to their corresponding salts to yield the
target guanidinium analogues 22a–c. The synthesis of the target
thiocarbamates proceeded as described in Scheme 3, in which
the initial step involved the isolation of the key isothiocyanate
19. The desired cycloalkanols (13b–d) were added to give the cor-
responding thiocarbamates 23a–c. Similarly, the thiourea ana-
logues (24a–c) were furnished via the reaction of 19 with the
appropriate cycloalkylamine (14a–c) in good yields (Scheme 3).

M. Szabo et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6782–6787
6785
H
N
ii)
NH2
i)
N
NH2
C
S
S
20
10
19
iii)
H
N
H
N
Cl
iv)
14a-c
N
SO3H
NH2
R1
N
H
H
22a-c
21
Scheme 2. Synthesis of guanidinium analogues of URB602. Reagents and conditions: (i) TCDI, DMAP, rt, 1 h, CH2Cl2; (ii) methanolic ammonia (iii) H2O2 (30% v/v), NaCl,
Na2MoO4Á2H2O, 0 °C ? rt, H2O; (iv) (a) cycloalkylamine (14a–c), rt, 24 h, CH3CN; (b) 1 M HCl.
ii) 13b-d
H
N
O
23a-c
R
NH2
N
S
S
i)
C
S
14a-c
iii)
10
19
H
N
H
N
24a-c
R
Scheme 3. Synthesis of thiocarbamate and thiourea analogues. Reagents and conditions: (i) TCDI, DMAP, rt, 1 h, DCM; (ii) cycloalkanol (13b–d), DMAP, 120 °C, 24 h, DMF; (iii)
cycloalkylamine (14a–c), DMAP, rt, 2 h, CH3CN.
Compounds were tested for their ability to inhibit human re-
combinant MAGL in serial dilutions (1:10) from 100 M to 1 nM
(six concentrations in triplicate) using methanol as the solvent.
inhibitory effect, as was the case with ring substituted analogues
(15f), suggesting that bulkier groups may impede activity due to
steric hindrance. The introduction of a bicyclic moiety (15h) also
seemed to offer no beneficial effects towards decreasing MAGL
activity.
l
We have quoted the % MAGL activity (Table 1) at three concentra-
tions (1
lM , 10
lM and 100
lM). The activity data for a handful of
compounds at the highest concentration of 100
l
M were not deter-
From the library of compounds synthesised representing the
disparate functional classes, the most effective inhibitor of MAGL
was clearly the p-OH substituted carbamate 16 significantly reduc-
ing MAGL activity to 83%, 46% and 26% of control values at 1, 10
mined due to the emergence of solubility issues. A similar method
was employed by Muccioli et al.25 to describe the activity of
URB602 and other carbamate inhibitors of MAGL. Importantly,
the results for URB602 (e.g., 71 4% MAGL activity at 10
comparable to that reported previously (Muccioli et al.25 84%
MAGL activity 10
M). As documented in the literature,19 it is also
significant to note that complete inhibition of MAGL was not ob-
served; a feature possibly resulting from the target compounds
sharing the scaffold of URB602, a partially reversible inhibitor.
Not all synthesised compounds are shown in Table 1 due to
un-obtainable or inconclusive results.
To evaluate the biological effects of the isosteric replacements,
we compared the profiles of all the analogues containing the de-
scribed functional groups and a cyclohexyl side chain with that
of URB602. The guanidine analogue (22b) produced little to no
inhibition. Furthermore this result suggests that MAGL does not
accommodate a positively charged species at its binding site. Fu-
ture analogues should presumably be designed to remain neutral
at physiological pH to retain activity. The thiocarbamate (23b)
and thiourea (24b) functional groups showed minimal inhibition
l
M) were
and 100
compared to the parent compound URB602 (93%, 71% and 73% of
control values at 1, 10 and 100 M, respectively). The cycloheptyl
urea analogue 18c, although not noteworthy at 1 and 10 M, pro-
duced a signficant reduction of MAGL activity to 55% of controls at
100 M. The p-Cl substituted carbamate 17 reduced MAGL activity
to 85% and 81% of control values at 1 and 10 M, respectively,
which was consistent with molecular modelling predictions.
Figure illustrates the pronounced inhibitory activity of
lM, respectively. These values were notably enhanced
l
l
l
l
l
4
compounds 16 and 18c against MAGL compared to the parent
compound, URB602 (15c) across all concentrations.
Figure 5 gives a detailed view of the docked carbamate 16 inter-
acting with key residues in the upper active site. Significantly, the
modelling suggests that it makes a hydrogen bond between its
p-hydroxyl group and Ser185. This compound was the only ligand
to make this interaction, as neither URB602 nor SAR629 interacts
with Ser185, which could explain its enhanced pharmacological
activity. The design of ‘next generation’ ligands as MAGL inhibitors
may possibly include the use of this hydrogen bond interaction as a
starting point.
at 1 and 10 lM (Table 1). The urea analogue (18b; previously syn-
thesised by King et al.19) showed a comparable % inhibition of
MAGL activity to URB602.
There was no clear relationship evident between ring sizes 5–7
and pharmacological activity. However, ring sizes greater than se-
ven, such as compound 15e (R1 = cyclooctyl), had a much weaker
In summary, molecular modelling identified the upper active
site as the most favourable binding site for carbamate analogues.
Due to the close proximity of the active site and upper active site

6786
M. Szabo et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6782–6787
Table 1
Selected synthesised compounds and their inhibitory effects against human recombinant MAGL
MAGL activity (% of control SEM)
R
H
1
l
M
10
l
M
100
85
lM
N
Z
R1
X
CH
15a
X = O, Z = O, R = H
97
4
86
4
2
15b
18a
X = O, Z = O, R = H
X = O, Z = NH, R = H
93
80
5
5
71
73
9
4
n.d.a
n.d.
CH
CH
15c (URB602)
16
X = O, Z = O, R = H
X = O, Z = O, R = OH
93
83
6
1
71
46
4
2
73
26
1
2
17
X = O, Z = O, R = Cl
X = O, Z = NH, R = H
X = S, Z = O, R = H
X = S, Z = NH, R = H
85
98
73
93
2
6
6
2
81
79
83
76
1
3
3
3
81
78
n.d.
n.d.
4
8
18b
23b
24b
15d
18c
23c
X = O, Z = O, R = H
X = O, Z = NH, R = H
X = S, Z = O, R = H
94
96
79
2
1
4
71
80
83
6
4
5
n.d.
55
n.d.
5
CH
CH
15e
X = O, Z = O, R = H
101
1
2
92
2
n.d.
(-) -
15f
X = O, Z = O, R = H
X = O, Z = O, R = H
106
95
101
79
3
n.d.
n.d.
CH
15h
3
4
CH
a
Not determined; due to solubility issues at the nominated concentration.
Figure 4. MAGL inhibition by URB602 (s, carbamate), analogue 18c (., urea) and
analogue 16 (j, carbamate) expressing the% of enzyme activity relative to controls
at the highest ligand concentration of 100 lM.
regions, prospective work may extend towards the possibility of
developing bitopic ligands as potential inhibitors of MAGL.26 SAR
studies of URB602 analogues found the carbamate 16 to be the
most promising MAGL inhibitor reducing activity to 46% and 26%
Figure 5. Intermolecular interactions of the p-OH substituted ligand 16 docked
non-covalently into the upper active site cavity, showing key hydrogen bond
(yellow) and hydrophobic interactions with highlighted residues.
of controls at a concentration of 10 and 100 lM, respectively.
Molecular modelling proposed that this may be due to the unique
hydrogen bond with Ser185 resulting from the introduction of the
p-OH group. Additionally, the urea analogue (18c) also proved to
be a moderate inhibitor of MAGL thereby supporting carbamate
and urea functionalities as promising scaffolds for the design of im-
proved MAGL inhibitors.
Acknowledgments
M.S. and M.A. are recipients of the Australian Postgraduate
Award (APA). M.A. is a recipient of the Monash University Post-
graduate Publication Award (PPA). Thank you to Dr. Jason Dang
for helping obtain NMR spectral data and HPLC chromatograms.

M. Szabo et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6782–6787
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Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.09.038.
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