Loratadine analogues as MAGL inhibitors Dedicated to Dr. Sameer Agarwal, principal scientist at Zydus Research Centre (ZRC, India)

Article abstract of DOI:10.1016/j.bmcl.2015.02.037

Compound 12a (JZP-361) acted as a potent and reversible inhibitor of human recombinant MAGL (hMAGL, IC₅₀ = 46 nM), and was found to have almost 150-fold higher selectivity over human recombinant fatty acid amide hydrolase (hFAAH, IC₅₀ = 7.24 μM) and 35-fold higher selectivity over human α/β-hydrolase-6 (hABHD6, IC₅₀ = 1.79 μM). Additionally, compound 12a retained H₁ antagonistic affinity (pA₂ = 6.81) but did not show cannabinoid receptor activity, when tested at concentrations ≤10 μM. Hence, compound 12a represents a novel dual-acting pharmacological tool possessing both MAGL-inhibitory and antihistaminergic activities.

Full text of DOI:10.1016/j.bmcl.2015.02.037

Bioorganic & Medicinal Chemistry Letters 25 (2015) 1436–1442
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Loratadine analogues as MAGL inhibitors
a
b
c
a
Jayendra Z. Patel a, , Stephen Ahenkorah , Miia Vaara , Marek Staszewski , Yahaya Adams ,
⇑
a
b
a
b
c
´
Tuomo Laitinen , Dina Navia-Paldanius , Teija Parkkari , Juha R. Savinainen , Krzysztof Walczynski ,
Jarmo T. Laitinen b, Tapio J. Nevalainen a
a School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland
b School of Medicine, Institute of Biomedicine/Physiology, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland
c Department of Synthesis and Technology of Drugs, Faculty of Pharmacy, Medical University of Lodz, 90-151 Lodz, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Compound 12a (JZP-361) acted as a potent and reversible inhibitor of human recombinant MAGL
Received 13 January 2015
Revised 10 February 2015
Accepted 16 February 2015
Available online 24 February 2015
(hMAGL, IC50 = 46 nM), and was found to have almost 150-fold higher selectivity over human recombi-
nant fatty acid amide hydrolase (hFAAH, IC50 = 7.24
b-hydrolase-6 (hABHD6, IC50 = 1.79 M). Additionally, compound 12a retained H1 antagonistic affinity
(pA2 = 6.81) but did not show cannabinoid receptor activity, when tested at concentrations 610 M.
lM) and 35-fold higher selectivity over human a/
l
l
Hence, compound 12a represents a novel dual-acting pharmacological tool possessing both MAGL-
inhibitory and antihistaminergic activities.
Dedicated to Dr. Sameer Agarwal, principal
scientist at Zydus Research Centre (ZRC,
India)
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Monoacylglycerol lipase
2-Arachidonoyl glycerol
Fatty acid amide hydrolase
a/b hydrolase-6
Loratadine
Monoacylglycerol lipase (MAGL) is a 33-kDa membrane-associ-
residue have been reported.13–18 Additionally, three cysteine resi-
dues (Cys201, Cys208, and Cys242) located close to the catalytic site
of MAGL have been postulated to be targeted by some inhibi-
tors19–23 (see review articles24–27). The majority of the current
MAGL inhibitors, act in an irreversible manner and only a few have
been reported to have a reversible mode of action,21,28,29 although
reversibly-acting MAGL inhibitors have been claimed to be safer
alternatives than their irreversible counterparts.29,30
In 2008, Sanofi-Aventis published a patent of constrained piper-
azine bearing triazolopyridine ureas as MAGL inhibitors (e.g., 1,
Fig. 1).31 Subsequently, several research groups including our
own, have described the synthesis of piperidine/piperazine based
carbamates/ureas, such as SAR629 (2),14,32 JZL184 (3),15 ML30
(4),33 KML29 (5),17 CK16 (6),16 MJN110 (7),18 JJKK-048 (8a)32 and
compound 8b34 and characterized these molecules as potent and
selective MAGL inhibitors (Fig. 1). When assessing the structure–
activity-relationships (SARs) of these compounds, it is evident that
the two bulky hydrophobic aromatic rings, a piperidine/piperazine
linker, and a good leaving group are required in order to achieve
both high potency and selectivity toward MAGL over other possible
off-targets such as fatty acid amide hydrolase (FAAH) and/or
ABHD6.15–17,24–27
ated enzyme that belongs to the serine hydrolase superfamily. In
the central nervous system (CNS), MAGL is the principal enzyme
responsible for the in vivo degradation of 2-arachidonoyl glycerol
(2-AG), an endogenous ligand of the cannabinoid receptors.1–3 In
addition to MAGL, two additional serine hydrolases,
a/b-hydrolase
domain-containing 6 (ABHD6) and /b-hydrolase domain-contain-
a
ing 12 (ABHD12) participate in the degradation of 2-AG in the CNS.4,5
Several studies support the hypothesis that inhibition of MAGL
may represent a useful and novel approach for the treatment of
pain, inflammation, vomiting, and nausea.6–9 Additionally, MAGL
has been reported to be involved in the regulation of the fatty acid
network that promotes cancer pathogenesis.10 Hence, inhibition of
MAGL may well be a promising target in drug development pro-
grams to treat different diseases.11 The active site of MAGL con-
tains a classical catalytic triad (Ser122-Asp239-His269) and a lipase
motif GxSxG both of which are typical for serine hydrolases.12 At
present, various MAGL inhibitors targeting the nucleophilic Ser122
⇑
Corresponding author. Tel.: +358 40 355 3887.
E-mail address: jayendra.patel@uef.fi (J.Z. Patel).
http://dx.doi.org/10.1016/j.bmcl.2015.02.037
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.

J. Z. Patel et al. / Bioorg. Med. Chem. Lett. 25 (2015) 1436–1442
1437
Figure 1. Representative structures of known MAGL inhibitors (1–7, 8a and 8b) and marketed drug loratadine (9).
Loratadine (9, see Fig. 1), a histamine H1 receptor antagonist, is
a marketed drug which has been used clinically to treat allergies.
The structural features of this drug include two constrained aro-
matic rings, a piperidine moiety, and a carbamate functional group,
features which are rather similar to those present in the previously
reported active MAGL inhibitors. Since the carbamate functionality
present in loratadine is not susceptible to MAGL attack, we decided
to replace it with a more electrophilic carbamate/urea moiety.
Therefore, we synthesized a small series of loratadine analogues
and screened their activity against the human recombinant
MAGL and FAAH (hMAGL and hFAAH, respectively). Selected
compounds were tested further against other possible
endocannabinoid targets and H1 receptor antagonistic activity,
and the obtained data were then used to explore the preliminary
SAR. We also elucidated the mode of inhibition of the best com-
pound in this series toward MAGL. Finally, a molecular modeling
approach was employed to explore the binding interaction of the
best compound with MAGL as well as with the histamine H1
receptor.
A straightforward synthesis of loratadine analogues (12a–12l)
was performed as per procedures described in the literature with
some minor modifications (Scheme 1, see Supplementary informa-
tion). Commercially available loratadine (9) was converted into
desloratadine (10) with aqueous alkali.35 The urea analogues
(12a, 12b and 12d) were made by coupling of desloratadine with
1,10-carbonyl-di-(1,2,4-triazole) (CDT), 1,10-carbonylbis-benzo-
triazole, and, 1,10-carbonyldiimidazole (CDI), respectively.32 In
the synthesis of the urea analogue 12c, desloratadine was convert-
ed to the corresponding carbamoyl chloride via treatment with
triphosgene and then it was coupled with 1H-1,2,3-triazolo
[4,5-b]pyridine.32 The carbamate analogue 12e was synthesized
by coupling of desloratadine with hexafluoroisopropanoyl chlo-
ride, produced in situ by the treatment of hexafluoroisopropanol
with triphosgene.17 The carbamate analogues 12f–12h were made
by coupling of desloratadine with N,N0-disuccinimidyl carbonate
(DSC), 4-nitrophenyl chloroformate, and 2,4-dinitrophenyl chloro-
formate, respectively.15,18 The latter intermediate was prepared via
reaction of 2,4-dinitrophenol with triphosgene. The dithiocarba-
mate derivative 12i was obtained by reaction of dithiocarbamic
acid salt; prepared in situ by reaction of desloratadine with CS2
in the presence of triethylamine, with 2,4-dinitrofluorobenzene.16
The urea analogue 12j was prepared by reaction of desloratadine
with cyclohexyl isocyanate. The urea analogues 12k and 12l were
prepared by coupling of desloratadine with N-cyclohexyl-N-
methylcarbamoyl chloride and N-methyl-N-phenylcarbamoyl
chloride, respectively. The former intermediate was prepared via
the reaction of N-cyclohexyl-N-methylamine with triphosgene.
At first, the inhibitory activities of the synthesized compounds
were tested at
a 10 lM concentration against hFAAH and
hMAGL using previously validated methodologies36,37 (see
Supplementary information) and the results are summarized in
Table 1. In this study, loratadine (9) was found to be inactive
towards both MAGL and FAAH when tested at 10 lM concentra-
tion. As the 1,2,4-triazole-based urea analogue JJKK-048 (8a) was
recently found as the best MAGL inhibitor in terms of both potency
and selectivity,32 we replaced the ethoxy group present in lorata-
dine with the 1,2,4-triazole group (compound 12a).
Consequently, compound 12a displayed excellent inhibitory activ-
ity against MAGL in the low nanomolar range (IC50 = 46 nM) and
importantly, it was found to possess ꢀ150-fold higher selectivity
for MAGL than towards hFAAH (IC50 = 7.24 lM).
Next, we tested loratadine analogues having various N-substitu-
tions on the piperidine ring (compounds 12b–12l, Table 1).
Benzotriazole and triazolopyridine containing urea analogues
(compounds 12b and 12c) were also found to be good MAGL inhi-
bitors, albeit being less potent (2–4 fold) than compound 12a.
Surprisingly, the imidazole urea analogue 12d was found to be
inactive towards both MAGL and FAAH. Among the carbamate
analogues, hexafluoroisopropyl (HFIP) and succinimide analogues
(12e and 12f) exhibited weak MAGL inhibition while the

1438
J. Z. Patel et al. / Bioorg. Med. Chem. Lett. 25 (2015) 1436–1442
Scheme 1. Synthesis of loratadine analogues 12a–12l. Reagents and conditions: (a) aq KOH, EtOH, reflux, 16–18 h; (b) DIPEA, RCOR (R = 11a, 11b, 11d, 11f, respectively),
DCM, 22–25 °C, 24–26 h; (c) (i) pyridine, DCM, triphosgene, 0–25 °C, 2–3 h, (ii) carbamoyl chloride from (i) followed by RH (R = 11c), DIPEA, DMAP, DCM, 0–25 °C, 24–26 h;
(d) DIPEA or pyridine, RCOCl (R = 11e, 11g, 11h, 11i, 11j, respectively), DCM, 0–25 °C, 16–24 h; (e) (i) CS2, Et3N, 22–25 °C, 16 h; (ii) R-F (R = 2,4-dinitrophenyl), DMF, 22–25 °C,
24 h; (f) RNCO (R = cyclohexyl), THF, reflux, 4 h.
para-nitrophenyl analogue (12g) was found to be inactive. In order
to cross-check the behaviour of compound 12g, we synthesized the
2,4-dinitrophenyl analogue of compound 12g (compound 12h) as
well as the corresponding dithiocarbamate analogue of compound
12h (compound 12i). However, these analogues also did not dis-
play any significant MAGL inhibitory activities. This could be
because these compounds do not fit well into the MAGL binding
pocket because of their bulky phenyl leaving group. As expected,
analogues with less electrophilic/poor leaving groups (12j–12l)
were found to be inactive towards MAGL. None of the compounds
12b–12l showed any significant inhibition of FAAH. Overall, these
results are consistent with our earlier findings demonstrating that
high potency of MAGL inhibitors can be achieved if they have leav-
ing-groups with a conjugate acid pKa of 8–10.32,34
Then, we decided to study the effect of the 1,2,4-triazole leaving
group on another marketed H1-antihistamine known as cyprohep-
tadine (13) which is also used to treat allergic reactions.
Cyproheptadine (13) was converted into an ethyl ester analogue
(14) via ethylchloroformate and subsequently treated with alkali
to produce the amine (15) (Scheme 2, see Supplementary informa-
tion). Finally, coupling of amine 15 with 1,10-carbonyl-di-(1,2,4-
triazole) (CDT) in DMSO produced the triazole urea analogue 16.
Compound 16 was found to be equally potent as compound 12a
as a MAGL inhibitor and had comparable selectivity over FAAH
(see Table 1).
cannabinoid CB1 and CB2 receptor-mediated G protein activity
using the [35S]GTP
S binding assay, tested with previously validated
methods.39,40 In this assay, compound 12a showed no agonist or
antagonist activity when tested at 10 M concentration (Table 3).
c
l
Since the above described analogues are derived from marketed
H1 antagonists, we tested the H1 antagonist properties of com-
pounds 12a and 16 in the guinea pig ileum tissue preparation
according to the method described by Arunlakshana et al.41 (see
Supplementary information). We found that both of these ana-
logues retained H1 antagonistic properties (Table 4) indicating that
they behave as dual blockers of MAGL activity and H1 receptors.
The reversibility of MAGL inhibition by compound 12a was test-
ed by using a dilution-method where the enzyme is first pretreated
for 60 min with the inhibitor, followed by substrate addition and
40-fold dilution, essentially as previously described.32 In these
experiments, we found that within the time-frame studied, binding
of 12a (JZP-361) appeared to be slowly reversible, as the potency
of this compound to inhibit MAGL was slightly but significantly
lower after 90 min incubation in comparison to the early time
point (10 min) (Fig. 2). A slowly reversible mode of inhibition has
been previously described also for other serine hydrolases such
as acetylcholinesterase42 and acylprotein thioesterase.43 The refer-
ence compounds, MAFP (methylarachidonyl fluorophosphonate, an
established irreversible inhibitor) and ATM-114 (5-ethoxy-3-(3-
phenoxyphenyl)-1,3,4-oxadiazol-2(3H)-one, a reversible inhibitor),
behaved in this assay as previously reported44 with the exception
that we observed no statistically significant reduction in the
potency of ATM-114 with a prolonged incubation time. Instead,
the inhibitor efficacy, that is, maximal inhibition achieved at
ATM-114 concentrations between 10ꢁ7 and 10ꢁ4 M, showed a
time-dependent decline that was statistically significant at each
time-point examined (Fig. 2), evidence for a rapid mode of
reversible inhibition.
We further screened compounds 12a and 16 at 10 lM against
supplementary 2-AG hydrolases—hABHD6 and hABHD12 using
the previously validated methodology38 (see Supplementary infor-
mation). Both compounds, 12a and 16 were found to inhibit
hABHD6 in the low micromolar range (IC50 1.78 lM and 0.75 lM,
respectively), however, no inhibition of hABHD12 was observed
(Table 2). In short, compound 12a shows 35-fold selectivity over
hABHD6 while towards its main off-target FAAH, as described
above, it has around 150-fold selectivity.
To rule out cross-activity with the other proteins of the endo-
cannabinoid system, compound 12a (JZP-361), which appeared to
be the best MAGL inhibitor in this series in terms of both potency
and selectivity, was evaluated for its ability to stimulate
Molecular modeling studies were employed in order to gain
molecular level insights into the binding of compound 12a with
human MAGL and human histamine H1 receptor, (see
Supplementary information). These studies suggested that
compound 12a (JZP-361) fitted well into the MAGL active site

J. Z. Patel et al. / Bioorg. Med. Chem. Lett. 25 (2015) 1436–1442
1439
Table 1
Inhibitory activities of analogues 12a–12l and 16 against MAGL and FAAH
Compound
R
pI50 (range) [IC50, l l
M]a or % inhibition at 10 Mb
hMAGL (
l
M)
hFAAH (lM)
9
—
NIc
11%
12a (JZP-361)
7.34 (7.21–7.47) [0.046]
6.68 (6.66–6.69) [0.208]
7.01 (7.01–7.02) [0.098]
5.14 (5.12–5.16) [7.24]
12b
12c
22%
30%
12d
12e
NI
7%
6.19 (6.11–6.26) [0.645]
15%
12f
5.59 (5.58–5.59) [2.57]
12%
12g
12h
12i
27%
NI
6%
14%
12%
14%
12j
12k
12l
NI
NI
NI
9%
NI
11%
16
—
—
—
7.33 (7.32–7.34) [0.047]
9.44 0.05 [0.00036]e
9.16 (9.02–9.30) [0.0007]
5.16 (5.14–5.19) [6.91]
5.32 0.05 [4.8]e
5.79 (5.69–5.88) [1.62]
8a (JJKK-048)d
8bf
a
pI50 values (ꢁlog10 [IC50]) represent the mean (range) from two independent experiments performed in duplicate. IC50 values were calculated for those compounds
having P50% inhibition at 10 M and were derived from the mean pI50 values as shown in brackets.
The percentage (%) of inhibition is calculated as the mean from two independent experiments performed in duplicate.
l
b
c
d
e
f
NI indicates no inhibition at 10 lM.
JJKK-048: ({4-[bis-(benzo[d][1,3]dioxol-5-yl)methyl]-piperidin-1-yl}(1H-1,2,4-triazol-1-yl)methanone) used as MAGL reference standard (See Ref. 32).
pI50 values (ꢁlog10 [IC50]) represent the mean SEM from three independent experiments performed in duplicate.
See Ref. 34.

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J. Z. Patel et al. / Bioorg. Med. Chem. Lett. 25 (2015) 1436–1442
Scheme 2. Synthesis of 1,2,4-triazole urea derivative of cyproheptadine 16. Reagents and conditions: (a) toluene, ClCOOEt, reflux, 3 h; (b) aq KOH, EtOH, reflux, 16–18 h;
(c) DIPEA, RCOR (R = 11a), DMSO, 22–25 °C, 24 h.
Table 2
Table 4
Inhibitory activities of analogues 12a and 16 against ABHD6 and ABHD12
Histamine H1 antagonistic affinity of analogues 12a and 16 as tested on the in vitro
test system on the guinea pig jejunum
Compound
pI50 (range) [IC50,
hABHD6
l
M]a or % inhibition at 10
hABHD12
l
Mb
Compound
pA2 (SEM)a
Nb (caviae)c
NIc
NI
12a (JZP-361)
16
Loratadine (9)
Pyrilamine
6.81 (0.021)
6.50 (0.189)
7.14 (0.042)
8.84 (0.031)
2(2)
3(2)
3(2)
3(2)
12a (JZP-361)
5.75 (5.66–5.84) [1.78]
6.12 (5.98–6.27) [0.75]
7.32 0.06 [0.048]e
16
THLd
6.72 0.07 [0.19]e
a–c,e
See footnotes for Table 1.
a
b
c
d
SEM—standard error of the mean.
N—number of different animal preparations.
caviae—number of animals.
THL, tetrahydrolipstatin (orlistat, See Ref. 38).
comprising the catalytic triad Ser122-His169-Asp239 and the oxyan-
ion hole Met123-Ala51 (Fig. 3), which is in good agreement with ear-
lier findings with other MAGL inhibitors.14,45–47 Compound 12a, a
slow reversible inhibitor of MAGL, was found to bind in a similar
orientation as several other 1,2,4-triazole bearing irreversible
MAGL inhibitors such as SAR629 (2) and JJKK-048 (8a) (image
not shown). Thus the molecular modeling was able to explain, at
least partly, how the Y-shaped ligands possess good shape comple-
mentarity with the MAGL active site. In the case of the histamine
H1 receptor, compound 12a has a similar shape as doxepin, a ligand
which has been complexed with the resolved H1 receptor crystal
structure.48 Accordingly, our modeling studies indicated that com-
pound 12a docked in a similar orientation as doxepin, forming
favourable interactions with the aromatic side chain residues
Trp1584.56, Phe4326.52, Phe4356.55 and Trp4286.48 (Fig. 3). It is note-
worthy that although the activity data were obtained using guinea
pig preparation whereas the modeling study was based on human
H1 receptor structure, the two H1 receptor orthologues share high
sequence homology in their transmembrane domains and identical
amino acid residues are present in the ligand binding cavity (data
not shown).
selectivity over FAAH and ꢀ35-fold higher selectivity over
ABHD6. In the [35S] GTP
S binding assay, compound 12a exhibited
c
no activity at the cannabinoid CB1 and CB2 receptors. Reversibility
studies indicated that the binding mode of JZP-361 was slowly
reversible. In addition, in our molecular modeling study, com-
pound 12a displayed favourable interactions within the active site
of hMAGL including the important hydrogen-bonding of the car-
bonyl oxygen to the oxyanion hole. Moreover, compound 12a also
underwent favourable interactions with aromatic side chain resi-
dues Trp1584.56, Phe4326.52, Phe4356.55 and Trp4286.48 of the
human histamine H1 receptor.
As compounds 12a and 16 fully retained H1 antagonistic activ-
ity, these compounds represent novel dual-acting pharmacological
tools that could be tested in inflammation models where simulta-
neous blockade of MAGL and H1-receptors would be desirable.
Although speculative at this point, one could envision conditions
where MAGL-dependent 2-AG hydrolysis liberates arachidonic
acid, the substrate for COX-2-catalyzed production of the proin-
flammatory compound, prostaglandin E2. This lipid mediator
could, in turn, evoke inflammation through mast cell activation
and subsequent histamine release, thereby increasing both vascu-
lar permeability and edema formation. Recent research suggests
that such a scenario is possible.49 Our results also point to the pos-
sibility that some of the previously described MAGL inhibitors
might also exert H1-antihistamine activity.
In summary, our preliminary attempt to modify the carbamate
functionality of loratadine resulted in the production of potent
MAGL inhibitors. Several urea/carbamate analogues were exam-
ined and compound 12a (JZP-361) was identified as a potent
hMAGL inhibitor (IC50 = 46 nM) having ꢀ150-fold higher
Table 3
Activity of compound 12a (JZP-361) at CB1 and CB2 receptors
Compound
Agonist activity
CB1R antagonist activitya
CB1Ra
35S]GTP
CB2Rb
[
c
S binding % basal (mean (range), n = 2)
[ cS binding % HU210-evoked response
35S]GTP
(mean (range), n = 2)
12a (JZP-361)
90 (87–92)
101 (96–107)
80 (80–80)
HU210 (1
HU210 (10 nM)
AM251 (1 M)
SR144528 (1 M)
l
M)
304 (297–311)
—
—
—
—
—
—
172 (169–174)
—
53 (51–57)
l
35 (33–39)
—
l
a
Rat cerebellar membranes.
hCB2R-CHO cell membranes.
b

J. Z. Patel et al. / Bioorg. Med. Chem. Lett. 25 (2015) 1436–1442
1441
Figure 2. Inhibition of MAGL by JZP-361 (12a) indicates a slowly reversible mode of inhibition. Unlike the established irreversible MAGL inhibitor MAFP, a rapid 40-fold
dilution of inhibitor-treated hMAGL preparation results in a statistically significant time-dependent decline in potency of JZP-361 (90 min compared to 10 min time point,
unpaired t-test, p <0.05#). A dramatic time-dependent change in the efficacy (maximal inhibition obtained at different concentrations) of the reversible MAGL inhibitor ATM-
11444 indicates a weaker mode of reversible binding. Note however, that due to ambiguous dose-response curves, the potencies of ATM-114 at early and late time-points are
not significantly different from each other. Note also that due to methodological limitations, the IC50 values obtained by the dilution method are not directly comparable to
those obtained using the routine assay protocol.32,44 Data are mean SEM from three independent experiments. Statistical comparisons between maximal inhibition at
various time-points within the same inhibitor concentration (for ATM-114: 10 min vs 30/60/90 min) were conducted using one-way Anova, followed by Tukey’s multiple
comparison test (p <0.05⁄, p <0.01⁄⁄, p <0.001⁄⁄⁄).
Figure 3. Favourable docking poses of compound 12a (JZP-361) to the human MAGL active site (left) and to the human H1 receptor (right). The catalytic triad residues (Ser122
His169-Asp239) of MAGL are shown in orange and the oxyanion hole residues are also depicted (Met123-Ala51). The active site surface is illustrated but residues defining the
-
shape of the cavity are omitted for clarity. For the histamine H1 receptor, key residues are shown in orange and potent
p–p interactions are depicted with dashed lines.
Residue numbering is according to Shimamura et al.48
DDCB have provided financial support for this study. Dr. Ewen
Macdonald is acknowledged for revising the language of this article.
Acknowledgments
We thank Ms. Minna Glad, Ms. Tiina Koivunen, Ms. Helly
Rissanen, Ms. Taija Hukkanen and Ms. Satu Marttila for their skillful
technical assistance. CSC–Scientific Computing, Ltd is greatly
acknowledged for software licenses and computational resources.
The help from Mr. Utkarsh Trivedi, owner of Darsh Chemicals
(Baroda, India), is much appreciated. Graduate School of Drug
Design, UEF (for J.Z.P.), The Academy of Finland (Grants 139140
for T.J.N., 127653 for T.P., 139620 for J.T.L.) and Biocenter Finland/
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2015.02.
037. These data include MOL files and InChiKeys of the most
important compounds described in this article.

1442
J. Z. Patel et al. / Bioorg. Med. Chem. Lett. 25 (2015) 1436–1442
29. Hernández-Torres, G.; Cipriano, M.; Hedén, E.; Björklund, E.; Canales, Á.; Zian,
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