Isothiazole and isoxazole fused pyrimidones as PDE7 inhibitors: SAR and pharmacokinetic evaluation

Article abstract of DOI:10.1016/j.bmcl.2012.03.025

The synthesis and structure-activity relationship studies of isothiazole and isoxazole fused pyrimidones as PDE7 inhibitors are discussed. The pharmacokinetic profile of 10 and 21 with adequate CNS penetration, required for in vivo Parkinson's disease mod

Full text of DOI:10.1016/j.bmcl.2012.03.025

Bioorganic & Medicinal Chemistry Letters 22 (2012) 3223–3228
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Isothiazole and isoxazole fused pyrimidones as PDE7 inhibitors: SAR
and pharmacokinetic evaluation
Abhisek Banerjee, Pravin S. Yadav, Malini Bajpai, Ramachandra Rao Sangana, Srinivas Gullapalli,
⇑
Girish S. Gudi, Laxmikant A. Gharat
Glenmark Pharmaceuticals Limited, Navi Mumbai, Maharashtra 400 709, India
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 isothiazole and isoxazole fused pyrimidones
as PDE7 inhibitors are discussed. The pharmacokinetic profile of 10 and 21 with adequate CNS penetra-
tion, required for in vivo Parkinson’s disease models, are disclosed.
Received 30 January 2012
Revised 28 February 2012
Accepted 7 March 2012
Available online 23 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Phosphodiesterase 7 inhibitors
Isothiazolopyrimidone
Isoxazolopyrimidone
Parkinson’s disease
CNS penetration
N
O
Ar
NH
N
O
Ar
NH
Phosphodiesterase 7 (PDE7) an enzyme that selectively hydro-
lyzes cAMP, has been extensively targeted for the treatment of a
host of immunological and autoimmune conditions.1 The publica-
tion indicating the role of PDE7A in the activation and/or prolifer-
ation of T-cells was inspirational in this context.2 However, the
hypothesis was contradicted with the observation that PDE7A
knockout mice (PDE7AÀ/À) did not show deficiencies in T-cell func-
tions.3 A number of structurally diverse, potent and selective PDE7
inhibitors were identified to evaluate the potential of PDE7 as
pharmacological target of immune response. However, to date,
none has been advanced to the clinical trials.4
Two isoenzymes of PDE7, PDE7A and 7B are reported to be ex-
pressed in rat brain. Within the brain, PDE7A mRNA is abundant in
the olfactory bulb, hippocampus, and several brain-stem nuclei.
The highest concentrations of PDE7B transcripts in the brain are
found in the striatal complex, cerebellum, dentate gyrus of the hip-
pocampus and in several thalamic nuclei.1 Since regulation of
cAMP-PKA-CREB pathway plays a key role in striatum controlled
motor functions, cognition, long term memory, neurogenesis,5
neuroprotection and neuroinflammatory responses,6 recent inter-
ests have emerged with the PDE7 inhibitors in the context of Par-
kinson’s disease (PD).7
N
N
N
N
(I)
(II)
N
Ar
NH
N
O
Ar
NH
N
N
N
N
O
(III)
(IV)
Ar: subsituted aryl or heteroaryl
NH2
R3
R2
N
N
O
X
N
N
N
NH
NH
O
Parkinson’s disease (PD) is a neurodegenerative disorder associ-
ated with the loss of dopaminergic neurons in the substantia nigra
pars compacta (SNc) leading to dysfunction of transmission of
R1
O
V
( )
1
( )
X: O, S; R1: cyclohexyl, aryl;
PDE7A IC50: 1.30 nM
⇑
Corresponding author. Tel.: +91 022 6772 0000x3208.
E-mail address: laxmikant_gharat@glenmarkpharma.com (L.A. Gharat).
Figure 1. PDE7 inhibitors.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.03.025

3224
A. Banerjee et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3223–3228
information between input (striatum), output (GPi/SNr) and intrin-
sic nuclei (GPe, STN, SNc) in the basal ganglia. The primary symp-
toms include bradykinesia, resting tremor, muscle rigidity and
postural instability.8 The fine motor function under a tonic dopa-
minergic condition is controlled with a complex interplay of inte-
gration of cortical and thalamic information in striatum,
transmission to output nuclei to finally arrive at cerebral cortex
via a thalamic relay. The striatal information is projected to the
output nuclei either through a dopamine D1 receptor dependent
‘direct pathway’ to GPi/SNr or through D2 receptor dependent
‘indirect pathway’ through GPe and STN.9 The current therapies
available provide symptomatic relief and there is no effective
disease-modifying therapy. Levodopa (l-dopa), the metabolic pre-
cursor of dopamine, has been used primarily to manage early mo-
tor symptoms with limitation of development of dyskinesia upon
prolonged treatment. Moreover, it does not provide any benefit
over the non-motor symptoms of PD such as dementia, depression
and others.10 Therefore, targeting novel pathways addressing both
motor and non-motor symptoms of PD is in great demand.
Recently, in the lipopolysaccharide rat model of PD, it was
shown that PDE7 inhibition can protect dopaminergic neurons
against different insults, and thus provide support for the thera-
peutic potential of PDE7 inhibitors in the treatment of neurodegen-
erative disorders, particularly PD.11,12 Subsequently, dopamine
receptor intracellular signaling pathway has been proposed to be
down regulated by PDE7 and it has been shown that PDE7 inhibitor
alone or in combination with l-dopa increased neuronal activation
and restored paw stride length in MPTP treated mice model.13 Con-
sidering this background, our initial goal was to identify potent,
selective, CNS penetrant PDE7 inhibitors which could be evaluated
O
H2N
R1
CN
CN
HO
R1
CN
CN
a
b, c
R1
Cl
2
( )
4
( )
(3)
R1: cyclohexyl, aryl
d
H2N
R1
CN
NH2
CN
NH2
NH2
S
S
e
f
N
N
NH2
R1
R1
S
O
6
( )
5
( )
7
( )
CHO
R3
R3
R2
N
S
g
N
(9a-c)
R2
NH
R1
O
V
( )
O
m
X ,
n
R3: OMe, OEt, F
R2: -NO2, -CN,
h
O
N
THP ,
N
,
NBoc
N
O
m: 1-2; n: 1-3;
R2: -NH2
X: -N(Boc)-, -CH(NHBoc)-,
16-18
(10, 36-43)
k
-CH(OH)- (
),
R2: -NH(CH2)2NH2
-NHCONHMe (32)
11
( ),
j
24
25
-N(Me)- ( ), -CF2- ( ),
R2: -CONHMe (26)
-CH(CO2Et)-, -CONH- (31)
O
k
28
k for
m for
n for
;
N
H
12-15 34-35
19
,
27
(
)
H
N
H
N
O
O
l
,
O
m
X ,
n
NH
,
N
N
NH
20
30
(
29
)
)
(
33
(
)
(
)
m: 1-2; n: 1-3;
o
21-22
X: -N(Ac)- ( ), -N(SO2Me)- (
23
)
X: -NH- (12, 13), -CH(NH2)- (14-15, 34-35),
28 19
-CH(CONHMe)- ( ), -CH(CH2OH)- (
)
Scheme 1. Reagents and conditions: (a) malonitrile, NaH, THF, 0–5 °C, 2 h; (b) POCl3, reflux, 12–14 h; (c) aq. NH3, rt, 2 h; (d) H2S, Et3N, benzene; (e) H2O2, MeOH, 50 °C, 5 h; (f)
conc. H2SO4, 80 °C, 0.5 h; (g) DMA, cat. I2, 130 °C, 1 h; (h) Fe, NH4Cl, MeOH, rt, 2 h; (j) For 11: (i) tert-butyl (2-oxoethyl)carbamate, NaBH(OAc)3, AcOH, DCE, rt, 12 h; (ii) TFA,
CH2Cl2, rt, 1 h; For 32:(i) PhOCOCl, Et3N,THF, rt, 1 h; (ii) MeNH2–HCl, DMSO, 50 °C, 5 h; (k) (i) NaOH, MeOH, 50 °C, 2 h; (ii) MeNH2-HCl, PyBOP, DIPEA, DMF, rt, 12 h; (l) (i)
trimethylsulphonium iodide, NaH, DMSO, rt, 18 h; (ii) LiOH, THF–MeOH–H2O, rt, 2 h; (iii) (R)-phenylglycinol, EDCl, HOBt, DIPEA, DMF, rt, 12 h; (iv) 6 N HCl, Dioxane, 100 °C,
1 h; (v) MeNH2–HCl, PyBOP, DIPEA, DMF, rt, 12 h; (m) HCl in EtOAc, rt, 4 h; (n) LAH, THF, rt, 5 h; (o) AcCl (for 21–22) or MeSO2Cl (for 23), Et3N, CH2Cl2, rt, 1 h.

A. Banerjee et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3223–3228
3225
The synthetic strategy utilized in the preparation of isothiazol-
opyrimidones (V: X = S; R1 = cyclohexyl, aryl) is described in
Scheme 1. The condensation of the appropriate acid chloride with
malononitrile in the presence of NaH provided 3 which was con-
verted to 4 via sequential treatment with POCl3 and ammonium
hydroxide. The treatment of 4 with hydrogen sulfide gas provided
5 which upon cyclization in presence of H2O2 provided 6.16 The
hydrolysis of 6 provided the intermediate 7 which was then con-
densed with various aldehydes (9a–c) in presence of catalytic
amount of iodine to provide V.
The synthesis of the aldehydes (9a–c) is briefly described in
Scheme 2. The nucleophilic aromatic substitution of 2-alkoxy-4-
fluorobenzaldehyde (8a) with a variety of cyclic amines which
were commercially available or prepared following the known
methods, provided aldehyde 9a. The aldehyde 9b was prepared
from 3-iodophenol (8b) following a three steps protocol: Casiraghi
formylation,17 methylation and Heck or, Suzuki or copper cata-
lyzed cyanation. The aldehyde 9c was synthesized from 2,4-dihy-
droxybenzaldehyde (8c) following Mitsunobu and alkylation
conditions subsequently.
As depicted in Scheme 1 the isothiazole analogs 16–18, 24, 25,
and 32 were obtained directly by condensation of the intermediate
7 with the appropriate aldehydes (9a). The synthesis of the com-
pounds 10,18 36–43 were accomplished upon reduction of the nitro
group in V using iron and NH4Cl in MeOH. The reductive amination
of 10 with tert-butyl (2-oxoethyl)carbamate followed by treatment
with TFA provided 11. The synthesis of the compound 32 was per-
formed following a two step protocol: treatment of 10 with phe-
nylchloroformate and then with methylamine hydrochloride in
DMSO at 50 °C. The synthesis of the compound 26 was performed
by conversion of the nitrile in V to the corresponding acid and then
amidation with methylamine hydrochloride. Following the similar
two step protocol of hydrolysis and amidation of the esters in V,
compounds 27 and 28 were obtained. The Corey–Chaykovsky
cyclopropanation of the acrylic ester in V and subsequent hydroly-
sis provided the trans racemic cyclopropyl acids. The resolution of
the racemic acids following the method described by Kozikowski19
and subsequent amide formation with methylamine hydrochloride
provided the compounds 29 and 30. The removal of the protecting
groups (Boc or THP) in V (R2: heterocycle/O-linked heterocycle)
with a saturated solution of HCl in ethyl acetate provided the com-
pounds 1218–15, 34, and 35. The reduction of the ester in V (where
X: CH(CO2Et)) with lithium aluminium hydride provided the com-
pound 19. The acylation of compounds 12 and 13 provided com-
pounds 2118 and 22, respectively. Similarly, compound 23 was
synthesized from compound 12 under sulfonylation conditions,
using methanesulfonyl chloride.
CHO
CHO
N
R3
R3
a
F
m
n
(8a)
X
R3: OMe, OEt, F
(9a)
n: 1-3; m: 1-2;
X: -N(Boc)-, -CH(OH)-, -CH(NHBoc)-,
-N(Me)-, -CF2-, -CH(CO2Et)-, -CONH-
CHO
O
OH
b and
c or d
R2
I
8b
(9b)
(
)
O
R2: -CN,
N
THP
O
N
CHO
O
CHO
OEt
OH
e, f
OH
8c
(
)
NBoc
9c
(
)
Scheme 2. Reagents and conditions: (a) amine, K2CO3, DMSO, 80–120 °C; (b) (i)
(CH2O)n, MgCl2, Et3N, CH3CN, 80 °C; (ii) Mel, K2CO3, DMF; (c) CuCN, DMF, 90 °C; (d)
methyl acrylate/boronate ester, Pd(PPh3)4, K2CO3, DMF, 120 °C; (e) (3R)-3-hydroxy-
pyrrolidine-1-carboxylate, PPh3, DIAD, THF, rt; (f) Etl, K2CO3, DMF.
in animal models to increase the understanding of the target in the
PD therapy.
Among the various heterocyclic structures that have been ex-
plored for the discovery of novel and selective PDE7 inhibitors,1,4
we were particularly interested in the pyrimidone fused heterocy-
clic scaffolds I–IV disclosed by Asubio Pharma (Fig. 1). The repre-
sentative compound 1 was highly potent, more than 1000-fold
selective against other PDE isoforms and had reasonable CNS pen-
etration in mouse.14 Inspired by this novel structure, we decided to
explore isothiazole and isoxazole fused pyrimidones (V), to iden-
tify various pyrimidone fused heterocyclic scaffolds as PDE7 inhib-
itors similar to an approach described for PDE5 inhibitors.15 Also,
we were keen on examining a possible replacement of the cyclo-
alkyl group (R1) represented in I–IV with an aromatic group. This
communication describes our preliminary efforts towards the goal
mentioned above.
The synthesis of the isoxazolopyrimidone (45) was completed
by condensation of the intermediate 4420 with aldehyde 9a fol-
lowed by removal of the Boc group with HCl in ethyl acetate
(Scheme 3).
The target compounds were tested for their inhibitory activity
at the cloned human recombinant PDE7A, PDE7B and other PDE
CHO
O
NH
NH2
NH2
O
O
N
a, b
N
+
N
O
O
N
N
O
NH
PDE7A IC50: 31 8.05 nM
(45)
(44)
N
Boc
(9a)
Scheme 3. Reagents and conditions: (a) DMA, cat, I2, 130 °C, 1 h; (b) HCl in EtOAc, rt, 1 h.

3226
A. Banerjee et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3223–3228
Table 1
Table 1 (continued)
SAR of the R2 position of Isothiazolopyrimidone
Example
R2
PDE7A IC50 (nM) SDc
18 3.09
R3
R2
O
N
O
28a
S
N
H
N
N
NH
H
N
O
29a
35 8.00
Example
R2
PDE7A IC50 (nM) SDc
14 4.5
10a
–NH2
H
O
N
H
N
11a
12a
30a
31a
38 8.07
15 4.37
46 10.53
NH2
NH
9
4
2.73
0.52
O
O
N
NH
NH
13a
14a
15a
N
H
N
N
N
H
N
32a
33a
17 4.95
25 2.88
NH2
23 4.12
NH2
H
N
8
1.79
N
N
N
OH
a
b
c
16a
17a
18a
R3 = OMe.
R3 = OEt.
18 3.97
11 4.51
IC50 values are means of three experiments.
OH
N
OH
7
1.12
Table 2
N
N
SAR of the R3 position of Isothiazolopyrimidone
OH
19a
20b
16 5.76
35 7.77
Example Structure
PDE7A IC50 (nM)
SDa
NH
O
NH2
NH2
NH2
O
N
O
N
N
N
N
O
21a
22a
16 4.59
12 2.10
S
S
S
N
15
34
35
8
1.79
N
N
N
NH
O
N
N
O
S
O
O
23a
66 18.77
N
N
O
12 4.76
N
N
NH
N
F
24b
25a
88 11.96
106 22.15
F
N
O
F
26a
27a
125 11.99
47 7.54
N
O
N
101 37.01
H
NH
O
N
H
a
IC50 values are means of three experiments.

A. Banerjee et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3223–3228
3227
Table 3
less active. Thus, we examined the structure–activity relationship
at the R2 position of isothiazolopyrimidone (V, R1: cyclohexyl;
R3: OMe, OEt) with the hope of improving the potency and the re-
sults are summarized in Table 1. To determine the available space
for expansion in the R2 region we decided to extend the H-bond
donor with a linker. The 1,2-diamino substitution (11) resulted a
threefold loss of activity whereas the piperazine (12) and 3-amino-
pyrrolidine substitutions (14) improved the PDE7A inhibitory
activity. A further improvement in potency was observed with
the increase in corresponding ring sizes (13 and 15). Similar trend
was also observed with compounds 16, 17 and 18 where alcohol
was used as H-bond donor. The placement of the hydrogen bond
donor was also an important aspect as the potency was somewhat
reduced in compounds 14, 19 and 20. Further investigation re-
vealed that H-bond acceptor is also capable of retaining the po-
tency (21 and 22). However, loss of activity was observed with
methylsulfonylpiperazine (23), methylpiperazine (24), and 4,4-
difluorpiperidine (25) substitutions.
Next, we incorporated the amide group (26) which was ninefold
less active than the corresponding amine (10). However, as antici-
pated the incorporation of a linker between the amide functional
group and the aromatic ring, improved the activity. The cinnamide
(27) and the piperidine carboxamide derivatives (29) were three
and sevenfold more potent than 26, respectively. The appropriate
length of the linker and positioning of the functional group proved
to be critical as the potency decreased in 29 and 30 compare to 28.
Interestingly, the cyclic amide 31 which was designed to possess
both H-bond donor and acceptor further improved the activity.
The urea derivative (32) and pyrazole derivative (33) also retained
the activity.
SAR of the R1 position of Isothiazolopyrimidone
O
NH2
N
O
S
N
NH
R1
Example
36
R1
PDE7A avg.%
PDE7A IC50 (nM) SDb
inhibition at 1
l
Ma
70%
95%
ND
F
F
37
39 6.36
38
39
75%
35%
ND
ND
F
Cl
F
40
41
90%
95%
80 8.67
30 6.41
Then the role of the R3 substituent in V was briefly investigated
and proved that the alkoxy substituent, capable of a strong hydro-
gen bonding interaction with the pyridone NH, is essential since
there was a significant loss in activity when R3 was substituted
with fluoro (35) (Table 2). However, there was no significant differ-
ence in potency between the methoxy (15) and the ethoxy substi-
tuted compounds (34).
F
F
42
43
95%
93%
46 5.25
14 1.47
Then we turned our attention to develop a SAR at the R1 posi-
tion by replacing the cyclohexyl moiety with the aryl groups. The
data in Table 3 indicated that mono and di-orthosubstitution (37,
40, 41, 43) increased potency against PDE7. In this SAR, the 2-
chloro-6-fluoro substituted compound (43) was similar in potency
to compound (10) (Scheme 3).
F
F
Cl
ND: not determined.
Finally, we also compared the PDE7A inhibitory activity of iso-
thiazole and isoxazole fused pyrimidones. The isoxazole compound
(45) with the substitution pattern that provided the most potent
a
% Inhibition values are means of two experiments.
IC50 values are means of three experiments.
b
isothiazole compound (13) was eightfold less potent (PDE7A IC50
:
isozymes following a two step radiometric assay using 3H-cAMP as
the radioligand.21
31 nM).
The PDE selectivity profile of representative compounds 10, 13
and 21 presented in Table 4 suggests that the compounds were
non-selective within PDE7 isoforms. However, they were selective
against other PDEs.
A direct comparison between 1 and 10 indicated that the
replacement of the pyrazole moiety with isothaizole has an impact
on the PDE7A activity as the later compound was nearly 10-fold
Table 4
PDE Selectivity profile of 10, 13 and 21
Compound
IC50 (nM)
PDE7A SDa
14 4.50
0.52
16 4.59
% Inhibition at 10
PDE 5A
l
Mc
PDE7Bb
PDE 1A
PDE 2A
PDE 3A
PDE 4D
PDE 8A1
PDE 9A2
PDE 10A
PDE 11A
10
13
21
31
17
8
17
38
30
28
16
9
3
4
6
45
67
21
11
3
8
7
16
1
12
8
13
6
3
19
28
35
6
4
a
b
c
IC50 values are means of three experiments.
IC50 values are means of two experiments.
% Inhibition values are means of two experiments.

3228
A. Banerjee et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3223–3228
Table 5
Pharmacokinetic profile of 10 and 21
Compound
Metabolic stability(% remaining)a
Rat PKb
1 mpk ivc,d
10 mpk orale
HLM
RLM
MLM
Cbrain (ng/g)
Cplasma (ng/mL)
Ratio
Cmax (ng/mL)
AUC (ng h/mL)
Tmax (h)
10
21
47
68
58
67
24
3
951
792
281
390
3.39
2.03
36
739
75
2877
1
2
a
b
c
Percentage of test compound remaining after 60 min incubation with liver microsomes at 37 °C.
Male SD rats were used for the experiments.
iv formulation: 20% NMP, 20% EtOH, 10% Cremophor EL, 50% PEG 200/H2O (3:2, premix).
Brain and plasma samples were collected 5 min post iv dose.
d
e
Oral formulation: 2.5 lL/mL Tween 80 + 0.5% (w/v) methyl cellulose suspension (q.s.).
6. (a) Volakakis, N.; Kadkhodaei, B.; Joodmardi, E.; Wallis, K.; Panman, L.; Panman,
L.; Silvaggi, J.; Spiegelman, B. M.; Perlmann, T. Proc. Natl. Acad. Sci. U.S.A. 2010,
107, 12317; (b) Lonze, B. E.; Ginty, D. D. Neuron 2002, 35, 605.
7. (a) Tansey, M. G.; McCoy, M. K.; Frank-Cannon, T. C. Exp. Neurol. 2007, 208, 1;
(b) McGeer, E. G.; McGeer, P. L. CNS Drugs 2007, 21, 789.
8. (a) Obeso, J. A.; Rodríguez-Oroz, M. C.; Rodríguez, M.; Lanciego, J. L.; Artieda, J.;
Gonzalo, N.; Olanow, C. W. Trends Neurosci. 2000, 23, S8; (b) Jenner, P.; Olanow,
C. W. Neurology 2006, 66, S24.
9. (a) Albin, R. L.; Young, A. B.; Penney, J. B. Trends Neurosci. 1989, 12, 366; (b)
DeLong, M. R. Trends Neurosci. 1990, 13, 281.
10. (a) Chaudhuri, K. R.; Healy, D. G.; Schapira, A. H. Lancet Neurol. 2006, 5, 235; (b)
Klivenyi, P.; Vecsei, L. Eur. J. Clin. Pharmacol. 2010, 66, 119.
In the present set of active PDE7A inhibitors we further evalu-
ated the pharmacokinetic profile of 10, and 21. The compounds
were metabolically stable in human and rat liver microsomes
(Table 5) and more importantly, they had adequate CNS penetra-
tion in male SD rats upon intravenous administration. Moreover,
compound 21 exhibited an acceptable oral pharmacokinetic profile
in rat (Table 5). Compounds 12, 13, 15 with basic nitrogen
(pKa > 8), did not have adequate CNS penetration and were also
non-selective in the panel of receptors (data not shown), thus no
further evaluation was performed.
In conclusion, we have reported the synthesis and SAR evalua-
tion of isothiazole and isoxazole fused pyrimidones as PDE7 inhib-
itors. In the isothiazole series various groups with H-bond donor
and/or acceptor at the R2 position of V provided potent PDE7 inhib-
itors. An exploratory effort also demonstrated that the cyclohexyl
group at R1 position of V could be replaced with 2,6-disubstituted
aromatics. Furthermore, we identified two compounds (10 and 21)
which had good CNS penetration and could be further profiled in
animal models to evaluate the potential of PDE7 as a target for PD.
11. Morales-Garcia, J. A.; Redondo, M.; Alonso-Gil, S.; Gil, C.; Perez, C.; Martinez, A.;
Santos, A.; Perez-Castillo, A. PLoS ONE 2011, 6, e17240.
12. The role of PDE7 Inhibitors to enhancing neuroprotection in well-characterized
cellular and animal models of spinal cord injury and stroke is demonstrated in
the following references, respectively: (a) Paterniti, I.; Mazzon, E.; Gil, C.;
Impllizzari, D.; Palomo, V.; Redondo, M.; Perez, D. I.; Esposito, E.; Martinez, A.;
Cuzzocrea, S. PLoS ONE 2011, 6, e15937; (b) Redondo, M.; Zarruk, J. G.; Ceballos,
P.; Pérez, D. I.; Pérez, C.; Perez-Castillo, A.; Moro, M. A.; Brea, J.; Val, C.; Cadavid,
M. I.; Loza, M. I.; Campillo, N. E.; Martínez, A.; Gil, C. Eur. J. Med. Chem. 2012, 47,
175.
13. Bergmann, J. E.; Cutshall, N. S.; Demopulos, G. A.; Florio, V. A.; Gaitanaris, G.;
Gray, P.; Hohmann, J.; Onrust, R.; Honhkui, Z. U.S. Pat. Appl. US 0,113,486,
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.03.025.
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