Potent and selective adenosine A2A receptor antagonists: [1,2,4]-triazolo[4,3-c]pyrimidin-3-ones

Article abstract of DOI:10.1016/j.bmcl.2011.02.045

Antagonism of the adenosine A_2A receptor affords a possible treatment of Parkinson's disease. In the course of investigating pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine A_2A antagonists, we prepared [1,2,4]-triazolo[4,3-c]pyrimidi

Full text of DOI:10.1016/j.bmcl.2011.02.045

Bioorganic & Medicinal Chemistry Letters 21 (2011) 2497–2501
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Potent and selective adenosine A2A receptor antagonists:
[1,2,4]-triazolo[4,3-c]pyrimidin-3-ones
⇑
Joel M. Harris , Bernard R. Neustadt, Hongtao Zhang, Jean Lachowicz, Mary Cohen-Williams,
Geoff Varty, Jinsong Hao, Andrew W. Stamford
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Antagonism of the adenosine A2A receptor affords a possible treatment of Parkinson’s disease. In the
course of investigating pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine A2A antagonists, we prepared
[1,2,4]-triazolo[4,3-c]pyrimidin-3-ones with potent and selective (vs A1) A2A antagonist activity. Struc-
ture–activity relationships are described for this series.
Received 26 October 2010
Revised 8 February 2011
Accepted 14 February 2011
Available online 24 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Adenosine
A2A
A2A receptor
A2A antagonist
Adenosine receptor
Parkinson’s disease
Parkinson’s disease (PD) is a severe neurological disorder
marked by degeneration of dopaminergic neurons.1 The use of
antagonism offers a novel target for the possible treatment of
PD.6 Generally, A2A antagonists have been classified as xanthine
and non-xanthine derivatives, such as KW-6002 (istradefylline)7
and SCH 420814 (preladenant)8 currently in clinical trials (Fig. 1).
Adenosine A2A receptor antagonists of several structural types have
been described.9,10
In our previous Reports, we disclosed the development of the
pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine (preladenant) as a
potential treatment for PD8 and the activity of a set of 7-aryl-
1,2,4-triazolo[1,5-c]pyrimidines of type 1 was also described.11
As a part of the investigation of these series, we also explored
1,2,4-triazolo[4,3-c]pyrimidin-3-one 2 and pyrazolo[4,3-e]-1,2,4-
triazolo[4,3-c]pyrimidin-3-one 3 derivatives (Fig. 2). We focused
our study on identifying a suitable replacement for the optimal
L
-
dopa as dopamine replacement therapy is the central focus of
treatment for Parkinson’s disease, however chronic administration
leads to motor skills complications and loss of drug efficacy and
dyskinesia.2 Other methods of treatment fail to achieve long-term
control of motor skills, speech, and other functions.3
Adenosine is an important neuromodulator in the central and
peripheral nervous systems. Adenosine modulates its effects
through the activation of four receptors located on cell mem-
branes, known as A1, A2A, A2B, and A3.4 Adenosine A2A antagonists
have demonstrated the ability to restore the deficits caused by
degeneration of the striatonigral dopamine system, which is com-
promised by the loss of striatal neurons in this disease.5 A2A
O
NH2
Me
N
Et
OMe
OMe
N
N
O
N
N
N
O
N
O
N
Et
N
N
MeO
N
N
Istradefylline
KW-6002
Preladenant
SCH 420814
Figure 1. A2A antagonists KW-6002 and preladenant.
⇑
Corresponding author. Tel.: +1 908 740 6515; fax: +1 908 740 7164.
E-mail address: joel.harris@merck.com (J.M. Harris).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.02.045

2498
J. M. Harris et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2497–2501
Table 1
NH2
N
NH2
N
NH2
N
O
O
1,2,4-Triazolo[4,3-c]pyrimidin-3-ones
N
N
O
N
N
N
N R2
N R2
a
Compound Structure
A2A Kia A1/A2A
(nM)
k. sol.b
(lM)
R1
R1
N
N
N
N
NH2
N
1
2
3
O
N
N
N
1
7.0
3
NA
NA
100
Figure 2. 1,2,4-Triazolo[4,3-c]pyrimidin-3-one 2 and pyrazolo[4,3-e]-1,2,4-triazol-
o[4,3-c]pyrimidin-3-one 3.
N
NH2
N
O
furan moiety, which has the potential to undergo oxidative metab-
olism12 and on improving the solubility of preladenant.13a In the
present report, we describe the synthesis and SAR of a novel series
of 1,2,4-triazolo[4,3-c]pyrimidin-3-ones 214 and pyrazolo[4,3-e]-
1,2,4-triazolo[4,3-c]pyrimidin-3-ones 3.
The compounds shown in Table 1 were prepared using the gen-
eral procedures described in Scheme 1. The Pd-catalyzed coupling
of 2-amino-4,6-dichloropyrimidine with aryl boronic acids yielded
chlorides 5 which underwent displacement with hydrazine to pro-
duce 6. Condensation of 6 with benzaldehyde, followed by reduc-
tion with NaBH3(CN) produced structures of type 7. Subsequent
cyclization of 7 with phosgene yielded compounds 2a–d. All com-
pounds reported herein gave satisfactory analytical results.15 We
also synthesized a fused tetracyclic analog 12 to restrict rotation
of the aryl substituent. Compound 12 was prepared in 8 steps from
N
2a
2b
1.0 26
N
NH2
N
O
N
N
1700
1
2
2
N
HO
NH2
N
O
N
N
2c
636
791
25
N
MeO
N
NH2
N
O
N
N
N
2d
12
100
NA
a
-tetralone. Initially,
and dimethyl carbonate to provide the intermediate
a
-tetralone was treated with sodium hydride
a-keto ester,
which upon reaction with sodium methoxide and thiourea in
methanol provided compound 9. Compound 10 was prepared by
reacting compound 9 with 10% chloroacetic acid at 100 °C. Subse-
quent treatment of compound 10 with POCl3 followed by displace-
ment with hydrazine gave compound 11. Lastly, reductive
amination of compound 11 with benzaldeyde, followed by cycliza-
tion with phosgene and displacement with ammonia provided
compound 12.
NH2
N
O
N
N
0.5 43
N
a
Average of duplicate determinations, human receptors.
A single measurement of kinetic solubility at pH 7.4.13b
b
The in vitro results of the A2A AR binding assays16 are expressed
as inhibition constants (Ki, nM) and A1/A2A describes the selectivity
over A1. Results in Table 1 show that compound 2a had higher A2A
affinity than compound 1, but only moderately improved selectiv-
ity over A1. Substituted aryl- analogs 2b–c and the pyridyl- analog
NH2
NH2
NH2
N
R1B(OH)2, Pd(PPh3)4
N
N
N
N
N
hydrazine
NH2
R1
R1
EtOH
96%
Cl
Cl
N
H
Cl
K2CO3, CH3CN
60-70%
4
5
6
NH2
NH2
N
O
phosgene
DIPEA
N
N
N
PhCHO, AcOH
CH2Cl2,
H
N
N
Ph
S
Ph
O
R1
R1
N
N
H
THF, 0oC
30%, 2 steps
then NaBH3(CN)
7
2a-d
1) NaH, Me2CO3
115oC
O
HN
NH
HN
NH
10% ClCH2CO2H
O
O
100oC
38%
2) NaOMe, MeOH
thiourea, 65oC
18%, 2 steps
8
9
10
Cl
NH2
N
O
1) PhCHO, AcOH
CH2Cl2,
N
N
N
N
1) POCl3, DMF, 110oC
NH2
then NaBH3(CN)
N
Ph
N
H
2) phosgene, DIPEA
THF, 0oC
3) 2M NH3 in iPrOH
20%, 5 steps
2) hydrazine hydratev
EtOH
11
12
Scheme 1. Synthesis of 1,2,4-triazolo[4,3-c]pyrimidin-3-ones 2a–d and 12.

J. M. Harris et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2497–2501
2499
NH2
N
NH2
1) tert-butyl carbazate
1) hydrazine hydrate
DMF, DIPEA
DMF, 80oC
N
N
N
Br
Cl
Cl
Cl
2)
Cl
N
N
Cl
2) 4M HCl in dioxane
CH3OH/CH2Cl2
CHO
NaH, DMF
13
14
NH2
N
NH2
O
1) R3CHO, TFA
then Et3SiH
N
N
N
N
NH2
Ra
R3
2) phosgene, DIPEA
N
N
H
N
N
THF, 0oC
Cl
N
Rb
N
N
H
3)
N
Ra Rb
15
16
DMF, 140 o
C
10-30%, 3 steps
Scheme 2. Pyrazolo[4,3-e]-1,2,4-triazolo[4,3-c]pyrimidin-3-ones 16.
Table 2
Receptor affinity and solubility of pyrazolo[4,3-e]-1,2,4-triazolo[4,3-c]pyrimidin-3-ones
NH2
O
N
N
N
R1
N
N
R2
A2A Kia (nM)
N
R1
R2
A1/A2A
k. sol.b
(lM)
a
Compound
17
18
H
Cl
0.3
0.4
1115
356
37
12
Me
N
19
20
H
>1500
5.2
NA
>250
18
Me
O
Cl
269
21
22
H
9.0
156
99
175
25
N
O
Cl
14.2
23
24
H
8.7
162
127
75
O
O
N
Cl
11.0
NA
N
25
26
H
28.4
6.7
53
NA
NA
N
N
Cl
224
MeO2S
N
27
28
H
8.9
157
133
75
12
Cl
10.5
Boc
N
29
30
H
>1300
556
NA
2
100
25
N
Cl
F
31
32
H
>1300
23.4
NA
60
NA
NA
N
F
N
Cl
O
33
34
H
>1300
15.6
NA
90
12
12
N
OMe
F
N
Cl
N
N
35
36
H
12.7
12.9
110
109
50
25
N
N
Cl
a
Average of duplicate determinations, human receptors.
A single measurement of kinetic solubility at pH 7.4.13.
b

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J. M. Harris et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2497–2501
2d had greatly decreased A2A affinity and selectivity. Compound 12
demonstrated that fusing the aryl group to the pyrimidin-3-one
core improved A2A affinity to <1 nM, but unfortunately did not im-
prove selectivity and was inactive in the rat catalepsy assay at an
oral dose of 10 mg/kg (Table 4).11,17
The solubility for compounds 2b–d was greatly improved over
preladenant, however, due to the lack of affinity for the A2A recep-
tor, we moved our attention to preparing analogs of type 3 based
on the SAR of the pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine
series. The synthesis of these analogs originated from known com-
pound 1518 and is shown in Scheme 2. Condensation of compound
15 with a suitable aldehyde in TFA followed by reduction with tri-
ethylsilane provided the appropriate hydrazide. Subsequent cycli-
zation with phosgene and displacement with various amines
yielded compounds of type 16.
A variety of analogs (17–39) were prepared varying substitution
at the 7-position and a benzyl, 3-chlorobenzyl, or cyclopropylm-
ethyl group at the 2-position of the molecule (Tables 2 and 3).
Compounds 17 and 18 with a vinyl group19 installed at the 7-posi-
tion afforded the most potent and selective A2A receptor antago-
nists in this set of compounds, however, these were devoid of
significant anti-cataleptic activity in the rat at an oral dose of
10 mg/kg (Table 4).11,18 Based on previous SAR of the pyrazol-
o[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine series8,9a incorporation of
a basic nitrogen in the side chain resulted in compounds with
acceptable binding affinities (5–15 nM) and selectivity (>100 fold
over A1). Introduction of a morpholine group 21 and 22 or a piper-
idine group 23–26 provided compounds with 7–30 nM A2A Ki val-
ues and selectivity over A1 of 50–225 fold. Several substituted
piperazines 27–36 were also investigated with varying degrees of
activity. Compounds of particular interest were the methyl-sulfo-
nyl substituted piperazines 27 and 28 and pyrazinyl–piperazines
35 and 36 which displayed >100-fold selectivity over A1.
Unfortunately, compounds 31 and 33 were inactive suggesting a
possible divergent structure–activity relationship compared to
the preladenant series. In general, A2A antagonist activity was
maintained or improved by replacing the furan moiety and with
a benzyl group or a 3-chlorobenzyl group, but the use of a cyclo-
propylmethyl group 37–39 as a benzyl isostere provided less po-
tent compounds.
Our goal of improving the solubility relative to preladenant8
was achieved with several compounds having solubility >25 lM
at pH 7.4. Ultimately, compounds with a benzyl group in the 2-po-
sition were more soluble, while compounds with a 3-chlorobenzyl
group had higher A2A affinity. Unfortunalely, these compounds
were inactive in the rat catalepsy assay, which was attributed to
their poor rat PK, exposure in rat brain, and pharmacokinetic prop-
erties compared to preladenant.8 The reasons for lack of activity in
the catalepsy assay are not well understood but could be due to
inadequate exposure of these compounds in the striatum or high
non-specific binding to brain tissue (Table 4).
In summary, the exploration of SAR of 1,2,4-triazolo[4,3-c]pyr-
imidin-3-one and pyrazolo[4,3-e]-1,2,4-triazolo[4,3-c]pyrimidin-
3-one analogs resulted in a novel class of potent and selective
A2A antagonists derived from compound 1 and preladenant. Substi-
tution with various piperazino–alkyl chains in the 7-position and
furan replacements in the 2-position were shown to be tolerated
and provided compounds with improved solubility compared to
preladenant, however adequate in vivo activity was not achieved.
Further optimization of the pyrazolo[4,3-e]-1,2,4-triazolo[1,5-
c]pyrimidine series of A2A receptor antagonists will be disclosed
in future publications.
Acknowledgements
We wish to thank Dr. William Greenlee for his support of this
work. In addition, we thank Drs. Charles McNemar, William Wind-
sor, and Mr. Ashwin Ranchod for providing solubility data. We
would also like to thank John Caldwell and Unmesh Shah for their
help in the preparation of this manuscript.
Table 3
Receptor affinity and solubility of pyrazolo[4,3-e]-1,2,4-triazolo[4,3-c]pyrimidin-3-
ones
NH2
N
O
References and notes
N
N
1. (a) Ferre, S.; von Euler, G.; Johansson, B.; Fredholm, B. B.; Fuxe, K. Proc. Natl.
Acad. Sci. U.S.A. 1991, 88, 7238; (b) Schwarzschild, M. A. guest editor Prog.
Neurobiol. 2007, 83, 261. Special issue: Targeting Adenosine A2A Receptors in
Parkinson’s Disease and Other CNS Disorders..
2. (a) Jankovic, J. Chin. Med. J. 2001, 114, 227; (b) Jankovic, J. Mov. Disord. 2005, 20,
S11.
3. For recent reviews of PD and Adenosine A2A antagonists see: (a) Cristalli, G.;
Lambertucci, C.; Marucci, G.; Volpini, R.; Dal Ben, D. Curr. Pharmaceutical Des.
2008, 14, 1525; (b) Yuzlenko, O.; Kiec-Kononowicz, K. Curr. Med. Chem. 2006,
13, 3609; (c) Schwarzschild, M. A.; Agnati, L.; Fuxe, K.; Chen, J.-F.; Morelli, M.
Trends Neurosci. 2006, 29, 647; (d) Xu, K.; Bastia, E.; Schwarzschild, M.
Pharmacol. Ther. 2005, 105, 267; (e) Kase, H.; Mori, A.; Jenner, P. Drug Discov.
Today 2004, 1, 51.
R1
N
N
N
a
Compound
37
Structure
A2A Kia (nM)
A1/A2A
55
k. sol.b
175
(lM)
27.4
Me
N
38
39
>1500
381
NA
4
>250
>250
Me
O
N
a
4. Fredholm, B. B.; Abbracchio, M. P.; Burnstock, G.; Daly, J. W.; Harden, T. K.;
Jacobson, K. A.; Leff, P.; Williams, M. Pharmacol. Rev. 1994, 46, 143.
5. (a) Jacobson, K. A.; van Galen, P. J. M.; Williams, M. J. Med. Chem. 1992, 35, 4007;
(b) Muller, C. E. Drugs Future 2000, 25, 1043.
Average of duplicate determinations, human receptors.
A single measurement of kinetic solubility at pH 7.4.13b
b
6. (a) Kase, H. Biosci., Biotechnol., Biochem. 2001, 65, 1447; (b) Jenner, P. Neurology
2003, 61, S32.
Table 4
7. (a) Jenner, P. Expert Opin. Investig. Drugs 2005, 14, 729; (b) Bara-Himenez, W.;
Sherzai, A.; Dimitrova, T.; Favit, A.; Bibbiani, F.; Gillespie, M.; Morris, M. J.;
Mouradian, M. M.; Chase, T. N. Neurology 2003, 61, 293; (c) Hauser, R. A.;
Hubble, J. P.; Truong, D. D. Neurology 2003, 61, 297.
8. Neustadt, B. R.; Hao, J.; Lindo, N.; Greenlee, W. J.; Stamford, A. W.; Tulshian, D.;
Ongini, E.; Hunter, J.; Monopoli, A.; Bertorelli, R.; Foster, C.; Arik, L.; Lachowicz,
J.; Ng, K.; Feng, K. Bioorg. Med. Chem. Lett. 2007, 17, 1376.
In vivo activity and rat PK of selected compounds
Compound Rat catalepsy,%
inhibition 1 h/4 h
@10mpka
Rat plasma
AUC @ 3mpk,
nMꢀhrb
Exposurec
in rat brain, clint mL/
ng/g
Rat
min/kg
12
17
18
20
0/18
0/8
13/15
13/20
0
<LOQ
<LOQ
NA
14.7
24.4
27.7
37.3
248
NA
398
9.
A number of recent reports on selective A2A receptor antagonists are
summarized in: (a) Shah, U.; Hodgson, R. Curr. Opin. Drug Discov. Devel. 2010,
13, 466; (b) Neustadt, B. R.; Liu, H.; Hao, J.; Greenlee, W. J.; Stamford, W.; Foster,
C.; Arik, L.; Lachowicz, J.; Zhang, H.; Bertorelli, R.; Fredduzzi, S.; Varty, G.;
Cohen-Williams, M.; Ng, K. Bioorg. Med. Chem. Lett. 2009, 19, 967.
39
a
Average for n = 3. Positive control SCH 4123488 active at 1 h and 4 h (75%, 80%).
Maximum reduction attainable is 60–80%.
10. (a) Mooranji, M.; Luo, Z.; Lin, E.; Vong, B. G.; Chen, Y.; Zhang, X.; Rueter, J. K.;
Gross, R. S.; Lanier, M. C.; Tellew, J. E.; Williams, J. P.; Lechner, S. M.; Malany, S.;
Santos, M.; Crespo, M. I.; Diaz, J.-L.; Saunders, J.; Slee, D. H. Bioorg. Med. Chem.
b
Area under the curve.20
At 6 h after dosing; LOQ is 10 ng/g.
c

J. M. Harris et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2497–2501
2501
Lett. 2008, 18, 5402; (b) Cole, A. G.; Stauffer, T. M.; Rokosz, L. L.; Metzger, A.;
Dillard, L. W.; Zeng, W.; Henderson, I. Bioorg. Med. Chem. Lett. 2009, 19, 378; (c)
Shao, Y.; Cole, A. G.; Brescia, M.-R.; Qin, L.-Y.; Duo, J.; Stauffer, T. M.; Rokosz, L.
L.; McGuinness, B. F.; Henderson, I. Bioorg. Med. Chem. Lett. 2009, 19, 1399; (d)
Lanier, M. C.; Moorjani, M.; Luo, Z.; Chen, Y.; Lin, E.; Tellew, J. E.; Zhang, X.;
Williams, J. P.; Gross, R. S.; Lechner, S. M.; Markison, S.; Joswig, T.; Kargo, W.;
Piercey, J.; Santos, M.; Malany, S.; Zhao, M.; Petroski, R.; Crespo, M. I.; Diaz, J.-L.;
Saunders, J.; Wen, J.; O’Brien, Z.; Jalali, K.; Madan, A.; Slee, D. H. J. Med. Chem.
2009, 52, 709; (e) Gillespie, R. J.; Bamford, S. J.; Gaur, S.; Jordan, A. M.;
Lerpiniere, J.; Mansell, H. L.; Stratton, G. C. Bioorg. Med. Chem. Lett. 2009, 19,
2664.
14. Previous work on this ring system for use as CB1 receptor antagonists is
disclosed in: Gu, G.; Mikkilineni, A. B.; Sher, P. M.; Murugesan, N.; Gu, Z. U. S.
Pat. Appl. Pub. 2006/0287341 A1.
15. Compound 2a: 1H NMR (CDCl3, 400 MHz) d 7.85 (m, 2H), 7.39 (m, 8H), 6.67 (s,
1H), 5.05 (s, 2H); 17: 1H NMR (CDCl3, 400 MHz) d 7.93 (s, 1H), 7.42–7.28 (m,
6H), 5.81 (d, J = 16 Hz, 1H), 5.05 (s, 2H), 4.93 (d, J = 8.8 Hz, 1H).
16. A detailed description of the adenosine receptor binding assay is provided in
Bioorg. Med. Chem. Lett. 2005, 15, 1333, Ref. 11. For Ki values cited here, SEM
was <15% of the derived Ki. Functional assays run on selected compounds
throughout the A2A program indicate that similar triazolopyrimidines are
antagonists with Kb values approximating the binding assay derived Ki values.
In addition, affinity for the rat A1 and A2A receptors did not differ from affinity
for the human receptor.
11. Matasi, J. J.; Caldwell, J. P.; Zhang, H.; Fawzi, A.; Cohen-Williams, M. E.; Varty, G.
B.; Tulshian, D. B. Bioorg. Med. Chem. Lett. 2005, 15, 3670.
12. (a) Zhang, Z.; Tellew, J. E.; Luo, Z.; Moorjani, M.; Lin, E.; Lanier, M. C.; Chen, Y.;
Williams, J. P.; Saunders, J.; Lechner, S. M.; Markison, S.; Joswig, T.; Petroxki, R.;
Piercey, J.; Kargo, W.; Malany, S.; Santos, M.; Gross, R. S.; Wen, J.; Jalali, K.;
O’Brien, Z.; Stotz, C. E.; Crespo, M. I.; Diaz, J.-L.; Slee, D. H. J. Med. Chem 2008, 51,
7099; (b) Kalgutkar, A. S.; Soglia, J. R. Exp. Opin. Drug Metab. Toxicol 2005, 1, 91;
(c) Dalvie, D. K.; Kalgutkar, A. S.; Khojasteh-Bakht, S. C.; Obach, R. S.; O’Donnell,
J. P. Chem. Res. Toxicol 2002, 15, 269.
17. Inhibition of haloperidol-induced catalepsy is an in vivo assay used to evaluate
Parkinson’s drugs (>30% inhibition is considered to be active in this assay).
Procedure described in: Ref 11.
18. Synthesis of compound 15 disclosed in: Neustadt, B. R.; Hao, J.; Liu, H.; Boyle, C.
D.; Chackalamannil, S.; Shah, U.; Stamford, A.; Harris, J. M. U.S. 2005/0239795
A1.
19. Compounds 17, 18, and 37 were the result of DBU induced elimination of the
appropriate chloroethyl-derivative.
13. (a) The solubility of preladenant as the crystalline free base in water was
0.2
l
M at native pH (5.1). A single measurement at pH 7.4 gave solubility
20. Procedure described in: Cox, K. A.; Dunn-Meynell, K.; Korfmacher, W. A.;
Broske, L.; Nomeir, A. A.; Lin, C.-C.; Cayen, M. N.; Barr, W. H. Drug Discov. Today
1999, 4, 232.
below 10 ng/mL. (b) A detailed description of the solubility assay is provided
in: Shah, U.; Boyle, C. D.; Chackalamannil, S.; Neustadt, B. R.; Lindo, N.;
Greenlee, W. J.; Foster, C.; Arik, L.; Zhai, Y.; Ng, K.; Wang, S.; Monopoli, A.;
Lachowicz, J. E. Bioorg. Med. Chem. Lett 2008, 18, 4199. Ref. 13.