Synthesis and structure-activity relationship of N-(3-azabicyclo[3.1.0]hex- 6-ylmethyl)-5-(2-pyridinyl)-1,3-thiazol-2-amines derivatives as NPY Y5 antagonists

Article abstract of DOI:10.1016/j.bmcl.2010.06.140

A novel class of small molecule NPY Y5 antagonists based around an azabicyclo[3.1.0]hexane scaffold was identified through modification of a screening hit. Structure-activity relationships and efforts undertaken to achieve a favourable pharmacokinetic profile in rat are described.

Full text of DOI:10.1016/j.bmcl.2010.06.140

Bioorganic & Medicinal Chemistry Letters 20 (2010) 4741–4744
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and structure–activity relationship
of N-(3-azabicyclo[3.1.0]hex-6-ylmethyl)-5-(2-pyridinyl)-1,3-thiazol-2-amines
derivatives as NPY Y5 antagonists
*
*
Matteo Biagetti , Colin Philip Leslie , Angelica Mazzali, Catia Seri, Domenica Antonia Pizzi,
Jonathan Bentley , Thorsten Genski à, Romano Di Fabio, Laura Zonzini, Laura Caberlotto
GlaxoSmithKline, Neurosciences Centre of Excellence for Drug Discovery, Medicines Research Centre, Verona, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel class of small molecule NPY Y5 antagonists based around an azabicyclo[3.1.0]hexane scaffold was
identified through modification of a screening hit. Structure–activity relationships and efforts undertaken
to achieve a favourable pharmacokinetic profile in rat are described.
Received 14 June 2010
Revised 25 June 2010
Accepted 29 June 2010
Available online 1 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Neuropeptide Y
NPY Y5
Antagonists
Neuropeptide Y (NPY) is a member of the pancreatic polypep-
tide family that also includes pancreatic polypeptide (PP) and pep-
tide YY (PYY).1–3 NPY is one of the most abundant neuropeptides in
the CNS of both humans and rodents4,5 and is a potent orexigenic
factor.6,7
receptors in the regulation of addictive behaviours.31 A screening
campaign of our corporate compound collection generated a num-
ber of promising chemotypes from which the aminothiazolepyri-
dine 1 was identified as an efficient, orally bioavailable and brain
penetrant Y5 antagonist (Fig. 1). A direct comparison of compound
1 with the structure of known Y5 antagonists21,23 revealed some
recurrent pharmacophoric features and suggested that the oppor-
tunity to further optimise this molecule lay with the modification
of the N-phenyl side chain.
Herein, we report structure–activity relationship (SAR) studies
undertaken in an effort to develop a novel class of NPY Y5 antago-
nists from 1.
Amongst a number of compounds prepared from commercially
available 4-(2-pyridinyl)-1,3-thiazol-2-amine 2, the azabicyclo-
hexane derivatives 3 showed appealing Y5 antagonist activities
(Fig. 2).
Its anatomical localisation and preclinical studies suggest that
NPY may be involved in a variety of physiological responses such
as food intake, water consumption, emotional behaviour, circadian
rhythms, endocrine and cardiovascular functions.8–10 In particular
a wealth of preclinical evidence points to a key role of NPY in the
regulation of both feeding behaviour and energy expenditure,
and hence agents modulating the interactions of NPY and its recep-
tors could provide novel centrally mediated treatments for eating
disorders.11–16 Of the five NPY receptors cloned to date (Y1, Y2,
Y4, Y5 and y6), the Y5 subtype has been one of the main candidates
implicated in mediating this physiological role of NPY. Accordingly,
many pharmaceutical companies have targeted antagonists of the
Y5 receptor for the treatment of obesity,17–28 although the results
of clinical trials reported to date have shown modest efficacy.29,30
Recently, emerging studies address a further role of NPY Y5
Despite the specific orientation of the end-capping carbamate
moiety dictated by the rigid [3.1.0] bicyclic linker both the endo
and the corresponding exo isomer of 3 were found to demonstrate
low-nanomolar NPY Y5 activity.
hNPY Y5 fpKi 7.8
N
* Corresponding authors. Tel.: +39 045 8218806; fax: +39 045 8218196 (M.B.);
tel.: +39 045 8218546; fax: +39 045 8218196 (C.P.L.).
E-mail addresses: matteo.2.biagetti@gsk.com (M. Biagetti), colin.p.leslie@gsk.-
com, colin.p.leslie@gmail.com (C.P. Leslie).
CF3
S
hNPY Y1/2 fpKi < 4.5
CYP450 1A2 < 0.1 uM
Clb 27 ml/min/kg
N
N
H
Present address: Evotec AG, 114 Milton Park, Abingdon, Oxfordshire, United
Kingdom.
F = 30%
B/B 4.2
1
à
Present address: AnalytiCon Discovery GmbH, Hermannswerder Haus 17, 14473
Potsdam, Germany.
Figure 1. Structure of hit compound 1.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.06.140

4742
M. Biagetti et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4741–4744
mide 8 in the presence of N-phenyl-tris(dimethylamino)imino-
phosphorane (BEMP) produces a readily separable mixture of
exo-10 and endo-10 in a ꢀ1:3.5 ratio. It is noteworthy that while
the use of a number of both organic and inorganic bases (Table 1,
entries 1–5) resulted ineffective to promote the cyclopropanation
of maleimide 8, as previously reported by Mikołajczyk and
co-workers.33 DBU successfully afforded the endo isomer (entry
6), albeit with lower yield compared to BEMP (entry 7) (Table 1).
endo-10 was readily converted into the Boc protected derivative
endo-7 by reduction with LiAlH4, then Pd-catalysed removal of the
benzyl group under a H2 atmosphere and in situ protection with
Boc anhydride, followed by oxidation with Dess–Martin
periodinane.
H
H
N
N
N
N
Boc
N
S
H
N
endo-3
hNPY Y5 fpKi 8.9
S
N
NH2
H
H
N
2
N
Boc
N
S
H
exo-3
hNPY Y5 fpKi 8.5
Figure 2. Structure of lead compound endo-3.
Finally, aldehydes exo-7 and endo-7 led to the required scaffolds
exo-11 and endo-11 through reductive amination promoted by Ti-
Cl(OiPr)3. Removal of the Boc groups afforded amines exo-12 and
endo-12, that were converted into the corresponding amides exo-
14 and endo-14 under standard conditions. Reductive amination
in the presence of a suitable aldehyde gave amines exo-13 and
endo-13 (Scheme 2).
The SAR exploration mainly focused on the amide decoration
and resulted in a fair number of potent derivatives supporting
the interesting potential of the new [3.1.0] linker (Table 2).
Indeed, it was found that a wide diversity of capping amides
was well tolerated. With the exception of the inactive methyl
derivative endo-15, both aliphatic and aromatic amides showed
very high NPY Y5 activities in the low- to sub-nanomolar range.
The profile of the amide endo-16 was also supported by a reason-
Although a preference is evident for the endo isomer, the fact
that the receptor is able to accommodate such differing conforma-
tional limitations substantiates the original proposition that this
area of the pharmacophore is the most tolerant to modification.
The stereoselective synthesis of the 3-azabicyclo[3.1.0]hexane
linker was achieved by two different synthetic strategies (Scheme
1). Commercially available 3-pyrroline (4) was protected with Boc
anhydride, and then reacted with ethyl diazoacetate (EDA), added
over 60 h by means of a syringe pump, in the presence of 5 mol % of
[Rh(OAc)2]2 to afford a mixture of the two isomers exo-6 and endo-
6 in a ꢀ3:1 ratio, that could be separated by silica gel chromatog-
raphy. Reduction of compounds exo-6 and endo-6 with LiAlH4
followed by oxidation with the Dess–Martin reagent afforded the
required aldehydes exo-7 and endo-7 with good yields. The
replacement of hazardous EDA with diphenylsulfonium (methoxy-
carbonyl)methylide allowed inversion of the stereochemical out-
come of the cyclopropanation step to favour the more active
endo isomer. Indeed, the reaction of sulfonium salt32 9 with malei-
able solubility (120 lg/ml, determined using a high throughput
Table 1
Reaction of the diphenylsulfonium salt 9 with maleimide 8
Entry
Base
Solvent
T (°C)
Yield (exo-10/endo-10)
1
2
3
4
5
6
7
LDA
NaH
K2CO3/NaOH
Et3N
LHMDS
DBU
THF
THF
rt
rt
45
rt
rt
rt
rt
—/—
—/—
—/—
—/—
0/14
10/37
17/61
Acetone
DCM
THF
DCM
DCM
COOEt
H
COOEt
H
(a)
(b)
H
H
+
N
Boc
N
H
BEMP
N
Boc
endo-6
N
Boc
exo-6
4
5
NH2
N
O
H
(c), (d)
H
(c), (d)
H
S
N
N
H
(a)
N
H
O
H
S
O
+
H
H
N
N
N
Boc
H
R
endo-7
exo-7
N
Boc
exo-7
N
endo-11 R = Boc
endo-12 R = H
2
(b)
(b)
Boc
endo-7
exo-11 R = BOC
exo-12 R = H
(f), (g), (d)
(d)
(c)
COOEt
COOEt
H
Ph
S
(e)
+
Ph
COOEt
BF4-
H
H
H
H
H
+
O
+
O
N
N
N
N
N
O
O
O
N
Bn
O
N
Bn
N
N
H
H
S
S
Bn
H
H
endo-10
exo-10
8
9
N
N
R1
R2
endo-13
exo-13
endo-14
exo-14
Scheme 1. Reagents and conditions: (a) (Boc)2O (1.05 equiv), DCM, rt 80%; (b) ethyl
diazoacetate (1.3 equiv), [Rh(OAc)2]2 5 mol %, DCM, syringe pump over 60 h, 3:1
exo:endo, 38% combined yield; (c) LiAlH4 (0.75 equiv), THF, rt, 1 h, 90%; (d) Dess–
Martin periodinane (1.2 equiv), DCM, rt, 90%; (e) BEMP (1.4 equiv), DCM, rt, 18 h,
1:3.5 exo:endo, 78% combined yield; (f) LiAlH4 (2.4 equiv), THF, 70 °C, 30 min, 83%;
(g) Pd(OH)2 (20% w/w), H2, (Boc)2O (1.2 equiv) EtOH, rt, 5 h, 100%.
O
Scheme 2. Reagents and conditions: (a) TiCl(OiPr)3 (1.5 equiv), NaBH(OAc)3
(4 equiv), DCM, rt; (b) TFA (10 equiv), DCM, rt, 95%; (c) acid chloride R2COCl
(1.05 equiv), Et3N (2 equiv), DCM, 0 °C; (d) aldehyde R1CHO (1.1 equiv), NaBH(OAc),
DCM, rt.

M. Biagetti et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4741–4744
4743
Table 2
Y5 activities of amide derivatives, clog P and in vitro metabolic stability
Table 4
Y5 activities of amine derivatives, clog P and in vitro metabolic stability
Compds
R2
hNPY Y5
fpKia
Clint h/rb
clog Pc
Compds
R1
hNPY Y5
fpkia
Clint h/rb
clog Pc
endo-15
endo-16
exo-17
endo-17
endo-18
endo-19
endo-20
endo-21
exo-22
endo-22
endo-23
endo-24
exo-25
endo-25
endo-26
endo-27
endo-28
endo-29
endo-30
Me
iPr
Phenyl
Phenyl
3-F-phenyl
3,5-DiF-phenyl
3-Pyridyl
4-Pyridyl
Benzyl
5.6
8.6
7.9
8.6
9.0
8.8
8.3
7.3
9.0
9.0
9.4
9.1
8.2
9.2
8.3
9.1
8.1
8.3
7.5
na
0.4
1.3
2.3
2.3
2.5
2.6
1.2
1.2
2.7
2.7
3.0
3.0
2.5
2.5
3.2
2.6
0.9
1.3
0.1
exo-31
H
iBu
Benzyl
3,5-Dimethyl-benzyl
3,5-DiF-benzyl
1-Phenylethyl
6.0
8.4
8.8
8.4
9.2
8.9
na
2.6/15
na
6/14
5/39
20/31
1.4
1.3
3.6
4.6
3.9
3.9
3/2.3
0.9/0.6
7/3
endo-32
endo-33
endo-34
endo-35
endo-36
9/7
17/11
10/1.9
na
6/3.7
15/15
37/48
31/44
23/17
na
50/50
23/22
0.7/0.7
1.6/0.9
na
a,b,c
See Table 2.
Benzyl
(pIC50 = 5.7), resulted highly cleared in a rat cassette dosing study
(Clb 98 ml/min/kg). The poor correlation between the Clint values
and the in vivo blood clearance observed for both endo-16 and
endo-28 hints that extrahepatic clearance routes may be operating.
In an attempt to better understand the factors responsible for
the high clearance observed with the amide derivatives, and to
generate further insights into the SAR, a number of N-alkylated
derivatives were prepared (Table 4).
1-Phenylethyl
1-Phenylcyclopropyl
2-Phenylethyl
2-Phenylethyl
1-Methyl-2-phenylpropyl
trans-2-Phenylcyclopropyl
3-Tetrahydrofuranyl
2-Tetrahydrofuranyl
4-Tetrahydropyranyl
Generally, these derivatives were as potent as the correspond-
ing amides, suggesting that the carbonyl group most likely was
not involved in a specific interaction within the binding pocket,
or in imparting the active conformation. However, further
in vitro characterisation of these amines showed moderate to high
Clint values and an unacceptable recurring CYP450 inhibition at
the 2D6 isoform, probably attributable to the basic center.35 It is,
however, noteworthy that these compounds, containing a basic
tertiary amine residue, maintain high Y5 potency as the majority
of Y5 antagonists reported in the scientific literature are neutral
at physiological pH.
In summary, a novel series of highly potent, functional NPY Y5
antagonists has been prepared based around a bicyclic [3.1.0] scaf-
fold. An extensive SAR exploration revealed a preference for the
endo-diastereoisomer and lipophilic capping groups alongside a
penchant for high intrinsic clearance. Optimisation of the in vitro
DMPK profile led to the identification of compound endo-28. Not-
withstanding its low intrinsic clearance and respectable physico-
chemical properties endo-28 was found to be highly cleared in
rat, revealing a poor in vitro/in vivo correlation which is currently
under further investigation.
a
The functional activity (fpKi) at the human NPY Y5 receptor stably expressed in
HEK293 cells was assessed using FLIPR/Ca2+ methodology in a 384 well format. Each
determination lies within 0.3 log units of the mean with a minimum of two
replicates.
b
Intrinsic clearance values (Clint) expressed as ml/min/g liver were determined
in human (h) and rat (r) liver microsomes; na = not available.
c
ACD log P version 11.
chemiluminescent nitrogen detection method) low CYP450 inhibi-
tion potential (IC50 P7 lM at 1A2, 2C9, 2C19 and 3A4 isoforms),
and a suitable selectivity profile over a panel of 22 other receptors
and ion channels. Compound endo-16 was further characterised in
in vivo rat cassette dosing PK studies revealing a blood clearance in
excess of liver blood flow (Clb = 137 ml/min/kg) and low oral bio-
availability (F = 6%) (Table 3).34
The endo-phenyl amide 17 confirmed to be more potent than
the corresponding exo-17 analogue but surprisingly it had drasti-
cally higher human and rat Clint values (Clint h/r = 7/3 ml/min/g li-
ver). Although the introduction of fluorine atoms on the phenyl
ring, as in endo-18 and endo-19, was unable to increase signifi-
cantly the potency, replacement with a less lipophilic pyridine
group, endo-20 and endo-21, resulted in a reduction of Y5 activity.
Interestingly, while both benzylamides exo-22 and endo-22 dis-
played equipotent Y5 antagonism, further homologation, leading
to exo-25 and endo-25, restored the prevalent activity of the
endo-analogue observed previously. Unfortunately, all these mod-
ifications were marked by a worsening Clint profile. Attempts to
overcome metabolic liabilities by hindering the benzylic position,
as in endo-23, endo-24, endo-26 and endo-27, were unsuccessful,
leading to higher intrinsic clearances and poor CYP450 profiles
with potent inhibition of the 3A4 isoform.
References and notes
1. Tatemoto, K.; Carlquist, M.; Mutt, V. Nature 1982, 296, 659.
2. Hammond, M. IDrugs 2001, 4, 920.
3. Larhammar, D.; Wraith, A.; Berglund, M. M.; Holmberg, S. K.; Lundell, I. Peptides
2001, 22, 295.
4. Adrian, T. E.; Allen, J. M.; Bloom, S. R.; Ghatei, M. A.; Rossor, M. N.; Roberts, G.
W.; Crow, T. J.; Tatemoto, K.; Polak, J. M. Nature 1983, 306, 585.
5. Dumont, Y.; Martel, J.-C.; Fournier, A.; St-Pierre, S.; Quirion, R. Prog. Neurobiol.
1992, 38, 125.
6. Stanley, B. G.; Leibowitz, S. F. Life Sci 1984, 35, 2635.
7. Clark, J. T.; Kalra, P. S.; Crowley, W. R.; Kalra, S. P. Endocrinology 1984, 115, 427.
8. Herzog, H.; Boey, D.; Lin, S. Neuropeptides 2004, 38, 189.
9. Hokfelt, T.; Broberger, C.; Zhang, X.; Diez, M.; Kopp, J.; Xu, Z.; Landry, M.; Bao,
L.; Schalling, M.; Koistinaho, J.; DeArmond, S. J.; Prusiner, S.; Gong, J.; Walsh, J.
H. Brain Res. Brain Res. Rev. 1998, 26, 154.
Disappointingly, even compound endo-28, characterised by an
attractive in vitro profile, having low intrinsic clearance (Clint h/
r = 0.7/0.7 ml/min/g liver), low CYP450 inhibition potential (IC50
>10 lM at 1A2, 2C9, 2C19 and 3A4 isoforms), low protein binding
(fraction unbound = 26%), excellent selectivity against NPY Y1 and
10. Gerald, C.; Walker, M. W.; Criscione, L.; Gustafson, E. L.; Batzl-Hartmann, C.;
Smith, K. E.; Vaysse, P.; Durkin, M. M.; Laz, T. M.; Linemeyer, D. L.; Schaffhauser,
A. O.; Whitebread, S.; Hofbauer, K. G.; Taber, R. I.; Branchek, T. A.; Weinshank,
R. L. Nature 1996, 382, 168.
Y2 receptors (fpKi <5) and modest activity at the hERG channel
11. Kamiji, M. M.; Inui, A. Endocr. Rev. 2007, 28, 664.
Table 3
Selected DMPK dataa for compounds endo-25 and endo-28
12. Ladyman, S. R.; Woodside, B. Physiol. Behav. 2009, 97, 91.
13. Levens, N. R.; Galizzi, J.-P.; Félétou, M. CNS Neurol. Disord. Drug Targets 2006, 5,
263.
Compds
Clb (ml/min/kg)
B/B rat
WBB%b rat
F%
14. Ishihara, A.; Katani, A.; Mashiko, S.; Tanaka, T.; Hidaka, M.; Gomori, A.; Iwaasa,
H.; Murai, N.; Egashira, S.-I.; Murai, T.; Mitobe, Y.; Matsushita, H.; Okamoto, O.;
Sato, N.; Jitsuka, M.; Fukuroda, T.; Ohe, T.; Guan, X.; MacNeil, D. J.; Van der
Ploeg, L. H. T.; Nishikibe, M.; Ishii, Y.; Ihara, M.; Fukami, T. PNAS 2006, 103,
7154.
endo-16
endo-28
137
98
0.7
<0.5
—
74
6
15
a
In vivo data determined by 0.5 mg/kg iv and 1 mg/kg po administration in rat.
Brain/blood ratio (B/B) determined at 1 h following iv dosing.
15. Marsh, D. J.; Hollopeter, G.; Kafer, K. E.; Palmiter, R. D. Nat. Med. 1998, 4, 718.
16. Larsen, P. J.; Woldbye, D. P. D. Nat. Med. 1998, 4, 671.
b
Whole blood binding was determined in an equilibrium dialysis assay.

4744
M. Biagetti et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4741–4744
17. MacNeil, D. J. Curr. Top. Med. Chem. 2007, 7, 1721.
18. Sato, N.; Ogino, Y.; Mashiko, S.; Ando, M. Expert Opin. Ther. Patents 2009, 19,
1401.
27. Fotsch, C.; Sonnenberg, J. D.; Chen, N.; Hale, C.; Karbon, W.; Norman, M. H. J.
Med. Chem. 2001, 44, 2344.
28. Kordik, C. P.; Luo, C.; Zanoni, B. C.; Levenberg, T. W.; Wilson, S. J.; Vaidya, A.
H.; Crooke, J. J.; Rosenthal, D. I.; Reitz, A. B. Bioorg. Med. Chem. Lett. 2001, 11,
2287.
29. Erondu, N.; Gantz, I.; Musser, B.; Suryawanshi, S.; Mallick, M.; Addy, C.; Cote, J.;
Bray, G.; Fujioka, K.; Bays, H.; Hollander, P.; Sanabria-Bohorquez, S. M.; Eng,
W.; Långström, B.; Hargreaves, R. J.; Burns, H. D.; Kanatani, A.; Fukami, T.;
MacNeil, D. J.; Gottesdiener, K. M.; Amatruda, J. M.; Kaufman, K. D.; Heymsfield,
S. B. Cell Metab. 2006, 4, 275.
30. Erondu, N.; Addy, C.; Lu, K.; Mallick, M.; Musser, B.; Gantz, I.; Proietto, J.;
Astrup, A.; Toubro, S.; Rissannen, A. M.; Tonstad, S.; Haynes, W. G.;
Gottesdiener, K. M.; Kaufman, K. D.; Amatruda, J. M.; Heysmfield, S. B.
Obesity 2007, 15, 2027.
31. Sørensen, G.; Woldbye, D.; Brucker, P. WO 2009/112033A1.
32. Müller, P.; Fernandez, D.; Nury, P.; Rossier, J.-C. Helv. Chim. Acta 1999, 82, 935.
33. Ruano, J. L. G.; Fajardo, C.; Martin, M. R.; Midura, W.; Mikołajczyk, M.
Tetrahedron: Asymmetry 2004, 15, 2475.
34. All work involving animals was carried out in accordance with European
directive 86/609/EEC governing animal welfare and protection, which is
acknowledged by Italian Legislative Decree No. 116, 27 January 1992, and
according to internal review performed by the GlaxoSmithKline Committee on
Animal Research & Ethics (CARE) and to the company Policy on the Care and
Use of Laboratory Animals.
19. Sakamoto, T.; Moriya, M.; Tsuge, H.; Takahashi, T.; Haga, Y.; Nohoshita, K.;
Okamoto, O.; Takahashi, H.; Sakuraba, A.; Hirohashi, T.; Shibata, T.; Kanno, T.;
Ito, J.; Iwaasa, H.; Gomori, A.; Ishihara, A.; Fukuroda, T.; Kanatani, A.; Fukami, T.
Bioorg. Med. Chem. 2009, 17, 5015.
20. Gillman, K. W.; Higgins, M. A.; Poindexter, G. S.; Browning, M.; Clarke, W. J.;
Flowers, S.; Grace, J. E.; Hoga, J. B.; McGovern, R. T.; Iben, L. G.; Mattson, G. K.;
Ortiz, A.; Rassnick, S.; Russel, J. W.; Antal-Zimanyi, I. Bioorg. Med. Chem. 2006,
14, 5517.
21. Nettekoven, M.; Guba, W.; Neidhart, W.; Mattei, P.; Pflieger, P.; Plancher, J.-M.;
Taylor, S. ChemMedChem 2006, 1, 45.
22. Torrens, A.; Mas, J.; Port, A.; Castrillo, J. A.; Sanfeliu, O.; Guitart, X.; Dordal, A.;
Romero, G.; Fisas, M. A.; Sanchez, E.; Hernandez, E.; Perez, P.; Perez, R.;
Bischmann, H. J. Med. Chem. 2005, 48, 2080.
23. Rueeger, H.; Gerspacher, M.; Buehlmayer, P.; Rigollier, P.; Yamaguchi, Y.;
Schmidlin, T.; Whitebread, S.; Nuesslein-Hildesheim, B.; Hanspeter, N.;
Leoluca, C. Bioorg. Med. Chem. Lett. 2004, 14, 2451.
24. Aquino, C. J.; Ramanjulu, J. M.; Heyer, D.; Daniels, A.; Palazzo, F.; Bezube, M.
Bioorg. Med. Chem. 2004, 2691.
25. Elliot, R. L.; Oliver, R. M.; LaFlamme, J. A.; Gillaspy, M. L.; Hammond, M.; Hank,
R. F.; Maurer, T. S.; Baker, D. L.; DaSilva-Jardine, P. A.; Stevenson, R. W.; Mack, C.
C.; Cassella, J. V. Bioorg. Med. Chem. Lett. 2003, 13, 3593.
26. Tabuchi, S.; Itani, H.; Sakata, Y.; Oohashi, H.; Satoh, Y. Bioorg. Med. Chem. Lett.
2002, 12, 1171.
35. Le Bourdonnec, B.; Leister, L. K. Curr. Med. Chem. 2009, 16, 3093.