Substituted benzoxazinones as potent positive allosteric AMPA receptor modulators: Part II

Article abstract of DOI:10.1016/j.bmcl.2011.05.024

AMPA receptors (AMPARs) are an important therapeutic target in the CNS. A series of substituted benzoxazinone derivatives with good to very good in vitro activity as positive allosteric AMPAR modulators was synthesized and evaluated. The appropriate substituent choice on the benzoxazinone fragment improved the affinity towards the AMPA receptor significantly in comparison to our lead molecule CX614.

Full text of DOI:10.1016/j.bmcl.2011.05.024

Bioorganic & Medicinal Chemistry Letters 21 (2011) 3927–3930
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Substituted benzoxazinones as potent positive allosteric AMPA receptor
modulators: Part II
⇑
Rudolf Mueller , Stanislaw Rachwal, Martina E. Tedder, Yong-Xin Li, Sheng Zhong, Aidan Hampson,
Jolanta Ulas, Mark Varney, Lena Nielsson, Gary Rogers
Cortex Pharmaceuticals Inc., 15231 Barranca Parkway, Irvine, CA 92618, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
AMPA receptors (AMPARs) are an important therapeutic target in the CNS. A series of substituted
benzoxazinone derivatives with good to very good in vitro activity as positive allosteric AMPAR modulators
was synthesized and evaluated. The appropriate substituent choice on the benzoxazinone fragment
improved the affinity towards the AMPA receptor significantly in comparison to our lead molecule CX614.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 17 March 2011
Revised 6 May 2011
Accepted 9 May 2011
Available online 14 May 2011
Keywords:
AMPA
Receptor
Modulator
Synthesis
(
L
)-Glutamic acid, the main excitatory neurotransmitter in the
O
O
O
O
CNS, operates through two main groups of postsynaptic receptors:
metabotropic Glu receptors (mGluRs) and ionotropic Glu receptors
(iGluRs). Each of these is further divided into subgroups, with the
O
O
O
N
N
N
R
O
iGluRs consisting of N-methyl-
D-aspartic acid (NMDA), kainic acid
(KA) and -amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid
a
CX 614
EC2x: 2.3 µM
Benzoxazines
(AMPA) receptors. The AMPA subtype mediates fast excitatory
neurotransmission in the mammalian central nervous system.
Positive allosteric modulators of these AMPA receptors (AM-
PARs) have been the subject of a wealth of studies and reviews.1–
Figure 1. Modification of the lead CX614 into benzoxazinones.
neurotrophic factor44–47 (BDNF), promoting synaptic plasticity
and neuronal survival in animal models of brain injury.
24
The therapeutic potential of these compounds for a range of
psychiatric and neurologic disorders such as attention deficit
hyperactivity disorder (ADHD), Schizophrenia, Huntington’s, Par-
kinson’s and Alzheimer’s disease or mood disorders is signifi-
cant.25–32 In the search for drug candidates to treat these
diseases, a range of positive AMPAR modulators (AMPAKINEÒs)
have been synthesized in our laboratories. During optimization
studies, we discovered that benzoxazines which have appropri-
ately substituted side-chains are potent AMPAR modulators.33,34
Instead of affecting glutamate binding itself, these molecules mod-
ulate the rate constants for transmitter binding, channel opening
and/or desensitisation. It was shown, that AMPAKINEÒs facilitate
the induction of long term potentiation (LTP), which is considered
a key element in learning and memory formation and therefore
might allow the development of cognitive enhancers.35–43 AMPA-
KINEÒs can also upregulate the production of brain derived
We wish to report the optimization of a series of benzoxazinone
derivatives based on our lead molecule CX614 (Fig. 1), which has
been studied extensively.1–5 As shown previously,34 replacement
of the 1,4-dioxine unit with a 1,3-oxazin-4-one ring, substituted
with simple alkyl sidechains, allowed us to rapidly modify and
investigate the role of substituents (R) in regard to their influence
on AMPAR activity. In this study, we describe the investigation of
more complex alkyl sidechains, substituted with heteroatoms,
aryl- and heteroaryl groups.
The affinity of these compounds to displace a Cortex tritated
AMPAKINE radioligand from the cyclothiazide AMPAR binding site
in rat forebrain cell membranes was measured. In addition the po-
tency and efficacy of the compounds on cultured rat embryonic hip-
pocampal neurons in a patch clamp electrophysiology assay
(measured as EC2x) was used as a guideline to optimize this class
of AMPAR modulators.34 The general synthetic route for the synthe-
sis of the benzoxazinones was performed as outlined in Scheme 1.
⇑
Corresponding author.
E-mail address: rudolfmueller@yahoo.com (R. Mueller).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.05.024

3928
R. Mueller et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3927–3930
O
O
the effect of heteroatoms and unsaturation, despite the potential
safety issues introducing these groups.
O
HO
O
HO
O
i
N
O
This led to other changes, such as phenyl rings, attached
through alkyl linkers, which were also explored (Fig. 2). Although
the phenyl analogue 5 was inactive, incorporating an alkyl linker
significantly improved activity, with the 2 carbon linked analogue
7a having the highest potency. Since the phenethyl derivative 7a
exhibited 10-fold higher activity compared to CX614 and was
equal to 4a, we investigated substituents on the aromatic system
in order to optimize binding to the receptor (Table 2).
The investigational drugs 7a–7r were synthesized in acceptable
to good yields (38–90%), using the appropriately substituted phen-
ethylamine derivatives, following the reaction sequence shown be-
fore (Scheme 1). Based on derivatives 7b–7g, it became clear, that a
substituent in the 3-position is favorable, whereas in the 2- and
4-positions it is detrimental for activity. It can also be seen, that
polar derivatives such as the amide 7m, do not work well, whereas
the less polar thioamide 7n is 12 times more active and the least
polar nitrile 7o is the most active in this group.
O
O
OH
2
1
ii
iii
iv
O
O
O
O
HO
O
N
N
H
N
N
X(CH2)n
O
X(CH2)n
O
3
4
Scheme 1. Synthesis of benzoxazinones: Reagents and conditions: (i) 1.0 equiv 1,
1.6 equiv 4-aminobutyraldehyde diethylacetal, 120 °C, 7 min; HCl, 20 °C, 60 min,
64–71% 2; (ii) 15 equiv KOH, MeOH/water, 1.5 h, 50 °C; (iii) 1.0 equiv DMAP,
1.0 equiv HOBT, 2.5 equiv NEt3, 2.0 equiv EDCI, 1.3 equiv amine, DMF, 20 °C, 4 h;
(iv) CHCl3, excess trioxane, cat. H2SO4, 2 h, 70 °C 20–90% 4a–4s (three steps).
Small electron withdrawing substituents in the 3-position are
preferable (7c, f, o, p), compared to electron donating groups
(7i). This lead to the 3,5-difluoro derivative 7r, which exhibited a
460-fold higher activity in comparison to CX614.
The commercially available diethyl 2,5-dihydroxy-terephthal-
ate 1 was transformed into the benzoxazinone 2, simply by heating
it together with 4-aminobutyraldehyde diethylacetal, followed by
ringclosure under acidic conditions. This versatile starting material
was prepared in larger quantities (ꢀ50 g) and was easily trans-
formed into the amides 3 by ester hydrolysis, followed by standard
amide formation, using the appropriate amine. Ring closure under
acidic conditions, using trioxane as a formaldehyde source yielded
the target compounds 4a–4r in acceptable to good yields (20–90%,
Table 1).
Since simple alkyl substituents (4a), attached to the benzoxaz-
inone scaffold, exhibited improved activity in comparison to
CX614, we investigated a series of similar derivatives with hetero
atoms incorporated in the side chain. Groups with increased polar-
ity, as exemplified in compounds 4b, 4h and 4s, had a detrimental
effect on AMPAR activity. In contrast, the unsaturated, nitrogen
containing analogs, the thiocyanate (4g), the azide (4i) and the ni-
trile (4p) exhibit higher potency in the EC2x assay and increased
amplitude of the excitatory postsynaptic potential (EPSP) in the
slice assay.34 These substituents were introduced into the side-
chain, because they are small and allowed us to rapidly determine
Based on the enhanced activity of some of the phenethyl deriva-
tives we anticipated that heteroaromatic substituents as shown in
Table 3 would also work well. The synthesis of these derivatives
was accomplished following the procedures outlined in Scheme 1,
using the appropriately substituted ethylamine derivative, or
following an alternative route, introducing the heterocycle at the
end of the synthesis (Scheme 2). In this procedure ethanolamine
was incorporated into the molecule, to form 9 and subsequently
10. This route has the advantage, that the alcohol function could
now be transformed into a leaving group followed by substitution
with a heterocycle of our choice. In some cases, depending on the
heterocycle, Mitsunobu conditions worked as well. This approach
allowed us to quickly synthesize a variety of interesting derivatives.
All three pyridyl isomers 11a–11c have comparable activity to
the phenyl derivative 7a, however the position of the nitrogen is
not as relevant as substituents in the phenyl series (compare to
7b–7d). A series of five-membered heterocyclic systems was also
investigated. The isoxazolyl derivative 11f is slightly less active
than 7a, whereas the thiophene isomers 11d and 11e are some
of the most potent AMPAR potentiators identified.
Table 1
Comparison of the imidazoles 11o and 11p demonstrates, that
the position of attachment of the imidazole ring is important for
activity, with the nitrogen linked analogue 11p being 100-fold
more active than the carbon liked derivative 11o, most likely due
Influence of O, S and N-substituents on AMPAR activity
a
Substituent
EC2x
(
lM)
Slice Ampl.b% (
lM)
Kic
(lM)
4a
4b
4c
4d
4e
4f
4g
4h
4i
CH3CH2–
HO(CH2)2–
0.2
1.3
1.2
17[10]
—
14[10]
12[3]
14[3]
6[3]
20
33
41
17
13
20
1
51
5.9
8.4
31
34
17
11
6.8
4.5
51
MeO(CH2)2–
MeS(CH2)2–
MeSO(CH2)2–
MeSO2(CH2)2–
NCS(CH2)2–
NCNH(CH2)2–
N3(CH2)2–
MeSO2NH(CH2)2–
MeSO2NMe(CH2)2–
MeSO2NMe(CH2)3–
NC(CH2)–
0.29
0.11
0.32
0.06
1.8
0.08
0.33
0.38
0.33
0.5
O
O
O
O
O
O
O
N
N
7[3]
N
2[10]
16[3]
10[3]
8[10]
9[10]
10[10]
19[10]
11[3]
22[10]
6[30]
N
O
4k
4l
5
EC2x: not active
6
EC2x: 6.0 µM
4m
4n
4o
4p
4r
NC(CH2)2–
NC(CH2)3–
NC(CH2)4–
H2NCO(CH2)2–
0.6
O
N
O
O
N
O
0.05
0.11
1.1
O
O
O
4s
N
N
a
EC2x values34 are defined as the concentration of compound required to double
O
the steady-state current induced by glutamate.
b
In vitro slice assay34: percentage increases in the amplitude of fEPSP, recorded
8
EC2x: 3.6 µM
7a
EC2x: 0.25 µM
at indicated concentration (— = no data available).
c
Displacement of tritiated AMPAKINE radioligand in cell membrane preparations
from adult rat forebrain.34
Figure 2. Optimal chain length for aryl-alkyl substituted benzoxazinones.

R. Mueller et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3927–3930
3929
Table 2
O
Influence of aromatic substitution on AMPAR activity
O
O
OH
a
Substituent
EC2x
(
lM)
Slice ampl.b % (
l
M)
Kic
(lM)
12
OH
7a
7b
7c
7d
7e
7f
7g
7h
7i
H-Ph
2-F-Ph
3-F-Ph
4-F-Ph
2-Cl-Ph
3-Cl-Ph
4-Cl-Ph
3-Br-Ph
3-MeO-Ph
3-CF3O-Ph
3-CF3-Ph
3-H2NCO-Ph
3-H2NCS-Ph
3-CN-Ph
3-NO2-Ph
3,5-F2-Ph
0.25
5.4
3[3], 19[30]
—
16[3]
6[30]
—
7[30]
—
—
7.9
36
0.5
—
—
1.8
—
150
69
13
2.5
620
—
3
3.6
0.3
H2N
H2N
HO
HO
0.011
1.2
i
i
O
O
O
ii
ii
7.1
O
O
O
O
C-7
N
0.02
>40
1.6
14
3.0
0.2
5.0
0.4
N
O
O
O
H
H
—
—
14
13
7k
7l
EC2x: 200 µM
EC2x: 2.0 µM
1[30]
—
5[10]
16[3]
8[3]
16[3]
7m
7n
7o
7p
7r
Scheme 3. Synthesis of oxazolo benzoxazinones 13 and 14: Reagents and condi-
tions: (i) 1.0 equiv DMAP, 1.0 equiv HOBT, 2.5 equiv NEt3, 2.0 equiv EDCI, 1.3 equiv
amine; (ii) CHCl3, excess HC(OMe)3, cat. TosOH, 20 min, 110 °C, (main isomers
shown).
0.027
0.015
0.005
a,b,c
See Table 1.
11l–11n) is important, similar to the substituent effect in the phe-
nyl series. This effect is more pronounced in the imidazole series
(11p–11s), which clearly shows, that small electron withdrawing
substituents improve the affinity to the receptor, with the 4-nitro-
imidazole 11r being the most active AMPAR positive modulator
identified to date.
The 1,2,4-triazol derivative 11t exhibits higher in vitro activity
compared to the 1,2,3-triazolyl derivatives 11v and 11w.
In order to validate the findings based on EC2x (single cell
recordings34) and binding data, we also generated rat hippocampal
slice data34 to measure the effect of these experimental drugs on a
network of neurons. In general, for example when 7c, 7o and 7r are
compared, the different datasets are in agreement with each other.
However we also noticed inconsistencies, for example comparing
7d and 7f. The artificial environment used in these in vitro exper-
iments may explain these differences.
Table 3
Influence of hetero aromatic substituents on AMPAR activity
Slice Ampl.b
% ( M)
Kic
M)
a
Substituent
EC2x
(l
M)
l
(
l
11a
11b
11c
11d
11e
11f
11g
11h
11i
2-Pyridyl
3-Pyridyl
4-Pyridyl
Thiophen-2-yl
Thiophen-3-yl
Isoxazol-3-yl
Pyrazol-1-yl
3-Cyanopyrazol-1-yl
4-Cyanopyrazol-1-yl
5-Cyanopyrazol-1-yl
4-Bromopyrazol-1-yl
4-Chloropyrazol-1-yl
4-Nitropyrazol-1-yl
Imidazol-4-yl
0.6
0.2
15[30]
15[3]
3[3], 15[10]
—
15[3]
4[3]
15[3]
10[3]
29[3]
16[3]
32[3]
23[1]
29[1]
—
38[10]
19[0.3]
—
31[3]
14[3]
8[1]
130
6.6
43
2
0.27
41
5.1
18
1
0.24
0.032
0.02
0.4
0.064
0.1
0.04
0.045
0.02
0.0037
0.0065
5.1
0.05
0.0007
1.8
11k
11l
22
2.5
0.33
0.24
225
6.6
0.06
227
2.1
4.2
5.1
62
11m
11n
11o
11p
11r
11s
11t
11u
11v
11w
When some pyrrolo benzoxazine derivatives were separated
into enantiomers (by chiral HPLC), they exhibited a clear difference
in affinity, with the active isomer being approximately 100-fold
more potent than the inactive. Unfortunately, we were not able
to obtain suitable crystals for X-ray analysis of the 3D structure
of these compounds.
Imidazol-1-yl
4-Nitroimidazol-1-yl
2-Methylimidazol-1-yl
1,2,4-Triazol-1-yl
3-Nitro-1,2,4-triazol-1-yl
Triazol-1-yl
0.063
0.01
0.16
0.8
Triazol-2-yl
7[3]
A very similar series of oxazolo benzoxazinones was synthe-
sized, starting with salicylic acid 12, utilising the chiral 1-amino-
propan-2-ols as shown in Scheme 3. The main isomers of each
reaction (13 and 14) had therefore a fixed stereocenter at C-7
and enabled determination of stereochemistry at the newly formed
stereocenter using NMR spectroscopy (NOE). Isomer 14 (Scheme 3)
is the more active enantiomer, which led to the inference, that the
active enantiomer in the pyrrolo benzoxazinone series is the R-
isomer, based on the fact, that the 3-dimensional shape of the cor-
responding molecules is essentially the same (we found that
methyl substituents attached to C-7 minimally influence affinity).
In summary, the introduction of a heterocyclic system in com-
bination with small electron withdrawing substituents and the 2
carbon spacer, leads to significant improvements in activity. The
nitroimidazole 11r, exhibits 3000-fold higher activity compared
to our starting lead compound CX614, and is one of the most po-
tent potentiators of the AMPAR reported to date. When the
in vitro binding data, EC2x and slice data are compared, we found
that the datasets are generally in agreement which each other.
a,b,c
See Table 1.
O
O
O
O
i
HO
O
HO
N
N
OH
H
N
O
O
2
9
iv
ii
O
O
O
O
O
O
O
N
iii
OH
Het
N
N
N
O
11
10
Scheme 2. Synthesis of benzoxazinones: Reagents: (i) 1..0 equiv 2, 3 equiv etha-
nolamine, 140 °C, 60 min, 93% 9; (ii) (a)isobutyric anhydride; (b) CHCl3, excess
trioxane, cat. H2SO4, 1 h, 70 °C; (c) KOH, MeOH 62% 10; (iii) MesCl, NEt3 then
heterocycle/NaH/DMF; (iv) conditions: see Scheme 1.
Acknowledgments
to the negative influence of the polar NH. The position of substitu-
tion on the pyrazole system seems to have almost no effect, com-
paring 11g–11k, however the nature of the substituent (11g, 11i,
The authors acknowledge Dr. Alex A. Cordi and Dr. Philippe
Hennig for their help determining the absolute configuration of
13 and 14.

3930
R. Mueller et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3927–3930
Morrow, J. A.; Pantling, J.; Rankovic, Z.; Smith, L. Bioorg. Med. Chem. Lett. 2011,
References and notes
21, 805.
22. Jamieson, C.; Campbell, R. A.; Cumming, I. A.; Gillen, K. J.; Gillespie, J.;
Kazemier, B.; Kiczun, M.; Lamont, Y.; Lyons, A. J.; Maclean, J. K. F.; Martin, F.;
Moir, E. M.; Morrow, J. A.; Pantling, J.; Rancovic, Z.; Smith, L. Bioorg. Med. Chem.
Lett. 2010, 20, 6072.
23. Jamieson, C.; Basten, S.; Campbell, R. A.; Cumming, I. A.; Gillen, K. J.; Gillespie,
J.; Kazemier, B.; Kiczun, M.; Lamont, Y.; Lyons, A. J.; Maclean, J. K. F.; Moir, E.
M.; Morrow, J. A.; Papakosta, M.; Rancovic, Z. Bioorg. Med. Chem. Lett. 2010, 20,
5753.
24. Cannazza, G.; Jozowiak, K.; Parenti, C.; Braghiroli, D.; Carrozzo, M. M.; Puia, G.;
Losi, G.; Baraldi, M.; Lindnaer, W.; Wainer, I. W. Bioorg. Med. Chem. Lett. 2009,
19, 1254.
25. Marenco, S.; Weinberger, D. R. C. N. S. Drugs 2006, 20, 173.
26. Alt, A.; Nisenbaum, E. S.; Bleakman, D.; Witkin, J. M. Biochem. Pharmacol. 2006,
77, 1273.
27. Kanju, P. M.; Parameshwaran, K.; Sims, C.; Bahr, B. A.; Shonesy, B. C.;
Suppiramaniam, V. Exp. Neurology 2008, 214, 55.
28. O’Neill, M. J.; Bleakman, D.; Zimmerman, D. M.; Nisenbaum, E. S. Curr. Drug
Targets CNS Neurol. Disord. 2004, 3, 181.
29. Sanacora, G.; Zarate, C. A.; Krystal, J. H.; Manji, H. K. Nature Rev. 2008, 7, 426.
30. Hashimoto, K. Brain Res. Rev. 2009, 61, 105.
31. Bloss, E. B.; Hunter, R. G.; Waters, E. M.; Munoz, C.; Bernard, K.; McEwen, B. S.
Exp. Neurology 2008, 210, 109.
32. Murray, T. K.; Whalley, K.; Robinson, C. S.; Ward, M. A.; Hicks, C. A.; Lodge, D.;
Vandergriff, J. L.; Baumbarger, P.; Siuda, E.; Gates, M.; Ogden, A. M.; Skolnick,
P.; Zimmerman, D. M.; Nisenbaum, E. S.; Bleakman, D.; O’Neill, M. J. J.
Pharmaco. Exp Ther. 2003, 306, 752.
33. Rogers, G. A.; Allan, M.; Harris, C.; Huang, J.; Marrs, C. M.; Mueller, R.; Rachwal,
S. US7799913, 2010.
34. Mueller, R.; Li, Y.X.; Hampson, A.; Zhong, S.; Harris, C.; Marrs, C.; Rachwal, S.;
Ulas, J.; Nielsson, L.; Rogers, G, M.; Bioorg. Med. Chem. Lett. 2011, preceding
paper.
35. Lynch, G. Curr. Opin. Pharmacol. 2004, 4, 4.
36. Lynch, G.; Gall, C. M. Trends Neurosci. 2006, 29, 554.
37. O’Neill, M. J.; Dix, S. IDrugs 2007, 10, 185.
38. Arai, A.; Kessler, M.; Rogers, G.; Lynch, G. J. Pharmacol. Exp. Ther 1996, 278, 627.
39. Staubli, U.; Rogers, G.; Lynch, G. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 777.
40. Raymond, C. R. Trends Neurosci. 2007, 30, 167.
41. Lamprecht, R.; LeDoux, J. Nature Rev. Neurosci. 2004, 5, 45.
42. Lynch, M. A. Physiol. Rev. 2004, 84, 87.
1. Morrow, J. A.; Maclean, J. K. F.; Jamieson, C. Curr. Opin. Drug Disc. Dev. 2006, 19,
571.
2. Jin, R.; Clark, S.; Weeks, A. M.; Dudman, J. T.; Gouaux, E.; Partin, K. M. J. Neurosci.
2005, 25, 9027.
3. Arai, A. C.; Kessler, M. Curr. Drug Targets 2007, 8, 583.
4. Harpsøe, K.; Liljefors, T.; Balle, T. J. Mol. Graph. Modell. 2008, 26, 874.
5. Harpsøe, K.; Varming, T.; Gouliaev, A. H.; Peters, D.; Liljefors, T. J. Mol. Graph.
Modell. 2007, 26, 213.
6. Sun, Y.; Olson, R.; Horning, M.; Armstrong, N.; Mayer, M.; Gouaux, E. Nature
2002, 417, 245.
7. Arai, A. C.; Xia, Y.-F.; Rogers, G.; Lynch, G.; Kessler, M. J. Pharmacol. Exp. Ther.
2002, 303, 1075.
8. Francotte, P.; De Tullio, P.; Goffin, E.; Dintilhac, G.; Graindorge, E.; Fraikin, P.;
Lestage, P.; Danober, L.; Thomas, J. Y.; Caignard, D. H.; Pirotte, B. J. Med. Chem.
2007, 50, 3153.
9. Francotte, P.; Tullio, P.; Podona, T.; Diouf, O.; Fraikin, P.; Lestage, P.; Danober, L.;
Thomas, J.-Y.; Caigard, D.-H.; Pirotte, B. Bioorg. Med. Chem. 2008, 16, 9948.
10. Zarrinmayeh, H.; Bleakman, D.; Gates, M. R.; Yu, H.; Zimmerman, D. M.;
Ornstein, P. L.; McKennon, T.; Arnold, M. B.; Wheeler, W. J.; Skolnick, P. J. Med.
Chem. 2001, 44, 302.
11. Magnus, N. A.; Stazak, M. A.; Udodong, U. E.; Wepsiec, J. P. Org. Process Res. Dev.
2006, 10, 899.
12. Phillips, D.; Sonnenberg, J.; Arai, A. C.; Vaswani, R.; Krutzik, P. O.; Kleisli, T.;
Kessler, M.; Granger, R.; Lynch, G.; Chamberlin, A. R. Bioorg. Med. Chem. 2002,
10, 1229.
13. Zarrinmayeh, H.; Tromiczak, E.; Zimmerman, D. M.; Rankl, N.; Ho, K. H.;
Dominguez, E.; Castaño, A.; Escribano, A.; Fernandez, C.; Jimenez, A.; Hornback,
W. J.; Nisenbaum, E. S. Bioorg. Med. Chem. Lett. 2006, 16, 5203.
14. Fernandez, M.-C.; Castaño, A.; Dominguez, E.; Escribano, A.; Jiang, D.; Jimenez,
A.; Hong, E.; Hornback, W. J.; Nisenbaum, E. S.; Rankl, N.; Tromiczak, E.;
Vaught, G.; Zarrinmayeh, H.; Zimmerman, D. M. Bioorg. Med. Chem. Lett. 2006,
16, 5057.
15. Ptak, C. P.; Ahmaed, A. H.; Oswald, R. E. Biochemistry 2009, 8594.
16. Thewlis, K. M.; Aldegheri, L.; Harries, M. H.; Mookherjee, C.; Oliosi, B.; Ward, S.
E. Bioorg. Med. Chem. Lett. 2010, 16, 7116.
17. Ward, S. E.; Harries, M.; Aldegheri, L.; Austin, N. E.; Ballantine, S.; Ballini, E.;
Bradley, D. M.; Bax, B. D.; Clarke, B. P.; Harris, A. J.; Harrison, S. A.; Melarange, R.
A.; Mookherjee, C.; Mosley, J.; Dal Negro, G.; Oliosi, B.; Smith, K. J.; Thewlis, K.
M.; Woolard, P. M.; Yusaf, S. P. J. Med. Chem. 2011, 54, 78.
18. Ward, S. E.; Harries, M.; Aldegheri, L.; Andreotti, D.; Ballantine, S.; Bax, B. D.;
Harris, A. J.; Harker, A. J.; Lund, J.; Melarange, R.; Mingardi, A.; Mookherjee, C.;
Mosley, J.; Neve, M.; Oliosi, B.; Profeta, R.; Smith, K. J.; Smith, P. W.; Spada, S.;
Thewlis, K. M.; Yusaf, S. P. J. Med. Chem. 2010, 53, 5801.
19. Ward, S. E.; Bax, B. D.; Harries, M. Br. J. Pharmacol. 2010, 160, 181.
20. Grove, S. J. A.; Jamieson, C.; Maclean, J. K. F.; Morrow, J. A.; Rancovic, Z. J. Med.
Chem. 2010, 53, 7271.
21. Jamieson, C.; Maclean, J. K. F.; Brown, C. I.; Campbell, R. A.; Gillen, K. J.;
Gillespie, J.; Kazemier, B.; Kiczun, M.; Lamont, Y.; Lyons, A. J.; Moir, E. M.;
43. Zivcovic, I.; Thompson, D. M.; Bertolino, M.; Uzunov, D.; Dibella, M.; Costa, E.;
Guidotti, A. J. Pharmacol. Exp. Ther. 2009, 272, 300.
44. Lauterborn, J. C.; Lynch, G.; Vanderklish, P.; Arai, A.; Gall, C. M. J. Neurosci. 2000, 8.
45. Lauterborn, J. C.; Pineda, E.; Chen, L. Y.; Ramirez, E. A.; Lynch, G.; Gall, C. M.
Neuroscience 2009, 159, 283.
46. Lauterborn, J. C.; Troung, G.; Baudry, M.; Bi, X.; Lynch, G.; Gall, C. J. Pharmacol.
Exp. Ther. 2003, 307, 297.
47. Clarkson, A. N.; Overman, J. J.; Zhong, S.; Mueller, R.; Lynch, G.; Carmichael, S. T.
J. Neurosci. 2011, 31, 3766.