Identification and optimisation of a series of tetrahydrobenzotriazoles as metabotropic glutamate receptor 5-selective positive allosteric modulators that improve performance in a preclinical model of cognition

Article abstract of DOI:10.1016/j.bmcl.2015.10.050

Herein we describe a series of tetrahydrobenzotriazoles as novel, potent metabotropic glutamate receptor subtype 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of the SAR surrounding the tetrahydrobenzotriazole core ultimately led to the ide

Full text of DOI:10.1016/j.bmcl.2015.10.050

Bioorganic & Medicinal Chemistry Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Identification and optimisation of a series of tetrahydrobenzotriazoles
as metabotropic glutamate receptor 5-selective positive allosteric
modulators that improve performance in a preclinical model of cognition
John M. Ellard a, Andrew Madin a, Oliver Philps a, Mark Hopkin a, Scott Henderson a, Louise Birch a,
Desmond O’Connor c, Tohru Arai d, Kazuma Takase e, Louise Morgan b, David Reynolds b, Sonia Talma b,
Eimear Howley b, Ben Powney b, Andrew H. Payne a, Adrian Hall a, Jane E. Gartlon b, Lee A. Dawson b,
Luis Castro a, Peter J. Atkinson b,
⇑
a Medicinal Chemistry, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK
b Pharmacology, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK
c DMPK, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK
d Next Generation Systems Core Function Unit, Eisai Product Creation Systems, Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635 Japan
e Biomarker and Personalized Medicine Core Function Unit, Eisai Product Creation Systems, Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635 Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein we describe a series of tetrahydrobenzotriazoles as novel, potent metabotropic glutamate recep-
tor subtype 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of the SAR surrounding the
tetrahydrobenzotriazole core ultimately led to the identification of 29 as a potent mGlu5 PAM with a
low maximal glutamate potency fold shift, acceptable in vitro DMPK parameters and in vivo PK profile
and efficacy in the rat novel object recognition (NOR) assay. As a result 29 was identified as a suitable
compound for progression to in vivo safety evaluation.
Received 27 August 2015
Revised 14 October 2015
Accepted 16 October 2015
Available online xxxx
Keywords:
Ó 2015 Published by Elsevier Ltd.
Metabotropic glutamate receptor 5 (mGlu5)
Positive allosteric modulator (PAM)
Cognition
Tetrahydrobenzotriazole
Glutamate is the major excitatory neurotransmitter in the
central nervous system (CNS) and activates both ionotropic
tool compounds support a pro-cognitive role for mGlu5. In vitro
mGlu5 PAMs have been shown to enhance NMDA mediated
synaptic plasticity and potentiate hippocampal LTP and LTD.4
These data are further supported by in vivo studies in which
mGlu5 PAMs have been shown to increase performance in
NOR, enhance hippocampal spatial learning in the Morris water
maze and improve performance in the Y-maze spatial alternation
task.4,5
Despite promising advances in the development of novel CNS
penetrant mGlu5 receptor PAMs, recent reports have emerged
describing the occurrence of adverse events in pre-clinical in vivo
studies. Conn et al. reported a lead example from a series of
dihydroimidazopyrimidinones which exhibited CNS mediated
adverse effects including pro-convulsive behaviour and dizziness.6
Researchers from Merck and Addex have also reported neurotoxi-
city with significant neuronal death observed, particularly in the
auditory cortex, with three distinct mGlu5 PAMs following
repeated dosing.7 In these studies it was suggested that
compounds with relatively low in vitro efficacy exhibited an
improved in vivo efficacy-toxicity window. In vitro PAM efficacy
(a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA),
N-methyl- -aspartate (NMDA) and kainate) and eight metabotro-
D
pic glutamate receptors (mGlu1 to mGlu8). mGlu5 receptors are
located extensively throughout the CNS and are physically and
functionally associated with NMDA receptors, contributing to
numerous synaptic events that underpin cognitive function.1–5
The emergence of small molecule mGlu positive allosteric mod-
ulators (PAMs) has provided new opportunities for improved
receptor subtype selectivity, tractability and regulatory control
over traditional orthosteric agonists. These compounds typically
enhance endogenous orthosteric ligand activation of the receptor
(without producing any intrinsic activity alone), and are thus
thought to limit potentially detrimental effects associated with
conventional receptor agonists. Several distinct mGlu5 selective
PAM chemotypes have been reported3 and numerous studies with
⇑
Corresponding author.
E-mail address: Peter_Atkinson@eisai.net (P.J. Atkinson).
http://dx.doi.org/10.1016/j.bmcl.2015.10.050
0960-894X/Ó 2015 Published by Elsevier Ltd.
Please cite this article in press as: Ellard, J. M.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.10.050

2
J. M. Ellard et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
Table 1
Triazole substituents
is often determined by measuring the leftward shift (increase in
potency) of the orthosteric ligand concentration–response curve
(often referred to as ‘fold-shift’) in the presence of increasing
N
O
concentrations of PAM compound. Thus,
a PAM compound
F
N
N
N
that exhibits a low maximal fold shift only produces a limited
enhancement of signal at any given concentration of orthosteric
ligand (in this case glutamate). Accordingly, Parmentier-Batteur
et al. suggested that the unbound plasma concentration required
for efficacy in an amphetamine-induced locomotor activity assay
corresponded to an estimated 2 fold glutamate potency shift
in vitro.7 It was therefore of interest to us to identify novel mGlu5
PAMs exhibiting low glutamate co-operativity (or ‘fold shift’) and
investigate this link further.
Our efforts to discover novel mGlu5 PAM chemotypes consisted
of three parallel approaches: A knowledge based design strategy, a
focused HTS and a ligand based in silico screening approach which
considered both the 3-dimensional shape and electronic features
identified from known mGlu5 PAMs and was conducted using
Cressett Fieldscreen. Each of these strategies provided novel mGlu5
PAM series which warranted further investigation. The benzotria-
zole (1, Fig. 1) was identified from in silico screening as a novel
mGlu5 PAM chemotype with moderate potency and maximal effi-
cacy (pEC50 6.4, 51% max).
Benzotriazole 1 also exhibited a higher than desirable cLogP
(cLogP 4.28) and a high degree of planarity and aromaticity. It
was postulated that replacement of the benzotriazole core with
an alternative 5,6-bicyclic system would provide a scaffold with
reduced lipophilicity and with the potential to introduce an sp3
centre linking to the oxadiazole substituent. This led to the identi-
fication of a tetrahydrobenzotriazole scaffold exemplified by 9
(Table 1) with a 10 fold improvement in potency and higher effi-
cacy than the benzotriazole hit (1).
N
R
Maximal glutamate fold shiftd
10
c
Example
R-group
pEC50 (% max)
9a
7.5 (103)
10a
11a
6.4 (78)
4e
3e
7.8 (106)
F
F
12a
<4.6
n.t.f
N
13b
14a
5.4 (91)
6.4 (96)
n.t.
4
N
O
15b
16a
6.4 (98)
8.3 (98)
n.t.
4
17a
8.0 (103)
7
Initially these systems were prepared with the ‘reversed’
isomeric oxadiazole to that found in the benzotriazole hit 1 since
O
these analogues were more readily accessible in
a reduced
18a
19a
7.5 (108)
7.8 (71)
8e
3
number of synthetic steps (Scheme 1). The benzotriazole
intermediates 5 were readily prepared in three steps by nucle-
ophilic substitution between an appropriate amine and methyl
4-fluoro-3-nitrobenzoate, followed by reduction of the nitro
group, diazotisation and subsequent cyclisation.9 Reduction of
the aromatic ring was accomplished by hydrogenation at 100 °C
and 100 bar of hydrogen gas over palladium on carbon to provide
the tetrahydrobenzotriazole (6). Following hydrolysis of the
methyl ester the 1,2,4-oxadiazole (8) was formed by EDC medi-
ated coupling with an N-hydroxyamidine and then cyclisation
in refluxing 1,4-dioxane. The individual enantiomers of the
tetrahydrobenzotriazoles were separated by preparative chiral
HPLC.
N
a
b
c
Single enantiomer.
Racemic.
Ca2+ flux PAM assay (in the presence of EC20 glutamate) utilising human U2OS
cells expressing human recombinant mGlu5 receptors; % max, compound response
(up to 25 lM) relative to the maximal glutamate response. Data represent mean of
n P 2.
d
Maximal leftward shift in the EC50- of glutamate induced by increasing con-
M) of test compound measured in rat cortical astrocytes.
centrations (up to 25
l
Unless otherwise stated n P 3.
e
n <3.
n.t. = not tested.
f
Resolution via diastereomeric salt formation with (1S,2S)-2-
amino-1-(4-nitrophenyl)propane-1,3-diol and the carboxylic acid
intermediate 7 was also accomplished where R1 was tert-butyl.
The chiral intermediates obtained in this manner were progressed
to provide single enantiomers of the fully substituted tetrahy-
potent tetrahydrobenzotriazole enantiomers had (S) absolute
stereochemistry.
As evidenced by the two enantiomers of the cyclopentyl ana-
logue (9 and 10, Table 1) there was a clear enantiomeric preference
for potency. Early exploration of the triazole substituent deter-
mined that non-aromatic groups had an optimal balance of proper-
ties. Despite having good potency, the 4-fluorophenyl analogue
(11) imparted very low solubility and a high degree of brain tissue
binding (Fubrain 0.3%) while the 3-pyridyl analogue (12) was found
to be inactive. Substituents bearing basic nitrogen atoms were also
found to poorly tolerated, for example the piperidine derivative
(13) displayed low activity. The cyclopentyl analogue (9) had good
potency but suffered with a high glutamate fold shift and rapid
drobenzotriazoles.
A small molecule X-ray structure of the
diastereomeric salt was used to confirm that the enantiomer of
the carboxylic acid intermediate which gave rise to the most
O
N
F
N
N
N
N
1
microsomal clearance (rat Clint 146
microsomal stability (rat Clint 22 l/min/mg) and glutamate fold
shift was improved by the tetrahydrofuran substituent (14) this
ll/min/mg). While the
l
Figure 1. Initial benzotriazole hit.
Please cite this article in press as: Ellard, J. M.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.10.050

J. M. Ellard et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
3
O
O
O
O2N
HN
H2N
HN
O2N
F
a
O
b
O
c
O
74-94%
84-100%
85-93%
R1
R1
2
5
3
4
O
O
O
d
e
f, g
N
N
N
N
N
N
O
O
OH
N
N
N
30-90%
63-97%
14-48%
R
R1
R1
6
7
N
O
R2
N
N
N
N
R1
8
Scheme 1. Reagents and conditions: (a) R1NH2, DIPEA, NMP, rt, 16 h; (b) H2, 10% Pd/C, EtOAc, rt 16 h; (c) NaNO2, AcOH, H2O, rt, 2 h; (d) H2, 10% Pd/C, AcOH, 100 °C, 100 bar, 2
x 16 h; (e) 1 M NaOH, MeOH, rt, 2 h; (f) R2C(NOH)NH2, EDC, HOBt, DIPEA, DMF, rt, 16 h; (g) 1,4-dioxane, reflux, 4 h.
Table 2
Table 3
Oxadiazole substituents
Oxadiazole replacements
N
O
A
F
R
N
N
N
N
N
N
N
c
Example
Ring A
pEC50 (% max)
Maximal glutamate fold shiftd
4
c
Example R-group
pEC50 (% max) Maximal glutamate fold shiftd
N
O
N
N
16a
8.3 (98)
16b
8.3 (98)
5.8 (67)
4
F
N
O
20a
n.t.e
27a
28b
29a
8.3 (85)
5.5 (53)
7.3 (80)
5
N
N
N
N
21a
22a
23a
5.9 (29)
6.0 (66)
6.7 (91)
n.t.e
n.t.
n.t.
n.t.e
3
O
O
N
N
N
a
b
c
Single enantiomer.
Racemic.
F
Ca2+ flux PAM assay (in the presence of EC20 glutamate) utilising human U2OS
cells expressing human recombinant mGlu5 receptors; % max, compound response
24b
7.7 (77)
7f
(up to 25 lM) relative to the maximal glutamate response. Data represent mean of
n P 2.
25a
26b
6.0 (68)
7.1 (87)
n.t.
6
d
N
Maximal leftward shift in the EC50À of glutamate induced by increasing con-
M) of test compound measured in rat cortical astrocytes.
centrations (up to 25
l
Unless otherwise stated n P 3.
CN
e
not tested.
a
b
c
Racemic.
Single enantiomer.
Ca2+ flux PAM assay (in the presence of EC20 glutamate) utilising human U2OS
ran substituent (17), although this analogue suffered from a higher
glutamate fold shift. The requirement for the tertiary centre to be
proximal to the triazole ring is further supported by the drop in
potency displayed by the iso-butyl analogue (18). The less lipophi-
lic 2-methylpropanenitrile analogue (19) was also found to have
good potency and one of the lowest glutamate fold shift observed
in the series.
cells expressing human recombinant mGlu5 receptors; % max, compound response
(up to 25 lM) relative to the maximal glutamate response. Data represent mean of
n P 2.
d
Maximal leftward shift in the EC50À of glutamate induced by increasing con-
M) of test compound measured in rat cortical astrocytes.
centrations (up to 25
l
Unless otherwise stated n P 3.
e
n.t. = not tested.
n <3.
f
Substituted phenyl rings were found to be the optimal
oxadiazole substituent (Table 2). The pyridyl analogue (20),
displayed poor activity and saturated heterocycles such as
morpholine 21 were only weakly active. Alkyl examples with the
exception of the isobutyl analogue (22) were inactive and the
cyclohexyl substituent (23) afforded only moderate potency. The
benzyl analogue (24) also displayed good potency but suffered
analogue also had significantly lower mGlu5 PAM potency. The iso-
propyl substituent (15) provided moderate activity but the intro-
duction of a tertiary substituent adjacent to the triazole ring was
found to be optimal for potency with the tert-butyl analogue (16)
displaying high potency and, importantly,
a relatively low
from very high microsomal clearance (rat Clint 120
While the para-fluoro phenyl (16) substituent did not impart an
ll/min/mg).
glutamate fold shift. The improvement in potency associated with
a tertiary substituent is also evident with the methyltetrahydropy-
Please cite this article in press as: Ellard, J. M.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.10.050

4
J. M. Ellard et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
Table 4
In vitro ADME profiles
a
b
f
Example
Human Clint
(
ll/min/mg)
Rat Clint
(
ll/min/mg)
MDCK Papp A to Bc (10À6 cmÀ1
)
MDCK efflux ratiod
Solubilitye
(
lM)
Rat Fubrain (%)
16
19
29
18
9
4
20
6
20
42
43
46
0.8
0.6
0.8
6
5.6
>100
1.3
1.5
5.6
a
b
c
d
e
f
3
3
l
l
M compound concentration, 0.5 mg/mL microsome concentration.
M compound concentration, 0.5 mg/mL microsome concentration.
Measured at 1
Papp A to B/Papp B to A.
lM compound concentration.
Kinetic solubility 0.01 M phosphate buffered saline at pH7.4, 1% final DMSO concentration.
Equilibrium dialysis from rat brain homogenate.
Table 5
In vivo profiles
Example
Cl (ml/min/kg)
Vss (L/kg)
Tmax/t½ (h)c
Fc (%)
Cmax plc (nM)
Total br:plc
NOR MEDd (mg/kg)
16
19
29
11a
4b
4.3a
2.5b
1.9a
4.0/6.5
6.0/7.0
2.7/2.9
46
45
114
438
891
1946
2.0
3.2
1.4
0.3
0.03e
0.3
14a
a
Rat, i.v. 0.5 mg/kg.
Rat i.v. 0.25 mg/kg.
Rat p.o. 3 mg/kg.
p.o. dosing with a 4 h pretreatment time (n = 12).
Lowest efficacious dose (LED).
b
c
d
e
advantage in terms of potency (being equipotent to the ortho-flu-
oro, meta-fluoro or unsubstituted phenyl analogues), it is required
for optimal microsomal stability. The fluoro substituent was iden-
tified as the preferred para substituent, being significantly more
potent than other groups investigated such as dimethylamino 25
and nitrile 26.
A number of replacements for the oxadiazole ring were also
investigated (examples shown in Table 3). The ‘reversed’ oxadia-
zole 27 was found to exhibit comparable potency to 16 but with
a marginally higher glutamate fold shift. In contrast, the 1,3,4-oxa-
diazole (28) suffered from a dramatic loss in potency. A promising
alternative to the oxadiazole ring was found in the N-linked tria-
zole analogue (29) which displayed a good balance of potency,
ADME properties and a low glutamate fold shift.
In considering reports of potential CNS safety liabilities
associated with mGlu5 PAMs, compounds exhibiting good dose
proportionality (relative to brain exposure) were favoured, thus
enabling a clear safety margin to be determined in subsequent
studies. In this regard, it was found that 29 exhibited good dose
proportionality in rat up to at least 30 mg/kg p.o. The superior dose
proportionality of 29 over 16 and 19 could be attributed at least in
part to the far greater solubility of this analogue.
Following in vivo pharmacokinetic (PK) evaluation (Table 5)
these compounds were evaluated in the rat NOR assay.10 All three
compounds displayed a significant improvement in cognitive per-
formance following a 4 hour pre-treatment time (minimal effica-
cious dose (MED) for 16 and 29 was 0.3 mg/kg, p.o. and for 19
the lowest efficacious dose (LED) was 0.03 mg/kg, p.o.). It was
noted that, at the MED, the predicted unbound concentration of
compound in the brain was lower than the functional EC50 deter-
mined in vitro. We attribute this disparity partially to the sensitiv-
ity of the behavioural (NOR) model that was used (relative to other
models). It is also possible that the in vitro functional calcium
assay, while providing relative potency measurements for struc-
ture–activity and pharmacokinetic-pharmacodynamic purposes,
may not fully recapitulate native receptor activity in the more
complex in vivo system.
All three compounds were selective for the mGlu5 subtype with
no detectable agonist, PAM or NAM activity at any of the other
mGlu receptor subtypes (as determined by Euroscreen using a con-
ventional concentration–response assay). A favourable selectivity
profile was also observed when extending testing to a 55 member
(ExpressProfile, Cerep) panel of receptors, ion channels and
transporters.11 In a hERG IonWorks assay 29 demonstrated weak
inhibition (pIC50 5.2) however this was deemed tolerable when
considering the relative plasma exposure at efficacious doses.
Based on these data 29 was identified as a potent mGlu5 PAM
with good in vitro potency and a low maximal glutamate potency
shift ratio. Further studies showed that Compound 29
demonstrated a favourable in vitro ADME and in vivo PK profile
coupled with pro-cognitive efficacy in the NOR model in rats. This
compound was therefore selected for progression into in vivo
safety studies, results of which will be presented in a separate
communication.
As a result of the extensive SAR exploration, three compounds
(16, 19 and 29) from the series were identified which combined
good mGlu5 PAM potencies, acceptable in vitro DMPK profiles
and a relatively low maximal glutamate fold shift. Therefore these
compounds were studied in greater detail.
The in vitro ADME profile of the compounds (Table 4) supported
progression to in vivo studies. All three compounds possessed good
apical to basal permeability in the MDCK-MDR1 permeability assay
and were not subject to efflux. In contrast to 16 and 19 which had
relatively low solubilities, 29 represented a significant improve-
ment in solubility. This trend was also mirrored in the degree of
brain tissue binding with 29 displaying an increased fraction
unbound relative to 16 and 19. In addition, these compounds did
not exhibit significant inhibition of the Cyp isoforms tested.
Moderate rat and human microsomal stability was observed for
16 while 29 exhibited moderate to low stability using rat and
human liver microsomes respectively. In contrast, 19 could be con-
sidered a low clearance compound by both human and rat liver
microsomes.
Each of 16, 19 and 29 were found to be bioavailable and
displayed good exposures following oral dosing to Sprague Dawley
rats (3 mg/kg). Additionally they were found to display low plasma
clearances, with moderate to high volumes of distribution. Both 16
and 19 also possessed long plasma half-lives and while 29
exhibited a slightly shorter half-life it was still acceptable for
progression to behavioural studies (Table 5).
Please cite this article in press as: Ellard, J. M.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.10.050

J. M. Ellard et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
5
5. (a) Balschun, D.; Zuschratter, W.; Wetzel, W. Neuroscience 2006, 142, 691; (b)
Liu, F.; Grauer, S.; Kelley, C.; Navarra, R.; Graf, R.; Zhang, G.; Atkinson, P. J.;
Popiolek, M.; Wantuch, C.; Khawaja, X.; Smith, D.; Olsen, M.; Kouranova, E.; Lai,
M.; Pruthi, F.; Pulicicchio, C.; Day, M.; Gilbert, A.; Pausch, M. H.; Brandon, N. J.;
Beyer, C. E.; Comery, T. A.; Logue, S.; Rosenzweig-Lipson, S.; Marquis, K. L. J.
Pharmacol. Exp. Ther. 2008, 327, 827; (c) Uslaner, J. M.; Parmentier-Batteur, S.;
Flick, R. B.; Surles, N. O.; Lam, J. S.; McNaughton, C. H.; Jacobson, M. A.; Hutson,
P. H. Neuropharmacology 2009, 2009, 531; (d) Reichel, C. M.; Schwendt, M.;
McGinty, J. F.; Olive, M. F.; See, R. E. Neuropsychopharmacology 2010, 36, 782.
6. Martín-Martín, M. L.; Bartolomé-Nebreda, J. M.; Conde-Ceide, S.; Alonso de
Diego, S. A.; López, S.; Martínez-Viturro, C. M.; Tong, H. M.; Lavreysen, H.;
Macdonald, G. J.; Steckler, T.; Mackie, C.; Bridges, T. M.; Daniels, J. S.;
Niswender, C. M.; Noetzel, M. J.; Jones, C. K.; Conn, P. J.; Lindsley, C. W.;
Stauffer, S. R. Bioorg. Med. Chem. Lett. 2015, 25, 1310.
Acknowledgements
The authors would like to thank Dr. Dae-Shik Kim for the reso-
lution of the acid 7. The authors would also like to thank Dr. Andy
Takle, Dr. Tomoyuki Shibuguchi, Dr. Yukio Ishikawa, Dr. Anne
Cooper and Dr. Teiji Kimura for helpful discussions during the
period of this work.
Supplementary data
Supplementary data (descriptions of the synthesis of 19 and 27
to 29) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.bmcl.2015.10.050.
7. Parmentier-Batteur, S.; Hutson, P. H.; Menzel, K.; Uslaner, J. M.; Mattson, B. A.;
O’Brien, J. A.; Magliaro, B. C.; Forest, T.; Stump, C. A.; Tynebor, R. M.; Anthony,
N. J.; Tucker, T. J.; Zhang, X. F.; Gomez, R.; Huszar, S. L.; Lamberg, N.; Fauré, H.;
Le Poul, E.; Poli, S.; Rosahl, T. W.; Rocher, J. P.; Hargreaves, R.; Williams, T. M.
Neuropharmacology 2014, 82, 161.
References and notes
8. Calculated using ChemDraw Ultra 12.0.
9. Semple, G.; Skinner, P. J.; Cherrier, M. C.; Webb, P. J.; Sage, C. R.; Tamura, S. Y.;
Chen, R.; Richman, J. G.; Connolly, D. T. J. Med. Chem. 2006, 49, 1227.
10. Johnson, D. J.; Forbes, I. T.; Watson, S. P.; Garzya, V.; Stevenson, G. I.; Walker, G.
R.; Mudhar, H. S.; Flynn, S. T.; Wyman, P. A.; Smith, P. W.; Murkitt, G. S.; Lucas,
A. J.; Mookherjee, C. R.; Watson, J. M.; Gartlon, J. E.; Bradford, A. M.; Brown, F.
Bioorg. Med. Chem. Lett. 2010, 20, 5434.
1. Ehlers, M. D. Curr. Biol. 1999, 9, R848.
2. Alagarsamy, S.; Marino, M. J.; Rouse, S. T.; Gereau, R. W. T.; Heinemann, S. F.;
Conn, P. J. Nat. Neurosci. 1999, 2, 234.
3. Lindsley, C. W.; Stauffer, S. R. Pharm. Pat. Anal. 2013, 2, 93.
4. (a) Conn, P. J.; Lindsley, C. W.; Jones, C. K. Trends Pharmacol. Sci. 2009, 30, 25; (b)
Ayala, J. E.; Chen, Y.; Banko, J. L.; Sheffler, D. J.; Williams, R.; Telk, A. N.; Watson,
N. L.; Xiang, Z.; Zhang, Y.; Jones, P. J.; Lindsley, C. W.; Olive, M. F.; Conn, P. J.
Neuropsychopharmacology 2009, 34, 2057.
11. http://www.cerep.fr/cerep/users/pages/catalog/profiles/detailprofile.asp?
profile=2117.
Please cite this article in press as: Ellard, J. M.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.10.050