The discovery of the benzazepine class of histamine H3 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2013.09.089

This Letter describes the discovery of a novel series of H₃ receptor antagonists. The initial medicinal chemistry strategy focused on deconstructing and simplifying an early screening hit which rapidly led to the discovery of a novel series of

Full text of DOI:10.1016/j.bmcl.2013.09.089

Bioorganic & Medicinal Chemistry Letters xxx (2013) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The discovery of the benzazepine class of histamine H3 receptor
antagonists
a
a
a
a
David M. Wilson a, , James Apps , Nicholas Bailey , Mark J. Bamford , Isabel J. Beresford ,
Michael A. Briggs a, Andrew R. Calver a, Barry Crook a, Robert P. Davis a, Susannah Davis a, David K. Dean a,
Leanne Harris a, Tom D. Heightman b, Terry Panchal a, Christopher A. Parr a, Nigel Quashie b,
Jon G. A. Steadman a, Joanne Schogger a, Sanjeet S. Sehmi a, Tania O. Stean a, Andrew K. Takle a,
Brenda K. Trail a, Trevor White a, Jason Witherington a, Angela Worby b, Andrew D. Medhurst a
⇑
a GlaxoSmithKline R&D, Neurology CEDD, Harlow, Essex CM19 5AW, United Kingdom
b GlaxoSmithKline R&D, Molecular Discovery Research, Harlow, Essex CM19 5AW, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter describes the discovery of a novel series of H3 receptor antagonists. The initial medicinal
chemistry strategy focused on deconstructing and simplifying an early screening hit which rapidly led
to the discovery of a novel series of H3 receptor antagonists based on the benzazepine core. Employing
an H3 driven pharmacodynamic model, the series was then further optimised through to a lead com-
pound that showed robust in vivo functional activity and possessed overall excellent developability
properties.
Received 2 August 2013
Revised 24 September 2013
Accepted 27 September 2013
Available online xxxx
Keywords:
H3 receptor antagonist
GPCR
Ó 2013 Elsevier Ltd. All rights reserved.
Benzazepine
Alzheimer’s disease
Neurotransmitters
Histamine
The histamine H3 receptor (H3R) was discovered in 1983 and
was initially described as an autoreceptor regulating the release
of histamine from histaminergic neurones.1 Subsequent studies la-
ter demonstrated that the H3R plays a pivotal role as a heterore-
effectively supported by the early discovery of potent H3R ligands
that have served as versatile in vivo probe molecules to explore the
pharmacology of this receptor system.8–10 This work has led to the
development of
a number of clinical hypotheses that have
ceptor, regulating the release of
a
number of important
strengthened the view that H3R antagonists or inverse agonists,
will have clinical utility in treating narcolepsy, schizophrenia and
Alzheimer’s disease.11–16 However, despite the early success in dis-
covering in vivo probes for the H3R, many of these first generation
inhibitors proved unsuitable for clinical progression due to poor
developability properties and toxicity issues. Consequently, there
has been significant drug discovery activity over the past decade
focused on addressing these problems and delivering the next gen-
eration of drug molecules to validate the H3R in the clinic.17–19
Herein we describe our efforts to identify next generation
antagonists that have improved developability properties and
which are suitable for exploring H3R function in the clinic. Our
starting point for optimisation was compound 1 (Table 1). This
molecule was identified via a focused screen of the GlaxoSmithK-
line compound collection and had excellent potency for the human
H3 receptor. However, the physicochemical properties of 1 were
sub-optimal and key parameters such as cLogP and MW were out-
side of the most optimal chemical space for a CNS drug.20 Further-
more, when 1 was profiled in vivo using a validated H3 driven
neurotransmitters including acetylcholine, dopamine and nor-
adrenaline.2–4 In 1999, the H3R was cloned and confirmed to be a
member of the GPCR superfamily and one of the four receptors
controlling histamine signalling.5 However, unlike the other three
histamine family members (H1, H2 and H4), the H3R is predomi-
nantly expressed in the central nervous system (CNS) and shows
particularly high levels of expression in brain regions such as the
cerebral cortex, hippocampus, basal ganglia and hypothalamus
which are associated with cognition and arousal.6,7 Consequently,
there has been significant interest in understanding the role of
the H3R in the CNS and, in particular, how this receptor system reg-
ulates critical functions such as cognition, attention, wakefulness
and pain recognition. Pre-clinical research activities have been
⇑
Corresponding author at present address: AstraZeneca, Alderley Park, Maccles-
field SK10 4TG, United Kingdom. Tel.: +44 01625 516321.
E-mail address: David.M.Wilson@astrazeneca.com (D.M. Wilson).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.09.089
Please cite this article in press as: Wilson, D. M.; et al. Bioorg. Med. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.bmcl.2013.09.089

2
D. M. Wilson et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
Table 1
Properties of H3 antagonist screening hit 1 and ciproxifan
H
O
N
N
H
O
H
N
O
O
O
Compound no.
N
O
N
1
2 (Ciproxifan)
b
hH3a/hH1 pKi
10.6/<5.6
465/4.8
96
7.2/<5.6
270/2.5
80
MW/cLogP
HSA binding (%)
Reversal of RAMH induced dipsogeniac
78% @ 10 mg/kg ip
100% @ 3 mg/kg po
a
Negative log of the antagonist dissociation constant derived from a functional GTP
cS assay using recombinantly expressed human H3 receptors and expressed as the
mean of P2 experiments.23
b
Negative log of the antagonist dissociation constant derived from a functional FLIPR based assay using recombinantly expressed hH1 receptors and expressed as the mean
of P2 experiments.24
% Reversal of R-a
-methyl histamine induced dipsogenia (drinking) in male Lister Hooded rats and carried out according to published protocols.22
c
Table 2
pharmacodynamic assay (PD), the compound showed only modest
efficacy and was unable to fully reverse the dipsogenia induced by
Constrained analogues of compound 1
the selective H3R agonist, R-a-methyl histamine (RAMH) despite
Ar
O
being dosed at 10 mg/kg ip.21,22 This was primarily attributed to
a sub-optimal pharmacokinetic profile as the tool literature H3R
antagonist ciproxifan (2), which possesses good oral exposure in
the rat and efficiently penetrates the CNS, was able to robustly re-
verse RAMH induced dipsogenia following a 3 mg/kg oral dose.
Consequently, the primary objective for the optimisation of 1
was to identify a lead molecule that had improved developability
properties combined with an in vivo pharmacokinetic profile that
would deliver efficacy that was at least comparable with ciproxifan
following oral dosing. To achieve this goal, the medicinal chemistry
effort focused from the outset on simplifying and deconstructing
compound 1 so as to identify a diversified molecular scaffold that
would be more amenable to further optimisation. Based upon
H3R homology modelling, the first phase of this ‘deconstruction
strategy’ focussed on refining the pyrrolidine amide system which
was thought to be over elaborate and not critical for H3R activity.
One approach that was initially explored was to constrain the ben-
zylamine motif in 1 as a minimal bicyclic scaffold, as outlined sche-
matically in Figure 1.
N
a
Compound no.
Ar
pKi hH3
cLogP
MW
260
H
N
3
7.8
3.4
H
H
N
N
4
5
8.6
8.4
3.0
3.4
274
288
a
Negative log of the antagonist dissociation constant derived from a functional
GTPcS assay using recombinantly expressed hH3 receptors and reported as the
mean of P2 experiments.23
either the propyl linker or the piperidine core were generally
poorly tolerated. Activity was abolished when a benzyl group (6)
was exchanged for the propylamine system. However, more subtle
changes, for example, exchange of the piperidine for either dimeth-
ylamine (7) or morpholine (8) also served to attenuate H3R activity.
Similarly, substitution of the piperidine group with either fluorines
(9) or a hydroxyl group (10) also reduced potency. Linker length
was also important for activity with an ethyl linker (11) proving
less optimal than propyl. However, significant changes such as
constraining the propylamine system in the form of a N-substi-
tuted piperidyl group (12) were very well tolerated and suggest
that a key requirement for potent H3R antagonism is the presence
of a highly basic centre (pKa >9.0) imbedded in a well defined lipo-
philic environment.
Having established the drivers of activity in the oxy-propyl-
amine portion of 5, attention then focussed on developing the
SAR in the N-1 position of the benzazepine core. Acetylation (13)
and arylation (14) of the N-1 position were tolerated although in
both cases resulted in a slight reduction in potency. Conversely,
alkylation by cyclopropylmethyl (15) and 2-tetrahydrofuranylm-
ethyl (16) were very well tolerated and gave rise to almost a 10-
fold increase in potency. However, when the propylamine SAR
was re-examined with the more optimal N1-cyclopropylmethyl
group in place, the shorter ethylamine system (17) in this case re-
tained activity (cf. with 11). Furthermore, the oxy-benzyl analogue
(18) showed robust activity which contrasted markedly with the
analogous analogue in N-1-H series (6). These surprising results
Encouragingly, these initial modifications yielded a series of po-
tent H3R antagonists (3–5) that had a reduced molecular footprint
compared to 1 and offered versatile and chemically tractable scaf-
folds that were readily amenable for further optimisation (Table 2).
In contrast to the pyrrolidine amide system in 1, the ‘oxy-pro-
pylamine’ motif was predicted by H3R homology modelling to be
essential for H3R activity, with the basic amine of the piperidine
group forming a critical interaction with the conserved aspartic
acid on trans-membrane region 3 (TM3) of the receptor. To explore
this hypothesis further, a number of analogues were prepared in
the chemically tractable N1–H benzazepine series (5) in order to
understand the SAR of the ‘oxy-propylamine’ motif in driving po-
tency across this series (Table 3). As anticipated, modifications to
R'
N
R´
N
R''
´( )n
O
N
O
N
n = 0,1,2
Figure 1. Initial medicinal chemistry strategy to deconstruct and simplify the
molecular scaffold of compound 1.
Please cite this article in press as: Wilson, D. M.; et al. Bioorg. Med. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.bmcl.2013.09.089

D. M. Wilson et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
3
Table 3
clearly indicate a critical role for the N-1 position of the benzaze-
pine in directing the SAR of the template. One possible explanation
for the observed SAR could be the potential for the N-1 alkylated
benzazepine core to mimic the oxy-propylamine system. In the
case of 18, this would allow the benzazepine core to compensate
for the loss of the important oxy-propylpiperidine group in 6 such
that the binding mode flips and the benzazepine N-1 basic centre
interacts directly with the conserved aspartic acid on TM3 of the
H3R whilst the cyclopropylmethyl substituent satisfies the need
for a small hydrophobic group in this area of the receptor. Impor-
tantly, these changes avoided any significant increase in human H1
activity and confirmed the benzazepine scaffold as being selective
for the H3R and hence suitable for further optimisation.
To explore this key discovery further, a series of N-1 substituted
analogues were prepared to understand the SAR around this criti-
cal position (Table 4). Small alkyl groups such as isobutyl (20) and
isopropyl (21) were well tolerated, however, reducing the size to
methyl (19) led to a significant reduction in potency. This was also
the case with the larger and more lipophilic benzyl group (22)
which abolished activity. In contrast, there was a positive potency
trend, as assessed by lipophilic ligand efficiency (LLE), when mov-
ing to small cycloalkyl groups with the maximum potency gain
peaking at the cyclobutyl analogue 24 (LLE 4.1) which represented
a >50-fold increase in potency relative to 18 (LLE 2.9) whilst not
increasing either the MW or cLogP of the template.25 However, be-
yond cyclopentyl (25), activity declined significantly such that
cyclohexyl (26; LLE 1.9) offered no potency advantage over 18
whilst having significantly reduced LLE. Taken together, the SAR
trends observed in Table 4 clearly support the hypothesis that
the basic N-1 alkylated benazepine core can mimic the oxy-pro-
pyl-piperidine group in both 1 and 5 and most likely adopts a sim-
ilar binding mode such that the basic centre interacts with the
conserved Asp on TM3 whilst the cyclobutyl group optimally satis-
fies the critical hydrophobic requirements in this area of the
receptor.
Initial SAR development around compound 5
O
R´
N
R´´
a
b
Compound no. R0
R00
H
pKi hH3
pKi hH1
5
8.4
5.9
N
6
H
H
H
<5.0
7.0
ND
ND
ND
7
N
O
8
7.0
N
F
9
H
H
<6.4
<5.0
ND
ND
F
N
HO
10
N
N
11
12
13
H
6.8
8.6
7.8
ND
N
H
<5.6
ND
Ac
N
14
15
16
17
18
Ph
8.0
9.3
9.3
9.1
8.0
6.0
5.7
N
N
N
–CH2cPr
5.7
O
N
–CH2cPr
–CH2cPr
<5.7
6.0
The discovery of the benzazepine core as a novel, potent, selec-
tive and ligand efficient H3R chemotype provided the medicinal
chemistry effort with significant additional scope for further opti-
misation. The scaffold was also synthetically accessible and suffi-
ciently versatile to support efficient lead optimisation.23
Compound (24) had excellent activity at the H3R but possessed
poor developability properties including high clearance in liver
a
Negative log of the antagonist dissociation constant derived from a functional
GTPcS assay using recombinantly expressed hH3 receptors and reported as the
mean of P2 experiments.23
b
Negative log of the antagonist dissociation constant derived from a functional
FLIPR based assay using recombinantly expressed hH1 receptors and expressed as
the mean of P2 experiments.24
Table 4
Optimisation of the benzazepine core: N-Alkyl SAR
O
N
R´
cLogP/LLE25
a
b
Compound no.
R0
pKi hH3
pKi rH3
Human P450 IC50 2D6 (
lM)
Microsomes CLi (mL/min/g)
Rat
Human
18
19
20
21
22
23
24
25
26
–CH2cPr
–Me
–CH2iPr
–iPr
–Bn
–cPr
–cBu
–cPent
–cHex
8.0
6.5
7.6
7.7
<6.0
8.3
9.6
9.1
8.0
6.9
—
—
—
—
1.5
—
—
—
—
>50
—
—
—
—
11
—
—
—
—
5.1/2.9
4.1/<2.4
5.6/2.0
5.0/2.7
5.9/<0.1
4.6/3.7
5.5/4.1
5.6/3.5
6.1/1.9
—
—
—
—
7.9
7.0
—
0.6
0.6
—
>50
>50
—
12
19
—
a
Negative log of the antagonist dissociation constant derived from a functional GTPcS assay using recombinantly expressed hH3 receptors and reported as the mean of P2
experiments.23
b
Negative log of the dissociation constant obtained from a radiolabel displacement assay carried out on membranes derived from cerebral cortical tissues and reported as
the mean of P2 experiments.22
Please cite this article in press as: Wilson, D. M.; et al. Bioorg. Med. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.bmcl.2013.09.089

4
D. M. Wilson et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
Table 5
Optimisation of the benzazepine core: 7-Benzoxy SAR
O
R
7
N
Compound no.
R
hH3 pKia
Human CYP450 IC50 2D6 (
l
M)
Microsomes CLi (mL/min/g)
cLogP (LLE)
% Reversal of RAMH induced
dipsogeniab (@ 3 mg/kg po)
R
H
24
27
Bn–
9.6
9.4
0.7
4.2
>50
12
5.5 (4.1)
4.0 (5.4)
ND
ND
O
N
2.5
3.4
HN
HN
28
29
9.3
9.5
19
—
0.7
1.2
0.9
0.5
3.4 (5.9)
2.8 (6.7)
44
ND
O
S N
30
31
9.1
9.0
13
—
2.9
1.1
0.5
0.9
2.3 (6.8)
3.1 (5.9)
6
O
O
N
N
100
O
O
N
32
33
9.3
8.8
—
2.9
3.5
0.8
1.2
3.1 (6.2)
2.3 (6.5)
89
11
Cl
O
N
N
O
43
ND: not determined.
a
Negative log of the antagonist dissociation constant derived from a functional GTPcS assay using recombinant expressed human H3 receptors and expressed as the mean
of P2 experiments.23
% Reversal of R-a
-methyl histamine induced dipsogenia (drinking) in male Lister Hooded rats and carried out according to published protocols.22
b
Table 6
microsomes, as well as being a potent inhibitor of the human cyto-
chrome P450 isoform (CYP450) 2D6. Consequently, the main focus
of the next phase of lead optimisation was to address the poor dev-
elopability properties and demonstrate that the benzazepine scaf-
fold could deliver a sustainable lead series. A driver of these
developability issues was thought to be the relatively high lipo-
philicity of the series. To address this problem, the medicinal
chemistry strategy centred on optimising the oxy-benzyl substitu-
ent with a specific intent of identifying replacements that would
balance the lipophilicity of the series and maximise the potential
for identifying a lead with oral activity and CNS exposure (Table 5).
Encouragingly, in the initial phase of optimisation it was quickly
demonstrated that groups containing polarity in the 7-oxy-benzyl
substituent (27–29) were well tolerated. Furthermore, reductions
in cLogP correlated well with improved metabolic stability in liver
microsomes and weaker inhibition of human CYP2D6. These
improvements in the developability properties also resulted in
the first evidence of oral activity in the H3R driven PD assay with
the 4-piperidylmethyl analogue (28) showing a modest reversal
of dipsogenia following a 3 mg/kg dose. This provided further
encouragement to target a narrow lipophilicity range in order to
understand the potential of the series to deliver robust efficacy
in the H3R driven PD assay. To develop this understanding, ana-
logues based around the 4-piperidyl group (29), which possessed
the most optimal physicochemical properties, were prepared tar-
geting a cLogP between 2 and 3. As anticipated, this small array
provided a range of analogues (30–33) with comparable levels of
potency and overall excellent developability properties. However,
despite the relative similarity of the compounds screened, efficacy
Profile of Lead Benzazepine 31
O
O
N
N
N
O
hH3/hH1 pKi
Rat H3 cortical binding pKi
Cerep panel (>50-targets)
In-house selectivity panel (>100-targets)
hERG% inhibition (patch clamp)
Chrom LogD/HSA binding/pKa
9.0/<5.0
7.9
>1000-fold
>100-fold
<30% @ 10
l
M
2.2a/49%a/9.2
2.2 mg/kg pob
Rat cortical ex vivo binding (ED50
Brain:blood concentrations/ratio
)
0.53:0.47
l
M/1.1:1.0c
Rat intravenous pharmacokinetics:
CLb (ml/min/kg)/Vss (l/kg)/T0.5 (h)
63/4.6/1.2d
Determined using a published spectroscopic method.22,26
Cortical ex vivo binding experiment in Lister Hooded rats carried out and
a
b
analysed according to published protocols.22
c
Determined from blood and brain samples taken from the cortical ex vivo
binding experiment after 2 h following a single oral dose of 3 mg/kg.27
d
1 h intravenous infusion where CLb = total (blood) clearance; Vss = volume of
distribution at steady-state. T0.5 = terminal half-life.
in the H3 driven PD assay differed markedly across the series. The
most efficacious analogue was the morpholine urea (31), which
fully inhibited the H3 agonist-induced dipsogenic effect following
a 3 mg/kg oral dose. Due to the design of the PD assay, blood sam-
ples were not taken during the course of the experiment thus a
close understanding of how compound exposure drove activity in
Please cite this article in press as: Wilson, D. M.; et al. Bioorg. Med. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.bmcl.2013.09.089

D. M. Wilson et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
5
Scheme 1. Reagents and conditions: (a) K2CO3, cat KI, 2-butanone, benzyl bromide, reflux (b) trifluoroacetic acid, dichloromethane, room temperature (c) 2.5% acetic acid in
dichloromethane, cyclobutanone, sodium triacetoxyborohydride, room temperature (d) 10% Pd/C, H2 (1 atmosphere), ethanol/THF (3:1), room temperature (e) 4-hydroxy-
piperidine-1-carboxylic acid tert-butyl ester, di-tert-butylazodicarboxylate, triphenylphosphine, THF, room temperature (f) trifluoroacetic acid, dichloromethane, room
temperature (g) morpholine carbamoyl chloride, diethylaminoethyl polystyrene, dichloromethane, room temperature.
Lemaire, M.; Porsolt, R. D.; Bennani, Y. L.; Sullivan, J. P.; Cowart, M. D.; Decker,
M. W.; Hancock, A. A. J. Pharmacol. Exp. Ther. 2005, 313, 176.
3. Blandina, P.; Giorgetti, M.; Bartolini, L.; Cecchi, M.; Timmerman, H.; Leurs, R.;
the model was lacking. Nevertheless, based upon the precedence
that well characterised H3R antagonists from across chemically di-
verse series robustly reverse the dipsogenic effects of RAMH (for
example 2), it was assumed that the lack of activity observed with
30 and 33 related to either their poor oral exposure and/or lack of
sufficient CNS penetration.
Pepeu, G.; Giovannini, M. G. Br. J. Pharmacol. 1996, 119, 1656.
4. Schlicker, E.; Kathmann, M. Pharmacochem. Libr. 1998, 30, 13.
5. Lovenberg, T. W.; Roland, B. L.; Wilson, S. J.; Jiang, X.; Pyati, J.; Huvar, A.;
Jackson, M. R.; Erlander, M. G. Mol. Pharmacol. 1999, 55, 1101.
6. Martinez-Mir, M. I.; Pollard, H.; Moreau, J.; Arrang, J. M.; Ruat, M.; Traiffort, E.;
Schwartz, J. C.; Palacios, J. M. Brain Res. 1990, 526, 322.
Based upon the robust oral activity shown in the H3 driven PD
assay, compound 31 was taken forward as the lead compound from
the series and profiled in a wide range of in vitro and in vivo assays
(Table 6). The synthesis of 31 was carried out in accordance with
published methodologies and is highlighted in Scheme 1.23 Against
a Cerep and in-house panel of diverse drug targets (>150; kinases,
GPCRs, enzymes and ion channels), 31 was shown to be highly
selective for the H3R with minimal off-target activity. The com-
pound was also shown to have excellent physicochemical proper-
ties with high aqueous solubility and low binding to human serum
albumin. To explore the potential of 31 to penetrate the CNS and
bind to brain H3R, the compound was evaluated in a rat cortical
ex vivo binding model (EVB).22 In this assay, 31 showed significant
receptor occupancy following oral dosing and had an ED50 of 2 mg/
kg. Analysis of the blood and brain samples taken during the EVB
experiment also confirmed that 31 had significant brain exposure
and a favourable brain:blood ratio that was consistent with the ob-
served level of H3R occupancy.
7. Pollard, H.; Moreau, J.; Arrang, J. M.; Schwartz, J. C. Neuroscience 1993, 52, 169.
8. Celanire, S.; Wijtmans, M.; Talaga, P.; Leurs, R.; de Esch, I. J. P. Drug Discovery
Today 2005, 10, 1613.
9. Berlin, M.; Boyce, C. W. Expert Opin. Ther. Pat. 2007, 17, 675.
10. Hudkins, R. L.; Raddatz, R. Annu. Rep. Med. Chem. 2007, 42, 49.
11. Hancock, A. A.; Fox, G. B. Expert Opin. Invest. Drugs 2004, 13(10), 1237.
12. Hancock, A. A.; Fox, G. B. Cognit. Enhancing Drugs 2004, 97.
13. Chazot, P. L. Drug News Perspect. 2010, 23(2), 99.
14. Arrang, J. Int. Rev. Neurobiol. 2007, 78, 247.
15. Kanbayashi, T.; Fujiki, M.; Tsutsui, S.; Sato, M.; Shimizu, T. Nippon Shinkei
Seishin Yakurigaku Zasshi 2009, 29, 109.
16. Esbenshade, T. A.; Browman, K. E.; Bitner, R. S.; Strakhova, M.; Cowart, M. D.;
Brioni, J. D. Br. J. Pharmacol. 2008, 154, 1166.
17. Cowart, M.; Faghih, R.; Curtis, M. P.; Gfesser, G. A.; Bennani, Y. L.; Black, L. A.;
Pan, L.; Marsh, K. C.; Sullivan, J. P.; Esbenshade, T. A.; Fox, G. B.; Hancock, A. A. J.
Med. Chem. 2005, 48, 38.
18. Raddatz, R.; Hudkins, R. L.; Mathiasen, J. R.; Gruner, J. A.; Flood, D. G.; Aimone,
L. D.; Le, S.; Schaffhauser, H.; Duzic, E.; Gasior, M.; Bozyczko-Coyne, D.; Marino,
M. J.; Ator, M. A.; Bacon, E. R.; Mallamo, J. P.; Williams, M. J. Pharmacol. Exp.
Ther. 2012, 340, 124.
19. Wager, T. T.; Pettersen, B. A.; Schmidt, A. W.; Spracklin, D. K.; Mente, S.; Butler,
T. W.; Howard, H.; Lettiere, D. J.; Rubitski, D. M.; Wong, D. F.; Nedza, F. M.;
Nelson, F. R.; Rollema, H.; Raggon, J. W.; Aubrecht, J.; Freeman, J. K.; Marcek, J.
M.; Cianfrogna, J.; Cook, K. W.; James, L. C.; Chatman, L. A.; Iredale, P. A.;
Banker, M. J.; Homiski, M. L.; Munzner, J. B.; Chandrasekaran, R. Y. J. Med. Chem.
2011, 54, 7602.
In summary, by adopting a deconstruction approach to the opti-
misation of the initial screening hit (1), the medicinal chemistry
campaign was successful in identifying a novel H3R antagonist
scaffold that possesses oral in vivo activity combined with overall
excellent developability properties. In the following paper in this
issue, the further optimisation of 31 is described leading to the
identification of two clinical candidates.
20. Wager, T. T.; Villalobos, A.; Verhoest, P. R.; Hou, X.; Shaffer, C. L. Expert Opin.
Drug Discovery 2011, 6, 371.
21. Clapham, J.; Kilpatrick, G. J. Eur. J. Pharmacol. 1993, 232, 99.
22. Medhurst, A. D.; Atkins, A. R.; Beresford, I. J.; Brackenborough, K.; Briggs, M. A.;
Calver, A. R.; Cilia, J.; Cluderay, J. E.; Crook, B.; Davis, J. B.; Davis, R. K.; Davis, R.
P.; Dawson, L. A.; Foley, A. G.; Gartlon, J.; Gonzalez, M. I.; Heslop, T.; Hirst, W.
D.; Jennings, C.; Jones, D. N. C.; Lacroix, L. P.; Martyn, A.; Ociepka, S.; Ray, A.;
Regan, C. M.; Roberts, J. C.; Schogger, J.; Southam, E.; Stean, T. O.; Trail, B. K.;
Upton, N.; Wadsworth, G.; Wald, J. A.; White, T.; Witherington, J.; Woolley, M.
L.; Worby, A.; Wilson, D. M. J. Pharmacol. Exp. Ther. 2007, 321, 1032.
23. Bamford, M. J.; Dean, D. K.; Sehmi, S. S.; Wilson, D. M.; Witherington, J.
WO2004/056369.
24. Procopiou, P. A.; Ancliff, R. A.; Bamford, M. J.; Browning, C.; Connor, H.; Davies,
S.; Fogden, Y. C.; Hodgson, S. T.; Holmes, D. S.; Looker, B. E.; Morriss, K. M. L.;
Parr, C. A.; Pickup, E. A.; Sehmi, S. S.; White, G. V.; Watts, C. J.; Wilson, D. M.;
Woodrow, M. D. J. Med. Chem. 2007, 50, 6706.
25. Leeson, P. D.; Springthorpe, B. Nat. Rev. Drug Disc. 2007, 6, 881.
26. Valko, K.; Nunhuck, S. B.; Hill, A. P. J. Pharm. Sci. 2011, 100, 849.
27. All animal studies were ethically reviewed and carried out in accordance with
Animals (Scientific Procedures) Act 1986 and the GSK Policy on the Care,
Welfare and Treatment of Animals.
Acknowledgments
We thank our colleagues John Davis, Frank King and Andrew
Parsons for their support and scientific input during the progres-
sion of this project.
References and notes
1. Arrang, J. M.; Garbarg, M.; Schwartz, J. C. Nature 1983, 302, 832.
2. Fox, G. B.; Esbenshade, T. A.; Pan, J. B.; Radek, R. J.; Krueger, K. M.; Yao, B. B.;
Browman, K. E.; Buckley, M. J.; Ballard, M. E.; Komater, V. A.; Miner, H.; Zhang,
M.; Faghih, R.; Rueter, L. E.; Bitner, R. S.; Drescher, K. U.; Wetter, J.; Marsh, K.;
Please cite this article in press as: Wilson, D. M.; et al. Bioorg. Med. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.bmcl.2013.09.089