The discovery of quinoline based single-ligand human H1and H3receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2016.11.022

A novel series of potent quinoline-based human H₁and H₃bivalent histamine receptor antagonists, suitable for intranasal administration for the potential treatment of allergic rhinitis associated nasal congestion, were identified. Com

Full text of DOI:10.1016/j.bmcl.2016.11.022

Accepted Manuscript
The Discovery of Quinoline Based Single-ligand Human H1 and H3 Receptor
Antagonists
Panayiotis A. Procopiou, Rachael A. Ancliff, Paul M. Gore, Ashley P. Hancock,
Simon T. Hodgson, Duncan S. Holmes, Steven P. Keeling, Brian E. Looker,
Nigel A. Parr, James E. Rowedder, Robert J. Slack
PII:
S0960-894X(16)31162-3
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.11.022
BMCL 24417
Reference:
Bioorganic & Medicinal Chemistry Letters
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Received Date:
Revised Date:
Accepted Date:
6 October 2016
8 November 2016
9 November 2016
Please cite this article as: Procopiou, P.A., Ancliff, R.A., Gore, P.M., Hancock, A.P., Hodgson, S.T., Holmes, D.S.,
Keeling, S.P., Looker, B.E., Parr, N.A., Rowedder, J.E., Slack, R.J., The Discovery of Quinoline Based Single-
ligand Human H1 and H3 Receptor Antagonists, Bioorganic & Medicinal Chemistry Letters (2016), doi: http://
dx.doi.org/10.1016/j.bmcl.2016.11.022
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The Discovery of Quinoline Based Single-ligand Human H1 and H3 Receptor
Antagonists
Panayiotis A. Procopiou,*a Rachael A. Ancliff,a Paul M. Gore,a Ashley P. Hancock,a Simon T.
Hodgson,a Duncan S. Holmes,a Steven P. Keeling,a Brian E. Looker,a Nigel A. Parr,a James E.
Rowedder,b Robert J. Slackc
a Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road,
Stevenage, Hertfordshire, SG1 2NY, United Kingdom
b R&D Platform Technology and Science, GlaxoSmithKline Medicines Research Centre,
Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom
c Respiratory Biology, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road,
Stevenage, Hertfordshire, SG1 2NY, United Kingdom
•
•
Corresponding author. Tel.: +44 1438 79049; fax: +44 1438 768302
E-mail address: pan.a.procopiou@gsk.com (P.A. Procopiou)

Abstract
A novel series of potent quinoline-based human H1 and H3 bivalant histamine receptor
antagonists, suitable for intranasal administration for the potential treatment of allergic
rhinitis associated nasal congestion, were identified. Compound 18b had slightly lower H1
potency (pA2 8.8 vs 9.7 for the clinical goldstandard azelastine), and H3 potency (pKi 9.1 vs
6.8 for azelastine), better selectivity over α , α and hERG, similar duration of action,
1A 1B
making 18b a good back-up compound to our previous candidate, but with a more desirable
profile.
Key words:
H1H3 Histamine receptor antagonist, single ligand, quinoline, allergic rhinitis, nasal
congestion.

Allergic rhinitis, also known as “hay fever” is a condition affecting at least 10 – 25% of the
world’s population and has shown a steady increase in prevalence during the last 50 years.1
Rhinitis and other allergic conditions are associated with the release of histamine from
various cell types, but particularly mast cells. The physiological effects of histamine are
mediated by four major G-protein-coupled receptors, termed H1, H2, H3, and H4, which differ
in their expression, signal transduction and histamine-binding characteristics.2 H1 receptor
antagonists, are the most commonly used first-line medication for allergic rhinitis.2,3 H1
receptor antagonists are effective in treating all the symptoms of allergic rhinitis (nasal
itching, sneezing and rhinorrhea), apart from nasal congestion. Hence they are often used in
combination with short-acting α-adrenergic agonist decongestants, such as ephedrine and
pseudoephedrine. These are potent vasoconstrictors with fast onset-time, available as over-
the counter oral preparations. However, the use of such agents is limited due to their
potential to produce hypertension, agitation, headache, tachycardia and insomnia.4 Novel
decongestant agents with a superior side effect profile and efficacy profile would be
advantageous in the treatment of allergic rhinitis.
The H3 receptor subtype is a presynaptic autoreceptor that controls the synthesis and release
of histamine as well as other neurotransmitters, such as acetylcholine, dopamine, GABA,
glutamate, 5-HT, substance P and noradrenaline.3 H3 receptors are expressed widely on both
CNS and peripheral tissues and are localised on the epithelium and nerves in human nasal
mucosa.5 In vitro experiments with isolated human turbinate mucosa have shown that (R)-α-
methylhistamine, an H3 receptor agonist, inhibited sympathetic vasoconstriction, whereas
clopenpropit, a selective H3 receptor antagonist, blocked this effect by reducing noradrenaline
release from sympathetic nerve endings in the nasal mucosa.6 It is thought that activation of
the H3 receptor on the presynaptic terminals of sympathetic neurones reduces noradrenaline
release and this may contribute, together with the activation of the postsynaptic H1 receptors,

to the nasal blockage caused by histamine release. Consistent with this hypothesis,
combination treatment of H1 and H3 antagonists have been shown to inhibit nasal congestion
in animal models.7 Further evidence for the contribution of H3 receptors to histamine-
induced blockage of the nasal airway in normal healthy human volunteers was provided by
acoustic rhinometry.8 In principle there are two ways of targeting dual H1H3 pharmacology,
either by using a combination of two individual selective antagonists or identifying a
molecule that exhibits antagonism at both receptors. Our group reported on a dual H1H3
receptor antagonist suitable for topical administration.9 A review of the patent literature on
H3 receptor antagonists covering the four-year period from 2010 was published recently.10 In
addition three compounds, our dual H1H3 receptor antagonist 1,9 Pfizer’s PF-03654746 (2),11
and J&J’s JNJ-39220675 (3)12 progressed to the clinic. Data from clinical trials investigating
the effects of 1,13 the H3 receptor antagonist 2 in the presence of the H1 receptor antagonist
fexofenadine (4),14 and the H3 receptor antagonist 315 in allergen-induced nasal congestion
were published recently. Nasal discomfort, such as burning sensation, irritation or itching
were reported by subjects dosed with 1 (1 mg i.n.)13 and development of this compound was
discontinued. In humans a combination of fexofenadine and 2 (1 or 10 mg p.o.) induced a
reduction in allergen-induced nasal congestion, however, moderate adverse effects, such as
insomnia, disorientation and anorexia were reported.14 The data from trials with 3 (10 mg,
single-dose, in the absence of any H1 receptor activity), showed a reduction of nasal
congestion by the equivalent of at least a 60 mg dose of pseudoephedrine as assessed by
acoustic rhinometry.15 In this paper we report our efforts in identifying an alternative series
of H1H3 dual receptor antagonists as back-up to 1.
Chart 1 Structures of H3 receptor antagonists recently investigated in the clinic for allergic
rhinitis (1-3) together with the structures of H1 receptor antagonists fexofenadine (4) and
azelastine (5)

The target profile for this work was a high affinity non-phthalazinone, human H1 and H3
antagonist, with selectivity over α and α receptors, low brain penetration to avoid CNS H3
1A
1B
effects, low oral bioavailability and no hERG liability. For this work we focused on
replacing the phthalazinone group present in our clinical candidate 1 with another template in
order to eliminate the possibility of the nasal irritancy observed with 1 being due the specific
chemotype used. Identification of novel H1 fragments was undertaken from compound
collection data mining and found 8-piperazine substituted quinolines to be potent H1
fragments (in red, scheme 1). A basic amine connected through an alkoxy chain to a
lipophilic group (in blue, scheme 1) is a common structural feature shared by several classes
of H3 antagonists, including our own dual antagonist 1.9 Initially, the chain-length (in black)
connecting the H1 and H3 fragments was investigated, starting with the two-carbon chain and
going up to four-carbons as in the case of 1. The compounds were synthesised by the route
outlined in scheme 1 starting with the appropriate hydroxyalkylphenol 6, alkylating the
phenolic hydroxyl with 1-bromo-3-chloropropane, followed by reaction with homopiperidine,
mesylation of the hydroxy group and finally reaction with 8-(piperazin-1-yl)quinoline 10 to
provide 11a-c. The compounds were screened for antagonist affinity at the human H1

receptor (determined by fluorescence imaging plate reader), human H3 receptor (determined
by a functional GTPγ[S]-assay), human α and α receptors (determined in intact fibroblast
1A
1B
cells by means of plate-based calcium imaging) and 3H-dofetilide hERG radioligand binding
affinity as described in our previous publications.9,16 Phthalazinone 1 and azelastine (5) were
used as reference compounds and the data from all the above screens together with the clogP
and measured logD at pH 7.4 are summarised in Table 1. Despite the impressive H1 and H3
affinities of these compounds, they lacked selectivity against α and α adrenoceptors. The
1A
1B
effects of antagonising α -adrenergic activity are hypotension, dizziness, lightheadedness, or
1
orthostatic hypotension (fainting when rising from a lying or sitting posture). Furthermore,
the more lipophilic compounds 11b and 11c (clogP 6.9 and 7.4 respectively) had increased
levels of hERG affinity, so further work focused on analogues having the two-carbon chain
linker.
HO
a
HO
b
n
n
O
Cl
OH
N
NH
N
c
RSO O
2
HO
n
n
N
O
N
O
d
O
N
N
N
n
N
Scheme 1. Reagents and conditions: a) 1-bromo-3-chloropropane, K2CO3, 2-butanone,
reflux, 18 h, 90-91%; b) homopiperidine, KI, K2CO3, 2-butanone, 78-81%; c) for 9a and 9c
MsCl, DIPEA, DCM, 94-100%, for 9b TsCl, pyridine, DCM, 60%; d) 8-(piperazin-1-

yl)quinoline, Et3N, NMP, microwave, 160°C, 15 min, for 11a 47%, for 11b 34%, for 11c
27%.
It is necessary to have a low brain concentration of H1 receptor antagonist in order to avoid
sedation. Azelastine, which is dosed intranasally, gave a brain-blood ratio of 7.5 following
intravenous infusion to the male CD rat.9 Studies with 11a have demonstrated even higher
brain-penetration (ratio of >13), so the addition of polar groups on the quinoline moiety to
reduce CNS penetration was investigated. Carboxylic acids 12a-f were synthesised using the
route outlined in scheme 2, starting from mesylate 13, reacting with N-Boc-piperazine to give
14, deprotecting the silyl ether with fluoride and converting the resulting phenol to the
chloride 15 using 1-bromo-3-chloropropane, followed by cleavage of the Boc protecting
group to give key intermediate 16. Aromatic nucleophilic substitution of triflate 17 with
piperazine 16, followed by ester hydrolysis provided analogue 12a. The remaining analogues
were prepared in a similar way using intermediate 16 and the appropriately substituted
quinoline ester possessing a triflate or halide leaving group, followed by ester hydrolysis.
The binding affinities of these analogues are presented in Table 1. The general consequence
of introducing a carboxylic acid group into the quinoline ring (12a-f) was the reduction of
lipophilicity (logD7.4 between – 1 and – 0.12) and a corresponding reduction of hERG and H1
affinity, but with little effect on H3 activity. The reduction of the H1 affinity for the C2 and
C3 substituted quinolines 12a and 12b was less severe than the remaining C4-C8 positions,
so additional compounds with substituents containing a carboxylic acid at these two positions
(12g-i) were synthesised.17 These analogues retained high affinity for both H1 and H3 and
selectivity against hERG, α and α receptors with 12h showing higher H1 affinity than the
1A
1B
C3 substituted analogue 12i.

Scheme 2. Reagents and conditions: a) N-Boc-piperazine, NaHCO3, MeCN, reflux, 2 d,
77%; b) TBAF, THF, 20°C, 3 h, 95%; c) 1-bromo-3-chloropropane, K2CO3, 2-butanone,
reflux, 24 h, 76%; d) homopiperidine, KI, K2CO3, 2-butanone, 57%; e) TFA, DCM, 100%;
f) Pd2(dba)3, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, Cs2CO3, THF,
reflux, 15%; g) NaOH, H2O, MeOH, 43%.
Additional targets (18a-c) combining this promising quinoline C2 position with a second
hydrophobic substituent at C6 aiming to slightly increase lipophilicity of 12h (logD7.4 = 0.18)
to the logD7.4 of azelastine i.e. between 1 and 2) in order to maintain or increase duration of
action. Substituents at positions other than the quinoline C6 were investigated, but had
reduced affinity. Analogues 18a-c were prepared from 4-bromo-2-fluoroaniline (19), which
was converted to quinoline 20 using the Skraup synthesis, followed by aromatic nucleophilic
substitution of fluoride with piperazine and protection with Boc2O to provide 21 (scheme
3).17 The latter was oxidised with SeO2 to aldehyde 22 and converted to 23, which was a

common intermediate for the synthesis of all three analogues 18a-c by reacting with the
appropriate B-alkyl-9-BBN derivative in the presence of 1,1′-
bis(diphenylphosphino)ferrocene]dichloropalladium(II) to provide 24. Deprotection with
TFA, followed by hydrogenation gave 25, which was then alkylated with mesylate 9a, and
finally the ester group was hydrolysed to give 18. These analogues retained H1 and H3
affinity, however, for 18c the selectivity against the human α receptor almost disappeared.
1A
Scheme 3. Reagent and conditions: a) crotonaldehyde, 5M HCl, PhMe, 100°C, 3 h, 57%;
b) (i) piperazine, 150°C, microwave, 30 min, (ii) Boc2O, Et3N, DMAP, MeCN, 16 h, 90%; c)
SeO2, 1,4-dioxane, 55-80°C, 16 h, 97%; d) Ph3P=CHCO2Me, THF, 65°C, 40 h, 70%; e) B-
Bn-9-BBN, K2CO3, 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), THF, DMF,
65°C, 95 h; f) (i) TFA, DCM (ii) H2, 10% Pd/C, AcOH, EtOAc, 2 h, 33% (for three steps);
g) (i) 9a, NaHCO3, MeCN, 80°C, 65 h, 36%, (ii) NaOH, H2O, MeOH, 35%.

In addition to the assays reported above, a more precise, lower throughput, modified version
of the human H1 FLIPR assay was run, which provided apparent pA2 values. Antagonist pA2
values were determined by generating histamine concentration – response curves either in the
absence or presence of a single concentration of antagonist (100 nM) at 30 min incubation.9
The data for 11a, 11c, and 18a-c are summarised in Table 2 and the compounds are compared
to 1 and 5. Duration of action in vitro was determined in the FLIPR assay by incubation of
adherent CHO cells with antagonist for 30 min, followed by washing, and then by repeat
histamine challenges at intervals of 90 and 270 min at 37 °C. Agonist dose ratios were
converted to receptor occupancies, which were plotted against time. A measure of duration
was obtained from the gradient of the percent receptor occupancy versus time plot. Results
were statistically analysed and related to azelastine in the same assay, and expressed as
slower, no-difference or faster wash-out than azelastine, with slower wash-out equating to
longer duration of action. The C3 propanoic acid derivative 12i was confirmed as low
potency and was rejected. The quinolines 11a and 11c possessing no carboxylic acid
substituents were equipotent, confirming the data from the first assay, and showing duration
of action longer than azelastine at both time points. The C6 ethyl substituted analogue 18a
had high affinity for H1 receptor (pA2 = 8.6), however, it had a shorter duration of action than
azelastine and was rejected. The remaining two analogues, 18b and 18c had high affinity for
the H1 receptor with the C6 butyl analogue 18b being more potent (pA2 = 8.8). The C6
benzyl analogue 18c was longer acting than azelastine at 90 min and had the same duration at
270 min, however, this compound was not selective against the human α receptor and was
1A
therefore rejected. The C6 butyl analogue 18b had the same duration of action as azelastine
at 270 min. Selected compounds possessing a carboxylic acid substituent were screened for
brain penetration in the rat and shown to have a low brain concentration (for example brain to

plasma ratio for 18c was 0.15), a vast improvement over 11a (ratio >13) and significantly
lower than azelastine (ratio 7.5) and 1 (0.6).18
In summary 18b compared to phthalazinone 1 had similar affinity for the human H1 and H3
receptors, better selectivity over α , α and hERG, lower logD7.4, higher PSA (69 vs 50), and
1A 1B
similar duration of action making 18b an alternative to 1 with a more desirable profile. In the
meantime the Pfizer group published a second paper with clinical data on a second H3
antagonist, PF-03654764, which is the iso-butyl amide analogue of 2.19 In this study the H3
antagonist plus fexofenadine was compared to pseudoephedrine plus fexofenadine. Although
the former group provided relief to allergic rhinitis nasal congestion compared to placebo, it
was not superior to the pseudoephedrine plus fexofenadine group.19 Furthermore side effects,
such as insomnia, headache and nausea were observed, which were clinically significant
compared to controls. Based on the data from the four clinical trials mentioned above it
seems that the combination of H3 with H1 antagonists cause significant relief of nasal
congestion, which is not as high as that obtained by the use of antihistamines in combination
with short-acting α-adrenergic agonist decongestants. This coupled with the reported
observation of side-effects associated with the use of oral H3 receptor antagonists, it was
decided not to progress 18b.20
Acknowledgements: We thank Yvonne. C. Fogden, Caroline Cook, Carla Daniel, Lisette
Magnee and Jonathan Raynor for technical assistance, Christopher Browning and Ms Linda J.
Russell for the duration studies, Yogini Patel, Clarissa Watts and Liz Pickup for the rat brain
penetration studies, and the late Michael Kranz for the modelling work. The authors were all
GSK employees and did not receive any financial support from any other funding authority.

Table 1. Antagonist affinitya of target compounds at the human H1 receptor (determined by
fluorescence imaging plate reader), human H3 receptor (determined by a functional GTPγ[S]-
assay), affinity at the human α and α receptors (determined in intact fibroblast cells by
1A
1B
means of plate-based calcium imaging), measured logD at pH 7.4, clogP (daylight) and
dofetilide hERG binding affinity.
cmpd
H1 pKi
H3 pKi
logD7.4 clogP
hERG
pIC50
α pKi
α pKi
1A
1B
(n)
(n)
(n)
(n)
1
3.2
(8)
8.6
7.3
(7)
8.0 0.1
(36)
9.6 0.0
(33)
7.4 0.0
7.5 0.1
(17)
(14)
5
2.3
(13)
1.9
4.0
6.5
7.0
8.92 0.02
(364)
6.83 0.05
(56)
7.3 0.0
(145)
7.3 0.0
(97)
(116)
11a
7.7 0.1
9.3 0.1
8.1 0.1
7.8 0.1
5.1 0.1
(1)
(17)
(14)
(12)
(10)
(6)
11b
11c
12a
1.8
(1)
6.9
7.4
4.6
7.1 0.1
9.4 0.0
7.5 0.1
7.0 0.1
6.0 0.2
(10)
(2)
(4)
(4)
(2)
5.8
(1)
2.2
(1)
7.8 0.1
9.2 0.0
7.1 0.2
7.3 0.1
(6)
(4)
(4)
<5.7
(7)
(4)
<5.7
(14)
-0.37
(1)
-
6.6 0.1
9.3 0.1
(11)
(10)

12b
12c
12d
12e
12f
12g
12h
12i
<5.7
(3)
<5.7
(6)
-0.78
(2)
4.4
4.4
4.3
4.3
4.3
4.4
4.0
4.0
5.1
6.4 0.1
8.8 0.1
4.7 0.1
(11)
<5.6
(7)
(14)
(5)
<4.2
(5)
<5.7
(6)
<5.7
(8)
-0.24
(2)
8.8 0.2
(10)
<5.7
(2)
<5.7
(6)
-
<4.2
(2)
6.0 0.2
8.5 0.2
(3)
<5.6
(4)
(6)
<5.7
(2)
<5.7
(6)
-1.0
(1)
4.4
(1)
8.7 0.1
(6)
<5.6
(6)
<5.7
(5)
<5.7
(8)
-0.12
(3)
8.9 0.1
4.5 0.0
(10)
(2)
<4.2
(2)
0.34
(1)
6.7 0.3
8.8 0.1
7.2 0.1
7.1 0.0
(2)
(4)
(2)
<5.7
(3)
(2)
0.18
(4)
7.9 0.1
8.8 0.1
6.7 0.4
4.8 0.1
(10)
(10)
(2)
<5.7
(3)
(7)
<5.7
(4)
-0.63
(2)
7.4 0.1
8.9 0.1
4.5 0.1
(10)
(10)
(3)
4.3
18a
<5.7
1.0
7.8 0.1
8.7 0.1
6.6 0.1

(8)
(7)
(5)
(3)
(1)
2.3
(1)
(1)
18b
18c
6.1
6.1
7.9 0.1
9.1 0.2
6.5 0.2
6.4 0.2
5.6 0.1
(8)
(8)
(6)
(4)
(5)
1.9
(2)
7.6 0.1
9.5 0.0
7.3 0.1
6.6 0.1
5.2 0.0
(22)
(22)
(9)
(6)
(2)
a Table 1 shows mean SEM (where applicable) of estimated functional pKi for n<3 the
SEM is the SD. n = number of experiments

Table 2. Antagonist pA2 Affinity at the Human H1 Receptor, determined by Fluorescence
Imaging Plate Reader, and in vitro Duration
pA2 SEMa
Compound
n
Wash out at
90 min
270 min
5
19
11
6
Reference
Reference
9.7 0.1
9.1 0.1
8.0 0.2
8.3 0.1
8.6 0.1
8.8 0.1
8.2 0.1
1
S
S
S
F
--
S
S
S
11a
11c
18a
18b
18c
5
S
6
--
9
ND
ND
19
a
All pA2 values taken from curve shifts generated at 30 min incubation time and with 100
nM antagonist. Table 2 shows mean pA2 SEM for n<3 the SEM is the SD. n = number of
experiments.

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Casale, T. B. J. Allergy Clin. Immunol. 2012, 129, 409-412.
15.
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16. Procopiou, P. A.; Ancliff, R. A.; Bamford, M. J.; Browning, C.; Connor, H.; Davies,
Barchuk, W. T.; Salapatek, A. M.; Tingting, G.; D’Angelo, P.; Liu, X. J. Allergy Clin.
S.; Fogden, Y. C.; Hodgson, S. T.; Holmes, D. S.; Looker, B. E.; Morriss, K. M. L.; Parr, C.
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19.
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Spectroscopic data for 18b: LCMS RT=2.38 min, 100%, ES+ve m/z 601 (M+H)+ and
20.
ES-ve m/z 599 (M-H)-; 1H NMR (CD3OD, 400 MHz) 8.50 (1H, s), 8.07 (1H, d, J 8.5 Hz),
7.37 (1H, d, J 8.5 Hz), 7.32 (1H, br s), 7.24 (2H, d, J 8.5 Hz), 7.10 (1H, br s), 6.92 (2H, d, J
8.5 Hz), 4.08 (2H, t, J 6 Hz), 3.63-3.52 (4H, m), 3.40-3.26 (11H, m, obscured by solvent),

3.20-3.14 (2H, m), 3.03-2.97 (2H, m), 2.83 (2H, t, J 7 Hz), 2.75 (2H, t, J 7.5 Hz), 2.26-2.18
(2H, m), 1.95-1.88 (4H, m), 1.77-1.64 (6H, m), 1.45-1.35 (2H, m), 0.96 (3H, t, J 7.5 Hz).

Graphical abstract
2
3-(8-(4-(4-(3-(azepan-1-yl)propoxy)phenethyl)piperazin-1-yl)-6-butylquinolin-2-yl)propanoic acid
pA2 = 8.8 for H1 receptor
pKi = 9.1 for H3 receptor