In vitro studies on a class of quinoline containing histamine H3 antagonists

Article abstract of DOI:10.1016/j.bmcl.2010.04.045

A series of quinoline containing histamine H₃ antagonists is reported herein. These analogs were synthesized via the Friedlander quinoline synthesis between an aminoaldehyde intermediate and a methyl ketone allowing for a wide diversity of subs

Full text of DOI:10.1016/j.bmcl.2010.04.045

Bioorganic & Medicinal Chemistry Letters 20 (2010) 3295–3300
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
In vitro studies on a class of quinoline containing histamine H3 antagonists
*
Huaqing Liu , Robert J. Altenbach, Gilbert J. Diaz, Arlene M. Manelli, Ruth L. Martin, Thomas R. Miller,
Timothy A. Esbenshade, Jorge D. Brioni, Marlon D. Cowart
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6123, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 January 2010
Revised 9 April 2010
Accepted 12 April 2010
Available online 18 April 2010
A series of quinoline containing histamine H3 antagonists is reported herein. These analogs were synthe-
sized via the Friedlander quinoline synthesis between an aminoaldehyde intermediate and a methyl
ketone allowing for a wide diversity of substituents at the 2-position of the quinoline ring.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Histamine H3
Neurotransimitter
hERG
Presently, there are four known histamine receptors H1, H2, H3
and H4.1–4 Drugs targeting H1 and H2 receptors have found clinical
utilities in treating allergic rhinitis and reducing gastric acid secre-
tion, respectively. The hope for novel clinical use targeting condi-
tions such as ADHD (H3) and asthma (H4) has prompted intense
efforts in the pharmaceutical industry to develop antagonists for
histamine H3 and H4 receptors. The histamine H3 receptor was first
reported and characterized more than 20 years ago.5 It is abun-
dantly localized in CNS neurons, with lesser distribution in specific
peripheral areas, predominantly neuronal.6 On histaminergic neu-
rons, the H3 receptor acts as a presynaptic autoreceptor that regu-
lates the release and synthesis of histamine; when localized on
non-histamine neurons, it modulates the release of other neuro-
transmitters, such as acetylcholine, dopamine, noradrenaline and
serotonin.7–11 Preclinical studies of the histaminergic system have
indicated the potential for H3 antagonists as therapeutic agents for
disorders involving attention, sleep, and cognition.10,11
Although ABT-239 has become a reference antagonist for pre-
clinical behavioral studies, it has the liability of significant off-tar-
get activity at the hERG channel.19 Thus, we were interested in
other structural series beyond benzofurans targeting new series
with equal or better affinity and good ADMET properties. Previous
studies on the alkyl linker and the amine moiety of the benzofuran
series uncovered that the ethyl-linked (R)-2-methylpyrrolidine
group provided high affinity for the H3 receptor.16,20 During our
investigation into modifications of the benzofuran, a series of
naphthalenes20 was discovered that provided good in vitro affinity
for the H3 receptor. Like 4, members of the new naphthalene series
were active in animal models of cognition. Beyond the 4-cyano-
phenyl group on the naphthalene and benzofuran cores, other ac-
tive groups such as heterocycles could be prepared through
cross-coupling reactions such as the Suzuki and Ullman reactions.
We report here a series of quinolines (general structure 13,
Scheme 1).21 An additional benefit of this series was the ability
to extensively probe the SAR of the series, due to the especially fac-
ile Friedlander condensation chemistry to install the R moiety on
13. This reaction (step f in Scheme 1) enables a very wide variety
of R group analogs to be readily generated.
Synthetic analogs of the natural ligand histamine were the first
H3 antagonists. These imidazole-based H3 antagonists (1–3)
(Fig. 1) were used to characterize the in vivo and in vitro pharmacol-
ogy of the H3 receptor.12 The known liability of CYP inhibition
induced by the imidazole moiety and the lower CNS penetration
encouraged the subsequent design of non-imidazole H3 antago-
nists.13,14 In recent years, there have been reports of a number of
structurally diverse non-imidazole H3 antagonist series. Examples
The quinolines reported here were prepared through the Fried-
lander quinoline condensation22 as the key step. As such, reaction
of the ortho-aminoaldehyde 12 with methyl ketones (Scheme 1)
was very efficient. Because a large variety of methyl ketones was
available commercially and from internal compound collections,
the chemistry allowed for the synthesis of a wide variety of deriv-
atives not easily available via the cross-coupling chemistry used
for the benzofurans.
include prominent compounds such 4,15 16 and 6.17 ABT-239 and
5
other benzofurans were found to be particularly potent and effective
in a number of behavioral assays.15,18,19
As shown in Scheme 1,23 4-nitrophenethyl bromide 7 was dis-
placed with (R)-2-methylpyrrolidine24 in DMF to afford compound
* Corresponding author.
E-mail address: huaqing.liu@abbott.com (H. Liu).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.04.045

3296
H. Liu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3295–3300
O
S
H
N
N
H
HN
O
N
H
HN
HN
N
N
1
2
3
Ciproxifan
Thioperamide
GT-2331
N
O
N
O
N
N
N
N
HN
F
O
O
F
F
4
5
6
NNC 38-1202
ABT-239
GSK-189254
Figure 1. Structures of some H3 antagonists.
H
N
NH2
NO2
a
NO2
b
c
O
N
N
Br
N
9
10
N
7
8
R
O
NH2
f
e
d
NH
N
CHO
N
13
12
N
CHO
11
Scheme 1. Reagents and conditions: (a) (R)-2-methylpyrrolidine tartrate, K2CO3/DMF, 65 °C, 24 h, 100%; (b) H2, 10% Pd/C, 45 psi, 45 min, quantitative; (c) pivaloyl chloride,
DCM, TEA, rt, 95%; (d) 3 equiv n-BuLi, 3 equiv TMEDA, ether, 0 °C, 30 min, then 6 equiv DMF, 0 °C to rt; (e) >50 mL 2 M HCl/g of 11, reflux 45 min 59% from aniline;
(f) RC(O)Me, NaOH, EtOH, reflux, 40–70%.
8, which was subsequently hydrogenated to aniline 9. Protection of
amino group as the pivaloyl amide 10 facilitated ortho directed
formylation in the next step to provide the protected ortho-amino-
aldehyde 11. Deprotection of the pivaloyl amide was best carried
out dilute in the hot aqueous acid to give moderate yields of the
ortho-aminoaldehyde 12; reactions run more concentrated gave
lower yield due to the formation of a cyclotrimer of 12 through self
condensation. Friedlander condensation yields varied, but were
widely successful with a variety of substrates.
Methyl ketone condensation partners containing groups sensi-
tive to alkoxide were labile in the Friedlander reaction. For exam-
ple, the nitrile-containing ketones used to generate compounds 35
and 43 provided a mixture of desired products (35 and 43) and side
products (compounds 36 and 44, respectively). In addition, the ke-
tone intermediate used to generate compound 70 was a chloropyr-
azine, the chlorine atom of which was displaced by ethoxide
during the Friedlander reaction.
quinoline compounds (19–48) possessed H3 binding potencies of
less than 5 nM human and 20 nM rat. Also interesting was the al-
most 10-fold decrease in both rat and human H3 affinities for dihy-
drothiazole 20, a non-aromatic ring, compared to thiazole 19. The
4-methylpiperidine analog, compound 51,26 was the most potent
compound of the series, having an affinity of 50 pM for the hH3R
and 80 pM at the rH3R.
Analogs 49, 50 and 52–76 were made, with the aryl or hetero-
aryl derivatives substituted with an additional ring. Most of these
second rings were at the distal position relative to the quinoline.
These additional ring substitutions were well tolerated or even im-
proved beyond most of the analogs of benzofuran series, with
potencies in the subnanomolar range, with exceptions being com-
pounds 63–66 and 73. These compounds indicate that increased
lipophilicity on the more distal ring may result in some decrease
in binding affinity for the H3 receptor. Three analogs, compounds
74–76, possessed a phenyl ring connected to the ‘‘ortho” position
of the middle ring. These analogs maintained high in vitro poten-
cies for the H3 receptor. One interesting SAR finding was the differ-
ences in potencies between compounds 73 and 74, wherein the
distal substituted 73 is over 50-fold less potent than the corre-
sponding ‘‘ortho” substituted 74. The fused analogs, compounds
77–87, were highly potent as well. In general, in vitro potencies
were very well maintained in spite of the different groups and
orientations.
A wide variety of analogs with aryl and heteroaryl substituents
on the 2-position of the quinoline were synthesized. The in vitro
binding potencies for these analogs at the rat and the human H3
receptor as well as the hERG channel are displayed in Table 1. Com-
pounds in this series were shown to be inverse agonists in the
GTPc
S binding assay.25 The 4-cyanophenyl analog 14 had similar
H3R affinity to that of the benzofuran, ABT-239, justifying the belief
that the quinoline core could support high in vitro affinity. A sur-
vey of the 2-position revealed that alkyl substitution (16–18) de-
creased affinity relative to 4-cyano phenyl. The size of the alkyl
group had no difference in terms of the H3 affinities.
In general, the monocyclic aryl and heteroaryl substitutions
(compounds 19–48, 51) had high affinity at both rat and human
H3Rs. Except for one compound (e.g., 45), single ring substituted
In addition to the in vitro H3R affinities, the new compounds
were also tested for interaction with hERG (Human Ether-a-go-
go Related Gene) channel in a competition binding assay ([3H]-dof-
etilide used as the radioligand).27 This voltage-gated potassium
channel has been associated with drug-induced long QT syn-
drome.28 Reducing or eliminating hERG binding at an early stage

Table 1
Binding data (Ki) of quinolines at human H3R, rat H3R and hERG channel. Selectivity (sel. Â 1000) for activity at human H3R over hERG shown
N
R
N
hERGb,c
Compd
R
H3 (nM)
hERGb,c
Compd
R
H3 (nM)
hERGb,c
a,b
a,b
a,b
Compd
R
H3 (nM)
Hum
Rat
l
M
Sel.
Hum
Rat
lM
Sel.
Hum
Rat
lM
Sel.
Cl
N
S
N
N
4
ABT-239
0.45
1.4
0.40
1.1
38
0.11
0.50
3.0
27
63
28
55
5.1
0.2
Cl
S
N
CN
14
15
16
0.69
7.4
12
3.9
41
65
0.78
10
1
1
5
39
40
41
0.22
0.25
0.15
1.9
6.9
31
4
64
65
66
6.8
25
21
31
58
71
0.4
0.06
0.02
0.02
N
S
CF3
Cl
O
H
0.48
0.45
0.87
6.6
0.38
0.5
N
N
S
N
Me
54
44
S
N
N
Cl
17
18
7.4
11
47
51
11
2
42
43
0.36
0.28
2.2
2.0
5.0
2.1
14
8
67
68
0.74
0.26
2.1
0.15
5.0
0.2
19
Cl
N
N
N
N
CN
t-Bu
1.7
0.2
0.91
N
N
CF3
N
S
CONH2
19
0.44
1.6
2.9
7
44
0.98
5.5
10
10
69
1.1
5.9
4.2
4
N
N
N
N
N
N
S
HO
OEt
N
20
21
3.8
17
6.3
5.1
2
45
46
230
1000
0.51
10
0.04
56
70
71
0.19
0.19
0.49
1.1
2.6
4.5
14
24
N
N
N
N
F3C
N
N
0.19
1.4
27
0.11
6.2
N
N
N
N
S
N
(continued on next page)

Table 1 (continued)
hERGb,c
Compd
R
H3 (nM)
hERGb,c
Sel.
Compd
R
H3 (nM)
hERGb,c
M Sel.
a,b
a,b
a,b
Compd
R
H3 (nM)
Hum
Rat
l
M
Sel.
Hum
Rat
lM
Hum
Rat
l
F
N
N
N
N
N
N
22
23
24
0.56
1.8
1.5
10
18
47
48
49
0.19
0.23
0.29
0.66
10
53
24
9
72
73
74
0.29
7.8
0.35
0.72
3
F
N
N
O
O
O
O
N
Br
O
N
5.5
5.4
0.22
1.5
0.1
2
1.0
5.6
2.6
36
0.44
0.40
0.06
3
Cl
N
N
CO2Et
N
N
Cl
0.71
0.72
0.16
0.40
O
N
CO2Et
Cl
N
25
3.5
16
4.2
1
50
1.7
1.4
0.03
0.02
75
0.41
0.59
1.5
4
N
N
N
Ph
Ph
O
N
N
Ph
H
N
N
26
27
28
3.2
14
10
10
4.4
3
51
52
53
0.05
1.0
0.08
2.3
5.6
112
0.7
42
76
77
78
0.10
2.9
0.31
8.5
1.6
16
0.2
1
O
N
N
S
NH
N
N
N
0.89
0.2
5.9
1.5
11
22
0.69
5.0
0.48
0.43
N
S
N
O
N
0.12
0.3
0.36
0.78
NH
N
S
N
S
N
N
N
29
30
0.16
0.45
0.68
1.6
10
63
14
54
55
1.1
6.8
4.5
0.34
0.93
0.3
1
79
80
0.10
0.85
0.25
4.9
0.71
10
7
N
N
N
S
N
N
N
6.2
0.95
12
S
N
N
S
N
N
NH
N
31
32
0.93
5.1
5.4
20
10
11
56
57
0.35
0.56
1.4
2.9
7.9
5.1
23
9
81
82
0.12
0.37
0.50
1.7
2
17
6
S
N
N
O
N
N
O
2.1
0.4
2.1
S
N
N
N
N
S
33
34
2.5
1.0
6.9
3.6
1.2
0.5
0.6
58
59
0.34
0.35
2.3
1.9
2.8
1.5
8
4
83
84
0.34
0.40
2.0
2.3
10
29
2
S
N
N
O
0.62
0.91
S
O
S
N

H. Liu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3295–3300
3299
of drug discovery has become a primary task of current drug dis-
covery. The large number of new compounds made in this quino-
line series allowed us to assess hERG and H3 affinities for a wide
range of substituents on the quinoline core, and to find com-
pounds that were highly selective over hERG, while maintaining
potent in vitro activity at the H3R. From Table 1, general trends
can be seen. In the monocyclic derivatives, analogs such as bro-
moisoxazole 23, furan 33, and thiophenes, 34 and 35, had unac-
ceptable high hERG affinities. Whereas, analogs with pyrazoles
(26–31), pyridines (37–39, 41 and 42) and pyrimidines (47 and
48) bound much less potently to the hERG channel, and thus pos-
sess a more favorable selectivity for H3 over hERG. In the case of
groups substituted with an additional ring, the more distal ring
seems to play a bigger influence on hERG binding. Although the
analogs allowing a direct comparison were not available, general
trends show that replacement of the phenyl of compound 54 with
groups such as pyrazine (56) and pyridine (58–60) result in a de-
crease in the hERG binding. The high selectivity of this series over
the hERG site was further evaluated by examining analogs in a
Purkinje fiber assay.29 Compounds 30 and 86 displayed no ad-
verse advents at high plasma concentration, 250 ng/mL and
200 ng/mL, respectively.
A selection of compounds (30, 49, 68, 70, 83 and 86) was chosen
for further PK and in vivo profiling.21 Compounds 30, 49, 68, 70 and
86 displayed good PK properties, blood–brain barrier penetration
andwerefound tobeefficaciousina socialrecognitionmemorytest
in adult rats. In addition, compounds 30 and 86 were found to be
efficacious at 0.1 and 0.3 mg/kg, respectively, in the 5-trial inhibi-
tory avoidance model, a primary model to assess the animal learn-
ing ability as well as impulsive behaviors.
In conclusion, a novel series of quinoline H3 antagonists was dis-
covered. The facile synthesis allowed a verywide variety of aromatic
and heteroaromatic substitutions to be synthesized. The SAR of the
analogs in this quinoline series showed very high H3R affinity and
selectivity over hERG for the majority of the compounds.
Acknowledgements
The authors thank Ms. Tracy Carr, Mr. David Witte and Mr.
John Baranowski for in vitro data of some of the compounds.
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H
NH2
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N
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a
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9
9A
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51
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sealed tube, 90 °C, 16 h, 68%.
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