Identification of 4-(1H-Imidazol-4(5)-ylmethyl)pyridine (Immethridine) as a Novel, Potent, and Highly Selective Histamine H3 Receptor Agonist

Article abstract of DOI:10.1021/jm049932u

In this study, the piperidine ring of immepip and its analogues was replaced by a rigid heterocyclic pyridine ring. Many compounds in the series exhibit high affinity and agonist activity at the human histamine H₃ receptor. Particularly, the 4-

Full text of DOI:10.1021/jm049932u

2414
J . Med. Chem. 2004, 47, 2414-2417
Ch a r t 1. Binding Affinities and Functional Activities of
Histamine H3 Receptor Ligands
Id en tifica tion of
4-(1H-Im id a zol-4(5)-ylm eth yl)p yr id in e
(Im m eth r id in e) a s a Novel, P oten t, a n d
High ly Selective Hista m in e H3 Recep tor
Agon ist
Ruengwit Kitbunnadaj,†,‡ Obbe P. Zuiderveld,†
Bernard Christophe,§ Saskia Hulscher,†
Wiro M. P. B. Menge,† Edith Gelens,† Erwin Snip,†
Remko A. Bakker,† Sylvain Celanire,§
Michel Gillard,§ Patrice Talaga,§
A previous study on conformationally constrained
analogues of histamine and its homologues demon-
strated that increased rigidity by incorporation of a
piperidine ring into the side chain results in increased
affinity and agonist efficacy at the human histamine H3
receptor. Immepip, a conformationally constrained ana-
logue of imbutamine, possesses improved affinity and
functional activity at the human H3 receptor (Chart 1).23
Although the piperidine ring is more rigid than the
aliphatic alkylamine, this ring system still shows some
flexibility. We hypothesized that the histamine H3
receptor affinity could be improved further by imparting
a conformational constraint of the side chain via re-
placement of the piperidine ring with an aromatic
pyridine ring. Our previous study also showed that
extension of the spacer between the imidazole and the
piperidine ring resulted in a potent neutral H3 antago-
nist (VUF5681, Chart 1).23 We therefore designed a new
series of compounds with variation in the spacer length
between the imidazole and pyridine ring and/or alter-
ation of nitrogen position in the pyridine ring (Figure
1).
Henk Timmerman,† and Rob Leurs*,†
Leiden/ Amsterdam Center of Drug Research (LACDR),
Division of Medicinal Chemistry, Faculty of Sciences,
Vrije Universiteit Amsterdam, The Netherlands, Department
of Pharmaceutical Chemistry and Pharmacognosy, Faculty
of Pharmaceutical Sciences, Naresuan University,
Phitsanulok, Thailand, and UCB Pharma,
Chemin du Foriest, B-1420 Braine-l’Alleud, Belgium
Received J anuary 23, 2004
Abstr a ct: In this study, the piperidine ring of immepip and
its analogues was replaced by a rigid heterocyclic pyridine ring.
Many compounds in the series exhibit high affinity and agonist
activity at the human histamine H3 receptor. Particularly, the
4-pyridinyl analogue of immepip (1c, immethridine) is identi-
fied as a novel potent and highly selective histamine H3
receptor agonist (pKi ) 9.07, pEC50 ) 9.74) with a 300-fold
selectivity over the closely related H4 receptor.
Histamine is a biogenic amine with multiple physi-
ological effects. It exerts its biological activities through
four histamine receptors, i.e., H1, H2, H3, and H4 recep-
tors, which all belong to the superfamily of heptahelical
(7TM) G-protein-coupled receptors.1-4 The histamine H1
and H2 receptors have been identified by pharmacologi-
cal means many years ago, and histamine H1 and H2
antagonists have been used clinically for the treatment
of allergy and gastric ulcers, respectively.5-8 The his-
tamine H3 receptor, however, was discovered in 1983
by Arrang et al. and was identified as a presynaptic
autoreceptor in the brain controlling the release of
histamine.9,10 Subsequently, the histamine H3 receptor
was also shown to act as presynaptic heteroreceptor at
nonhistaminergic neurons in the central and peripheral
nervous system modulating the release of neurotrans-
mitters such as acetylcholine,11 dopamine,12 serotonin,13
and noradrenaline.14 The therapeutic potential for
histamine H3 receptor antagonists and agonists has
been suggested in a variety of disorders; antagonists
have been proposed for several central nervous system
disorders, e.g., epilepsy,15 attention-deficit hyperactivity
disorder,16 Alzheimer’s disease,17 schizophrenia,18 and
obesity,19 while agonists could be of potential use in
myocardial ischemia,20 inflammatory,21 and gastric acid
related diseases.22
F igu r e 1. Design of novel histamine H3 receptor agonists
based on the hypothesis that increased rigidity leads to
increased activity.
Some of the ligands have been described before24 but
were synthesized differently in this work. Compounds
1a -c were synthesized from protected 4-iodoimidazole25
(4) as shown in Scheme 1. The iodo compound was
treated with EtMgBr, then with pyridinecarboxalde-
hydes to give the intermediate alcohols (5) in good yield
(85-90%). The alcohol was acetylated by acetic anhy-
dride using dimethylaminopyridine (DMAP) as a cata-
lyst to obtain 6, which was subsequently hydrogenated
under 50 atm of H2 to give 7 in moderate yield (70-
75%). Deprotection of 7, by heating in 30% HBr at reflux
temperature, provided 1a -c.
Compounds 2a -c were synthesized according to
Scheme 2. The intermediate aldehydes (9) were pre-
pared from commercially available 3-pyridinepropan-
1-ols via a Swern oxidation in moderate to good yield
(75-85%).26 By use of TosMIC-mediated imidazole
synthesis,27 2a -c were obtained in moderate yield (65-
75%).
* To whom correspondence should be addressed. Phone: (+31) 20
444-7600. Fax: (+31) 20 444-7610. E-mail: leurs@few.vu.nl.
† Vrije Universiteit Amsterdam.
The synthesis of 3-(1H-imidazol-4(5)-yl)propyl-
pyridines (3a -c) followed Scheme 3. The key inter-
‡ Naresuan University.
§ UCB Pharma.
10.1021/jm049932u CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/09/2004

Letters
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 10 2415
Ta ble 1. Affinities and Functional Activities of Pyridine-Containing Ligands on the Human Histamine H3 and H4 Receptors
human histamine H3 receptor
human histamine H4 receptor
compd
VUF
n
isomer
pKi ( SEMa
pEC50 ( SEMb
Rc
pKi ( SEMa
pEC50 ( SEMb
Rc
selectivityd
1a
1b
1c
2a
2b
2c
3a
3b
3c
4886
4857
immethridine
5912
5913
5889
5914
5915
5916
imbutamine
immepip
1
1
1
2
2
2
3
3
3
2
3
4
2
3
4
2
3
4
6.23 ( 0.00
7.28 ( 0.02
9.07 ( 0.00
5.93 ( 0.02
6.85 ( 0.03
8.16 ( 0.05
5.98 ( 0.01
7.48 ( 0.03
7.81 ( 0.03
8.39 ( 0.03
9.32 ( 0.04
6.22 ( 0.05
7.41 ( 0.12
9.74 ( 0.14
5.87 ( 0.09
6.45 ( 0.10
8.17 ( 0.02
6.04 ( 0.02
7.51 ( 0.03
7.71 ( 0.09
8.13 ( 0.08
9.88 ( 0.02
0.9
1.0
0.9
0.6
1.0
0.9
0.5
1.0
1.0
0.9
1.0
5.34 ( 0.02
6.16 ( 0.02
6.61 ( 0.02
4.91 ( 0.05
5.29 ( 0.05
5.88 ( 0.04
5.90 ( 0.06
6.32 ( 0.02
6.00 ( 0.01
7.84 ( 0.09
7.66 ( 0.04
4.98 ( 0.05
4.82 ( 0.23
6.04 ( 0.07
4.23 ( 0.19
4.49 ( 0.07
5.82 ( 0.34
5.50 ( 0.10
5.90 ( 0.13
5.81 ( 0.11
7.05 ( 0.04
7.25 ( 0.16
1.0
0.5
0.8
0.6
0.3
0.4
0.6
0.4
0.4
1.0
0.7
8
5
288
10
36
191
1
14
65
4
46
a
The pKi values were measured by [3H]-NR-methylhistamine or [3H]-histamine binding to membranes of SK-N-MC cells expressing
b
the human H3 or H4 receptor, respectively. The pEC50 values were determined by the inhibition of the cAMP-stimulated â-galactosidase
transcription in SK-N-MC cells expressing the human H3 or H4 receptor. The results were presented as the mean ( SEM of at least three
independent experiments. c R ) intrinsic activity as the ratio of the maximum response of each ligand to the maximum response of
d
histamine. Selectivity ) Ki(H4)/Ki(H3).
Sch em e 1. Synthetic Pathway for 1a -ca
Sch em e 3. Synthetic Pathway for 3a -ca
a
Reagents and conditions: (i) n-BuLi, THF, [2-(1,3-dioxolan-
2-yl)ethyl]triphenylphosphonium bromide, -30 °C, 3 h; (ii) H2, 5%
Pd/C, 1 atm, 24 h; (iii) 1 N HCl, room temp, 10 min; (iv) TosMIC,
NaCN, EtOH, room temp, 2 h; (v) saturated NH3 in EtOH, 90-
110 °C, 10-12 atm, 24 h.
a
Reagents and conditions: (i) EtMgBr, THF, pyridinecarbox-
aldehyde, room temp, 16 h; (ii) DMAP, DCM, acetic anhydride,
room temp, 3 h; (iii) H2 (50 atm), 10% Pd/C, MeOH, 24 h; (iv) 30%
HBr, reflux 24 h.
Ta ble 2. Activities of H3 Agonists on the Twitch Contraction
Induced on the Paced Myenteric Plexus Isolated from Guinea
Pig Ileuma
Sch em e 2. Synthetic Pathway for 2a -ca
compd
pD2 ( SEM
Emax ( SEM (%)
immethridine
immepip
imetit
7.45 ( 0.08
7.97 ( 0.10
7.88 ( 0.13
38.5 ( 7.56
25.2 ( 4.24
31.3 ( 6.00
a
The potency (pD2) and maximum inhibitory effect of contrac-
tion amplitude (% Emax) values were determined from concentra-
tion-response curves of ligands elicited on the paced isolated
guinea pig ileal myenteric plexus. The results were presented as
the mean ( SEM of at least five independent experiments.
a
Reagents and conditions: (i) oxalyl chloride, DMSO, DCM,
Many histamine analogues have been described as
selective H3 receptor agonists.28,29 For ligands with a
basic nitrogen in the side chain, increased rigidity
appears to result in an increase in binding affinity and
agonist potency at the human H3 receptor.23 The pip-
eridine side chain analogue, immepip, is a typical
example of such a ligand that exhibits a 10-fold higher
affinity for the human H3 receptor than its flexible
ligand (imbutamine) as seen in Table 1. Immepip is
currently one of the most potent H3 agonist known
(pKi ) 9.32 and pEC50 ) 9.88) but also shows reason-
able potency for the recently discovered histamine H4
receptor (pKi ) 7.66 and pEC50 ) 7.25). In our search
for potent and selective histamine H3 and H4 ligands,
a further conformational constraint in the side chain
triethylamine, -65 °C to room temp, 5 h; (ii) TosMIC, NaCN,
EtOH; (iii) saturated NH3 in EtOH, 90-110 °C, 10-12 atm, 24 h.
mediate ω-pyridinebutanals (14) were prepared from
corresponding pyridinecarboxaldehydes (11) following
the procedure earlier described.23 By use of the afore-
mentioned TosMIC chemistry, the imidazole products
3a -c were obtained in moderate yield (60-70%).
Characterization and physical properties of the target
compounds are shown in Table 3.
Binding affinities and functional activities of all
compounds were performed using SK-N-MC cells ex-
pressing the human histamine H3 or H4 receptor fol-
lowing procedure described in ref 23.

2416 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 10
Ta ble 3. Characterization and Physical Properties of Ligands
Letters
yielda
(%)
MSc
compd
salt
mpb (°C)
[M + 1]+
NMR (D2O)d
formula
C9H11N3Br2
1a
1b
HBr
55
225.1-226.3
(dec)
160.3
δ 8.6 (d, 1H, J ) 7 Hz), 8.5 (s, 1H), 8.4 (t, 1H, J )
7 Hz), 7.9 (t, 1H, J ) 7 Hz), 7.8 (d, 1H, J ) 7 Hz),
7.4 (s, 1H), 4.6 (s, 2H)
HBr
42
47
63
58
68
53
262.4-264.2
>300
160.4
160.4
174.3
174.5
174.6
188.4
δ 8.7 (m, 2H), 8.6 (s, 1H), 8.5 (d, 1H, J ) 7 Hz),
8.0 (t, 1H, J ) 7 Hz), 7.3 (s, 1H), 4.4 (s, 2H)
δ 8.6 (d, 2H, J ) 7 Hz), 8.5 (s, 1H), 7.9 (d, 2H,
J ) 7 Hz), 7.4 (s, 1H), 4.5 (s, 2H)
C9H11N3Br2
C9H11N3Br2
immethridine HBr
2a
2b
2c
3a
HBr
HBr
HBr
HCl
213.5-215.4
(dec)
225.8-226.5
δ 8.5 (d, 1H, J ) 7 Hz), 7.5 (m, 2H), 7.1 (m, 2H),
6.7 (s, 1H), 3.0 (m, 4H)
C10H13N3Br2‚0.3H2O
10H13N3Br2
δ 8.3 (m, 2H), 7.5 (s, 1H), 7.4 (d, 1H, J ) 8 Hz),
7.1 (m, 1H), 6.6 (s, 1H), 2.9 (m, 4H)
C
264.8-265.6
(dec)
174.3-175.6
δ 8.4 (d, 2H, J ) 7 Hz), 7.5 (s, 1H), 7.1 (d, 2H,
J ) 7 Hz), 2.9 (m, 4H)
δ 8.5 (d, 1H, J ) 7 Hz), 7.6 (m, 2H), 7.2 (m, 2H),
6.8 (s, 1H), 2.8 (t, 2H, J ) 7 Hz), 2.6 (t, 2H,
J ) 7 Hz), 2.0 (quint, 2H, J ) 7 Hz)
δ 8.5 (m, 2H), 7.6 (s, 1H), 7.5 (d, 1H, J ) 8 Hz), 7.2 (m,
1H), 6.8 (s, 1H), 2.6 (m, 4H), 2.0 (quint, 2H, J ) 7 Hz)
δ 8.5 (d, 2H, J ) 7 Hz), 7.6 (s, 1H), 7.1 (d, 2H,
J ) 7 Hz), 6.8 (s, 1H), 2.6 (m, 4H), 1.9 (m, 2H)
C10H13N3Br2
C11H15N3Cl2‚0.3H2O
3b
3c
HCl
HBr
57
55
190.4-191.1
188.3
188.6
C
C
11H15N3Cl2‚0.3H2O
220.4-221.1
(dec)
11H15N3Br2
a
b
Yields after recrystallization from EtOH/ether. Melting points were determined on an Electrothermal IA9200 apparatus. c Mass
spectrometry were performed on Finnigan LCQDECA ion-trap mass spectrometer using APCI technique. 1H NMR spectra were recorded
d
on Bruker AC-200 spectrometer with the residual undeuterated solvent peak as reference.
was achieved by a replacement of the piperidine ring
with a pyridine ring. Although none of the new com-
pounds exhibits greater affinity or agonist efficacy
than immepip, some do demonstrate greater selec-
tivity for the human H3 receptor (Table 1). At the human
H3 receptor, the 4-pyridinyl analogue of immepip,
immethridine (1c), also acts as a full agonist with high
affinity and potency (pKi ) 9.07 and pEC50 ) 9.74).
Although the affinity of immethridine at the human H3
receptor equals the affinity of immepip, immethridine
displays a 10-fold lower binding affinity at the human
H4 receptor (pKi ) 6.61 and pEC50 ) 6.04, Table 1). This
decreased binding affinity leads to a 300-fold selectivity
at the human H3 receptor over the H4 receptor. Further
evaluation of immethridine at the human H1 and H2
receptors indicated no binding affinity even at 10 µM
(data not shown). Therefore, immethridine is one of the
most potent and selective agonist for the human H3
receptor.
Consistent with observations in the piperidine-
containing series,23 the optimal spacer length within the
pyridine series is one methylene unit. Extension of the
spacer length between the imidazole ring and the
pyridine ring leads to reduced affinity and less agonist
activity at the human histamine H3 and H4 receptors.
Compounds 2c and 3c respectively exhibit pKi values
of 8.16 and 7.81 at the human H3 receptor and 5.88 and
6.00 at the human H4 receptor (Table 1).
H4 receptor activity. At the human histamine H3 recep-
tor, the full agonists 1a and 1b exhibit a significantly
reduced affinity (pKi ) 6.23 and 7.28, respectively)
compared to immethridine, whereas only a small de-
crease was observed at the human H4 receptor (pKi )
5.34 and 6.16, respectively; Table 1). This isomer
preference was also observed for the longer immethri-
dine homologues (2c f b f a and 3c f b f a ). On the
basis of these findings, we conclude that the pyridine
nitrogen plays a role in the binding to the human H3
receptor. Moreover, the position of the pyridine nitrogen
is crucial for H3 receptor binding affinity but is less
important for H4 receptor affinity.
Histamine and other H3 agonists inhibit the twitch
contraction of the paced myenteric plexus isolated from
guinea pig ileum through the activation of the hista-
minergic H3 presynaptic receptor.30-32 Immethridine
was therefore evaluated in this model. Similar to the
potent H3 agonists, i.e., imetit and immepip, immethri-
dine induces a concentration-dependent decrease of the
electrically induced twitch contraction of the guinea pig
ileal myenteric plexus. Immethridine again acts as a full
agonist and is slightly less effective (pD2 ) 7.45) than
immepip and imetit in this model (Table 2).
In this study, the replacement of the piperidine ring
of immepip with a 4-pyridine ring resulted in the
discovery of a potent and highly selective histamine H3
receptor agonist (immethridine). Although immethri-
dine possesses no improved affinity or functional activity
at the human H3 receptor (pKi ) 9.07, pEC50 ) 9.74, R
) 0.9) compared to immepip, a strongly reduced affinity
at the human H4 receptor was observed. With about
300-fold H3 receptor selectivity over the human H4
receptor and lack of binding affinity at the human
histamine H1 and H2 receptors, immethridine is cur-
rently one of the most potent and selective H3 re-
ceptor agonists. Previously, the nitrogen of histamine
and other histamine H3 receptor agonists such as
imbutamine and (R)-R-methylhistamine has been sug-
gested to form an ionic interaction with a conserved
aspartate residue (D114) in transmembrane domain 3.33
We previously observed that extension of the spacer
length in the 4-piperidine-containing series also resulted
in a decreased agonist efficacy at the human H3 recep-
tor, eventually resulting in a neutral antagonist (pro-
pylene spacer).23 In contrast, in the 4-pyridine-contain-
ing series, the longer homologues of immethridine (2c
and 3c) still behave as full agonists at the human H3
receptor. At the human H4 receptor, most of the
compounds in this series behave as partial agonists
(Table 1).
The 2- and 3-pyridinyl analogues exhibited decreased
affinity and agonist potency at the human H3 receptor,
but this change did not significantly affect the human

Letters
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 10 2417
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Because of the weakly basic property of the pyridine
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Therefore, immethridine might serve future molecular
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histamine H3 receptor.
Ack n ow led gm en t. The authors thank Dr. T. Loven-
berg, J ohnson & J ohnson Pharmaceutical Research and
Development, San Diego, CA, for the cells stably ex-
pressing the human histamine H3 and H4 receptors, and
Ms. Christel Delaunoy (UCB) for her technical support.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures. This material is available free of charge via the
Internet at http://pubs.acs.org.
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