Novel histamine H3 receptor antagonists based on the 4-[(1H-imidazol-4-yl)methyl]piperidine scaffold

Article abstract of DOI:10.1016/j.bmcl.2005.09.076

We report the discovery of novel histamine H₃ receptor antagonists based on 4-[(1H-imidazol-4-yl)methyl]piperidine. The most potent compounds in the series (e.g., 7) result from the attachment of a substituted aniline amide to the main pharmaco

Full text of DOI:10.1016/j.bmcl.2005.09.076

Bioorganic & Medicinal Chemistry Letters 16 (2006) 395–399
Novel histamine H3 receptor antagonists based on the
4-[(1H-imidazol-4-yl)methyl]piperidine scaffold
Wayne D. Vaccaro,ꢀ Rosy Sher, Michael Berlin,* Neng-Yang Shih, Robert Aslanian,
John H. Schwerdt, Kevin D. McCormick, John J. Piwinski, Robert E. West, Jr.,
John C. Anthes, Shirley M. Williams, Ren-Long Wu, H. Susan She, Maria A. Rivelli,
Jennifer C. Mutter, Michel R. Corboz, John A. Hey and Leonard Favreau
The Schering Plough Research Institute, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, USA
Received 18 August 2005; revised 17 September 2005; accepted 26 September 2005
Available online 21 October 2005
Abstract—We report the discovery of novel histamine H3 receptor antagonists based on 4-[(1H-imidazol-4-yl)methyl]piperidine. The
most potent compounds in the series (e.g., 7) result from the attachment of a substituted aniline amide to the main pharmacophore
piperidine via a two-methylene linker.
Ó 2005 Elsevier Ltd. All rights reserved.
Histamine H3 receptors have been reported to modulate
a number of neurotransmitters including histamine,1
serotonin,2 acetylcholine,3 norepinephrine,4 dopamine,5
and neuropeptides6 in both the central and peripheral
nervous systems. As a result, various therapeutic appli-
cations for H3 agonists and antagonists have been envi-
sioned.7 In addition, recent evidence in animals and
humans suggests that H3 antagonism may have a nasal
decongestant effect when combined with H1 antago-
nism.8 Downregulation of norepinephrine levels through
activation of presynaptic H3 heteroreceptors by hista-
mine released from mast cells results in vasodilation.
H3 antagonism would reestablish the release of norepi-
nephrine and lead to vasoconstriction (decongestion).
This hypothesis was demonstrated in a histamine-driven
cat model of nasal congestion.9 Allergic rhinitis affects
10–30% of U.S. population alone, and current treat-
ments for the congestion associated with rhinitis include
oral decongestants such as pseudoephedrine, topical
decongestants such as oxymetazoline, and nasal ste-
roids, all of which are known to have side effects such
as hypertension, agitation or insomnia. Our goal has
been to discover a novel, selective H3 antagonist that
can be used in combination with an H1 antagonist for
the treatment of the allergic and congestive nasal symp-
toms of seasonal or allergic rhinitis.
A number of H3 agonist and antagonist structural types
have been reported in recent years, divided between clas-
sical imidazole-based10 and non-imidazole series.11 It
has been observed that imidazole-based H3 antagonists
often share a common structural motif wherein a nitro-
gen containing heterocycle is linked usually by an alkyl
chain to a polar group which is then linked to a lipophil-
ic residue.12 A qualitative model describing receptor–
inhibitor binding interactions for imidazole-based li-
gands was proposed by Timmerman and co-workers.13
Previously, Timmerman reported [(1H-imidazol-4-
yl)methyl]piperidine 1 (Table 1) to be a potent H3 ago-
nist (Ki = 0.3 nM, pD2 = 8.0).14 According to the model,
compound 1 possesses the structural requirements for
H3 receptor affinity, but lacks the lipophilic element
necessary for H3 antagonism. We initiated the efforts
to vary the R group of 1 with the aim of improving
H3 antagonism.
Keywords: Histamine; H3 antagonists; Imidazole series; 4-[(1H-Imi-
dazol-4-yl)methyl]piperidine; Norepinephrine; Allergic rhinitis;
Decongestion.
All the compounds employed in this study were
*
Corresponding author. Tel.: +1 908 740 3909; fax: 1 908 740 7152;
e-mail: michael.berlin@spcorp.com
prepared from key intermediate
Trityl-protected 4-iodoimidazole 2 was converted to
4
(Scheme 1).
ꢀ
Present address: Bristol-Myers Squibb Pharmaceutical Research
Institute, PO Box 4000, Princeton, NJ 08543-4000, USA.
the corresponding Grignard reagent as described by
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.09.076

396
W. D. Vaccaro et al. / Bioorg. Med. Chem. Lett. 16 (2006) 395–399
Table 1. Histamine H3 receptor affinity and antagonist potency
HN
N
N
R
b
Compound
R
H
Ki (nM)a
pA2
Synthesis
1
0.4
H
N
5
6
7
8
160
90
NDc
ND
10.1
8.3
a, b
O
Cl
Cl
O
c, b
N
H
H
N
0.4
17
d, e, f, b
g, h, e, f, b
O
Cl
Cl
O
N
H
H
N
9
10
11
12
13
14
15
16
17
18
19
20
21
22
40
60
0.2
0.2
2
ND
ND
9.8
i, e, f, b
d, e, f, b
O
Cl
CH3
N
O
Cl
Cl
H
N
d, e, f, b
O
O
H
N
F
9.9
d, e, f, b
H
N
8.9
d, e, f, b
O
O
H
N
3
8.8
d, e, f, b
OMe
H
N
3
8.8
d, e, f, b
O
O
CO2Me
H
N
3
8.2
d, e, f, b
Cl
H
N
21
9
ND
7.9
d, e, f, b
O
O
N
H
j, k, l, b
Cl
Cl
H
N
13
2
ND
8.4
m, k, l, b
n, k, b
O
H
N
Cl
H
N
S
170
50
ND
ND
o, b
O2
Cl
Cl
H
N
p, b
O
O
(continued on next page)

W. D. Vaccaro et al. / Bioorg. Med. Chem. Lett. 16 (2006) 395–399
397
Table 1 (continued)
b
Compound
R
Ki (nM)a
pA2
Synthesis
p, b
Cl
O
23
24
25
26
27d
28
29
30
31
32
33
34
35
970
ND
N
H
O
O
4
8.3
7.9
p, k, b
O
O
Cl
2
20
44
5
p, k, b
ND
d, k, q, r
CN
O
ND
d, k, s, b, t
NOH
O
O
7.8
p, b
O
O
625
25
5
ND
u, v, f, b
p, k, b
p, k, b
p, b
CO2Me
O2
S
7.1
8.2
7.8
8.8
8.6
7.4
9
O
6
p, k, b
p, k, b
p, b
Cl
2
18
O
Synthesis: (a) 4, ArNCO, CH2Cl2; (b) HCl, MeOH; (c) 4, BrCH2CONHAr, 2,6-lutidine; (d) 4, CH2@CHCO2Me, MeOH; (e) LiOH, THF–H2O; (f)
R1R2NH, EDC, HOBT, CH2Cl2; (g) 4, BrCH2CH@CHCO2Et, Et3N, DMF; (h) H2, Pd/C; (i) 4, Br(CH2)4CO2Et, NaH, DMF; (j) 4, BrCH2CN,
K2CO3, KI, DMF; (k) LiAlH4, THF; (l) RCO2H, EDC, HOBT, DMF; (m) 4, CH2@CHCN, MeOH; (n) 4, CH2@CHCONHAr, MeOH; (o) 4,
CH2@CHSO2NHAr, MeOH; (p) 4, RCO2H, EDC, HOBT, DMF; (q) 4-hydroxybenzamide, 1,10-(azodicarbonyl)dipiperidine, Bu3P, THF; (r) POCl3,
CHCl3; (s) 4-hydroxybenzaldehyde, 1,10-(azodicarbonyl)dipiperidine, Bu3P, THF; (t) NH2OHÆHCl, pyridine; (u) methyl 4-hydroxybenzoate,
HOCH2CH2CH2OH, 1,10-(azodicarbonyl)dipiperidine, Bu3P, THF; (v) CrO3, H2SO4, H2O.
a Inhibition of [3H]-N-a-methylhistamine binding to guinea pig brain receptor.16 H3 binding Ki values are the average of at least two independent
determinations. The assay-to-assay variation was generally 2-fold.
b Antagonist potency in an electrically stimulated guinea pig ileum.17 pA2 values are the average of at least four independent determinations.
The assay-to-assay maximum variability in the series was 0.2.
c Not determined.
d Single oxime isomer, undetermined stereochemistry.
Ley and co-workers.15 Subsequent treatment with
OH
4-pyridinecarboxaldehyde provided the alcohol 3. We
found it necessary to convert the alcohol 3 to the cor-
responding acetate prior to hydrogenation to achieve
both reduction of the pyridine ring and hydrogenoly-
sis of the benzylic position to afford 4 in a single
operation. Prepared compounds along with the corre-
sponding synthetic routes are listed in Table 1.
a, b
c, d
I
Ph3C
N
Ph3C
N
Ph3C
N
N
N
N
N
NH
Scheme 1. Reagents and conditions: (a) EtMgBr, CH2Cl2; (b) 4-
pyridinecarboxaldehyde, 100% (two steps); (c) Ac2O, DMAP, CH2Cl2,
85%; (d) H2, PtO2, AcOH, 60 psi, 96%.

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W. D. Vaccaro et al. / Bioorg. Med. Chem. Lett. 16 (2006) 395–399
The most potent H3 antagonists are obtained when the
lipophilic right-side region of the molecule consists of
an aniline amide separated from the piperidine ring
by a two-methylene linker. For example, compound 7
is the most potent antagonist of the series (pA2 =
10.10 0.15), equipotent with clobenpropit.18 Moderate
variation in the halogen substitution of the phenyl ring
is well tolerated (11 and 12). In addition, these com-
pounds were shown to have excellent affinity for human
brain H3 receptor with Kiꢁs of 1.7, 0.4, and 1.9 nM for 7,
11, and 12, respectively.19,20 Linker length is critical to
H3 activity, as compounds with shorter (5 and 6) and
longer (8 and 9) linkers display dramatic drop in H3
receptor affinity. Most variations of the amide system
of 7, such as phenyl ring substitutions 13–15 or nitrogen
substitution as in 10, lead to decreased activity. A drop
in activity is also observed with reversed amide 18, ani-
line 20 and, especially, sulfonamide 21. Simple phenyl
ethers, tethered to the piperidine ring by a three-methy-
lene fragment, although noticeably less active than 7,
maintained single-digit H3 receptor affinity (24 and
25). So did the piperidine amide analog 28, as well as,
in both cases, their all-carbon-linked analogs 31 and
32. However, attempted substitution of the benzene ring
drastically reduced activity in all cases (26, 27, and 29).
Combination of the aniline amide with the piperidine
amide provided, depending on the linker, either a strong
drop or almost complete loss of activity (22 and 23).
Although noticeably less potent than 7, straight-chain
analog 34 still demonstrates good H3 affinity and
antagonism.
yl)methyl]piperidines. The success of this approach
would be essential for further interest in the imidazole-
based series.
In conclusion, substitution of the piperidine ring of the
known H3 pharmacophore 4-[(1H-imidazol-4-yl)meth-
yl]piperidine with lipophilic functional groups resulted
in some of the most potent H3 antagonists known today.
The compounds of this series possess high inhibitory
activity against CYP2D6 human enzyme, the efforts to
minimize which are described in the next paper.
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