Aminoalkoxybiphenylnitriles as histamine-3 receptor ligands

Article abstract of DOI:10.1016/S0960-894X(02)00648-0

Biaryl nitrile amines were prepared and found to have high affinity and selectivity for human and rat histamine H₃ receptors.

Full text of DOI:10.1016/S0960-894X(02)00648-0

Bioorganic & Medicinal Chemistry Letters 12 (2002) 3077–3079
Aminoalkoxybiphenylnitriles as Histamine-3 Receptor Ligands
Ramin Faghih,* Wesley Dwight,y Anil Vasudevan, Jurgen Dinges, Scott E. Conner,{
Timothy A. Esbenshade, Youssef L. Bennanix and Arthur A. Hancock
Neuroscience-Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6123, USA
Received 17 June 2002; accepted 2 August 2002
Abstract—Biaryl nitrile amines were prepared and found to have high affinity and selectivity for human and rat histamine H3
receptors.
# 2002 Elsevier Science Ltd. All rights reserved.
Histamine exerts a variety of physiological effects via
four known distinct G-protein coupled receptors.1 His-
tamine plays a major role in immediate hypersensitivity
reactions following release from mast cells. The action
of released histamine on airway and blood vessel
smooth muscle accounts for the symptoms of the aller-
gic response and is mediated by the H1 receptor2 and is
blocked by classic antihistamines. Histamine is also an
important regulator of gastric acid secretion through its
action on parietal cells. These effects are mediated via
the H2 receptor3 and these are blocked by H2 receptor
antagonists. The third histamine receptor4 was first
described as a presynaptic autoreceptor in the CNS
controlling the synthesis and release of histamine.
Recently, evidence suggesting the presence of H3 recep-
tors located presynaptically on hetero-receptors has
emerged. The bulk of medicinal chemistry with respect
to H3 receptor ligands is related to their potential to
treat CNS disorders. Some H3 antagonists have been
studied in models of learning, memory and schizo-
phrenia.5 Therefore a H3 antagonist with high receptor
selectivity and good BBB penetration may offer a new
approach for the treatment of a wide range of CNS
disorders. Recently we have described the SAR of a new
series of non-imidazole containing H3 blockers6 (Fig. 1).
In order to expand the SAR to provide a new isostere
for the ketone moiety seen in Figure 1 and to optimize
lipophilicity for CNS penetration, we prepared a series
of biaryl piperazine amides.
We wish to report herein on the preparation and SAR
of this series. Commercially available 4-bromophenol
was treated with 1-bromo-3-chloropropane in the pre-
sence of K2CO3 in refluxing 2-butanone for 24 h
(Scheme 1). The resulting O-propyl chloride (obtained
in ꢀ95% yield) was further treated, without purifica-
tion, with piperazine-1-carboxylic acid ethyl ester to
give the desired compounds (1) in 70–90% yield after
silica gel chromatography. Treatment of 1 under Suzuki
or Stille cross coupling reactions leads to the desired N-
ethylcarbamate piperazine derivatives. These were
assayed in a binding experiment using rat cortex in
order to probe the SAR of the H3 receptor.
Data from Table 1 indicate weak to moderate affinity
for the rat H3R, especially when compared with their
alkylketone homologues.6 However, based on favorable
physicochemical properties and moderate potency, the
biarylnitrile 4 was selected for further modification. The
basic piperazine in 4 was replaced with a variety of
amines (Scheme 2): morpholine, pyrrolidine, homo-
piperazine, 4-(R)-aminopyrrolidine, pyrrolidine[3,4-
c]pyrrolidine,9 etc., this time with significant improve-
ment in affinity at the rat H3R (e.g., compd 21 and 32
with pKi of 8.01 and 8.19, Table 2) when compared to
similar transformations in the alkylketone series.6 Small
alkyl-substituted pyrrolidines and piperidines provided
for an enhanced affinity at the rat H3R. From the data
*Corresponding author. Fax:+1-847-937-4143; e-mail: ramin.faghih
@abbott.com
yPresent address: Neurocrine Biosciences, San Diego, CA, USA.
{Present address: Eli Lilly, Indianapolis, IN, USA.
xPresent address: Athersys Inc., Cleveland, OH, USA
Figure 1.
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00648-0

3078
R. Faghih et al. / Bioorg. Med. Chem. Lett. 12 (2002) 3077–3079
Scheme 1. (a) Cl–(CH2)3–Br, K2CO3, 2-butanone, reflux 24 h; (b): N–COOEt-piperazine, KI/K2CO3, 2-butanone, reflux 72 h; (c): Suzuki or Stille,
PdCl2(Ph3)2, DMF, 24 h, 40–75%.
Scheme 2. (a) Cl–(CH2)3–Br, K2CO3, 2-butanone, reflux 24 h, 98%; (b) amines, KI/K2CO3, 2-butanone, reflux 72 h, 60–90%.
Table 1. Binding affinitiesa (pKi) at rat cortical H3 and human H1
potent than the S-enantiomer 28 at both rat (P=0.14,
unpaired t-test, RS/1) and human [P=0.04, unpaired t-
test, RS/1, see below] receptors) is noteworthy.
and H2 receptors7,8
Compdb:R
H3 H1 H2
R
H3 H1 H2
2: 40-Br-Ph
6.95 6.74 5.78 9: 4-Pyridine-4
5.56 5.43 4.24
6.64 6.35 4.48
6.68 6.12 4.01
6.62 6.36 5.44
While this work was in progress Lovenberg and collea-
gues reported the cloning of the human H3 receptor.10
Subsequently, both the guinea pig and rat H3 receptor
orthologues have also been successfully cloned.11 We
assayed using human cloned H3 receptors in binding
experiments selected examples of the biarylnitrile series
to explore their SAR at the human receptor (Table 3).
3: 40-OMe-Ph 6.59 6.45 4.00 10: 4-Thiophen-2
4: 40-CN-Ph 7.55 6.80 4.54 11: 4-Thiopen-3
5: 40-Cl-Ph
6.72 6.45 5.25 12: 40-OCF3-Ph
6: 40-NO2-Ph 7.01 7.09 5.08 13: 40-CN-20-Me-Ph 6.99 7.56 5.40
7: 20-NO2-Ph 6.21 6.79 5.12 14: 4-Pyrrol
8: 30-CN-Ph 5.95 6.42 4.62 15: 4-Imidazol
7.25 6.30 4.89
6.06 5.83 4.16
aValues were estimated from at least three separate competition
experiments (SEMꢁ0.2).
bSatisfactory 1H NMR, MS spectra and elemental analyses were
obtained for all new compounds.
Some interesting observations can be made from these
results: several N-ethylcarbamate piperazine com-
pounds such as 4 and 14 were an order of magnitude
less potent at the human recombinant receptor than at
the native rat receptor (pKi of 6.00 versus 7.55 or 6.00
versus 7.25 at human or rat H3, respectively). The rat
in Table 2 the stereoselective nature of the H3 receptor
(e.g., compound 27 statistically significantly more
Table 2. Binding affinitiesa (pKi) at rat cortical H3 and human H1 and H2 receptors
Amines
H3
H1
H2
Amines
26: Pyrrolidine
27: 3-(R)-OH-Pyrrolidine
H3
H1
H2
16: Piperazine
17: Homopiperazine
18: Morpholine
19: 2-Me-Piperidine
20: 3-Me-Piperidine
21: 4-Me-Piperidine
22: 3-OH-Piperidine
23: 4-OH-Piperidine
24: 2,6-di-Me-Piperidine
25: 4-NH2-Piperidine
6.23
7.87
7.60
7.64
7.58
8.01
7.09
7.50
7.79
6.89
5.05
5.41
5.49
5.46
6.56
6.37
5.11
6.24
5.40
5.45
4.64
5.11
4.42
4.73
4.93
5.04
4.89
5.00
4.62
4.47
7.38
7.29
6.90
7.20
7.53
7.87
8.19
7.81
7.18
5.30
5.35
5.25
4.86
5.43
5.72
6.25
5.41
5.54
4.17
4.77
4.72
5.13
5.00
5.00
5.04
4.82
4.91
28: 3-(S)-OH-Pyrrolidine
29: 3-(R)-NH2-Pyrrolidine
30: 3-(R)-NHMe-Pyrrolidine
31: 3-(R)-NMe2-Pyrrolidine
32:2,5-(R,R)-di-Me-Pyrrolidine
33: 3-(R)-Me-Pyrrolidine-3-ol
34: Pyrrolidine[3,4-c]Pyrrolidine
aSee corresponding footnote in Table 1.
Table 3. Binding affinitiesa (pKi) at human cloned H3 receptors10
Compd
hH3
Compd
hH3
Compd
hH3
4
6.00
6.00
6.93
8.08
7.44
8.15
8.77
21
22
23
24
25
26
27
7.86
7.52
6.91
8.67
6.70
8.14
8.08
28
29
30
31
32
33
34
7.71
8.21
8.07
8.56
9.17
8.39
7.82
14
16
17
18
19
20
aSee corresponding footnote in Table 1.

R. Faghih et al. / Bioorg. Med. Chem. Lett. 12 (2002) 3077–3079
3079
H3 receptor is highly homologous to the human recep-
tor, although two amino acid residues differences loca-
ted in the vicinity of the aspartate residue (Asp114) in the
TM3 helices important for the binding of positively
charged biogenic amines could help explain these dif-
ferences in binding between the two species. Ligneau
and colleagues also observed these types of differences
in binding with a number of H3 antagonists.12 In con-
trast, the biarylnitrile amines are displaying a reverse
preference, that is, equipotent or an order of magnitude
more potent at the human cloned receptor than at the
rat receptor.
Pyati, J.; Chang, H.; Wilson, S. J.; Erlander, M. G. J. Phar-
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In summary we have discovered highly potent ligands
for both human and rat H3 receptors, with several
exemplary compounds demonstrating an approximate
10-fold higher affinity for the human H3 receptor. These
results differ from a number of imidazole-based H3
antagonists that show a weaker affinity for human,
compared to rat H3 receptors, such as thioperamide,
ciproxifan or GT-2331.13 The high affinity of some of
these compounds (e.g., compd 31 or A-331440) for the
human receptor, coupled with other favorable physio-
logical and pharmacodynamic properties (to be descri-
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have therapeutic potential in various human diseases.
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