Synthesis and SAR of aminoalkoxy-biaryl-4-carboxamides: Novel and selective histamine H3 receptor antagonists

Article abstract of DOI:10.1016/S0960-894X(03)00118-5

Novel 4′-[(NR1R2-1-yl)]-propoxy-biaryl-4-carboxamides were designed and synthesized. All compounds were tested for affinity at histamine H₃receptors. Most compounds were highly potent and selective for human and rat H₃ receptors and selected examples such as A-349821 showed functional antagonism of H₃ receptors in vitro and in a mouse dipsogenia model.

Full text of DOI:10.1016/S0960-894X(03)00118-5

Bioorganic & Medicinal Chemistry Letters 13 (2003) 1325–1328
Synthesis and SAR of Aminoalkoxy-biaryl-4-carboxamides: Novel
and Selective Histamine H3 Receptor Antagonists
Ramin Faghih,* Wesley Dwight,y Jia Bao Pan, Gerard B. Fox, Kathy M. Krueger,
Timothy A. Esbenshade, Jill M. McVey, Kennan Marsh, Youssef L. Bennani{
and Arthur A. Hancock
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6123, USA
Received 8 November 2002; accepted 13 January 2003
Abstract—Novel 40-[(NR1R2-1-yl)]-propoxy-biaryl-4-carboxamides were designed and synthesized. All compounds were tested for
affinity at histamine H3receptors. Most compounds were highly potent and selective for human and rat H3 receptors and selected
examples such as A-349821 showed functional antagonism of H3 receptors in vitro and in a mouse dipsogenia model.
# 2003 Published by Elsevier Science Ltd.
Histamine mediates its action both in the CNS and the
periphery through 4 distinct receptors (H1–H4) known
to date.1 Histamine H1 and H2 receptor blockers are
important medicines in clinical use today. The H3-
receptor, primarily located in the CNS, is a presynaptic
receptor, which modulates the production and release of
histamine. Blockade of this receptor leads to increased
levels of histamine and other neurotransmitters
throughout the brain via effects on pre- and post-
synaptic H3 heteroreceptors.2 The wide distribution of
H3 receptors in the mammalian CNS indicates the
physiological role of this receptor. Therefore the ther-
apeutic potential as a novel drug development target in
indications associated with neurological disorders such
as attention-deficit hyperactivity disorder (ADHD),
Alzheimer’s disease (AD), Parkinson disease and epi-
lepsy as well as metabolic disorders such as obesity have
been proposed.3
series from our own laboratories4b as well as to pre-
viously described imidazole-based H3 antagonists such
as GT-23315 (pKi of 8.67ꢀ0.05 and 9.71ꢀ0.11 at
human cloned7 and rat cortical H3 receptors8) and
ciproxifan6 (pKi of 7.22ꢀ0.05 and 9.22ꢀ0.04).
During our efforts to develop a selective H3-blocker, we
investigated the chemistry of several biaryl systems.4a
By treatment of chloropropyloxy-biarylnitrile with pyr-
rolidine in a sealed-tube for 24 h at 120 ꢁC we obtained
both the displacement product (1) and a small amount
(ꢂ10%) of the corresponding carboxamide 2 as a minor
component (Scheme 1). Affinity measurements at the
H3-receptor revealed carboxamide 2 with pKi of
8.95ꢀ0.06 and 8.18ꢀ0.02 at human cloned and rat
cortical H3 receptors. Additional screening revealed
excellent selectivity vis-a-vis other histaminergic recep-
tors with pKi ꢃ5.72 at human H1 and H2 receptors.
We describe herein chemical, radioligand binding, in
vitro and in vivo pharmacological data on a novel non-
imidazole H3-receptor antagonist series,4 typified by
A-349821. This series of compounds is characterized by
high, but approximately equal, affinity for both the
human and rat receptor, in contrast to several previous
Solution-phase parallel synthesis and a matrix approach
were employed to prepare analogues of 2 quickly. Given
this lead molecule consists of, both amide and amine
functionalities, variation of each of these elements
allowed a practical, systematic strategy toward the rapid
delineation of the SAR of this biphenyl-amide series
(Scheme 2).
*Corresponding author. Fax:+1-847-937-4143; e-mail: ramin.fagih@
abbott.com
yPresent address: Neurocrine Biosciences, San Diego, CA, USA.
{Present address: Athersys Inc., Cleveland, OH, USA.
Thus, commercially available methyl-40-hydroxy[1,10-
biphenyl]-4-carboxylate (Scheme 2) was treated with
1-bromo-3-chloropropane in the presence of K2CO3 in
0960-894X/03/$ - see front matter # 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0960-894X(03)00118-5

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R. Faghih et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1325–1328
Scheme 1. (a) Pyrrolidine, 120 ꢁC, sealed tube, 24 h, 10%.
Scheme 2. (a) Cl–(CH2)3–Br, K2CO3, 2-butanone, reflux, 24 h, 100%; (b) LiOH, THF/H2O (3:1), rt, 98%; (c) SOCl2, 90 ꢁC, 4 h, 99%; (d) amines
(A–G) Hunig’s base, CH2Cl2, 0 ꢁC, 70–92%; (e) amines (1–7), K2CO3, KI, 2-butanone, reflux, 72 h, 60–88%.
refluxing 2-butanone for 24 h. The resulting O-alkyl
chloride was further treated, without purification, with
lithium hydroxide to give the desired acid in 98% yield
after silica-gel chromatoghraphy-filtration. Thionyl
chloride treatment of the biaryl carboxylic acid pro-
vided the biphenyl-acyl chloride ready for parallel
synthesis (Scheme 2). Agroup of 49 biphenyl- O-
propylamine amides were prepared in a matrix-parallel
fashion using the above set of 7ꢄ7 amines (Fig. 1).
pound A6 (A-349821) demonstrated excellent selectivity
towards other histaminergic receptors with pKi of
5.63ꢀ0.036 at human H1 and pKi of 5.00 at human H2
and H411 receptors. A-349821 was tested at a number of
biogenic amine receptors and transporters including
different subtypes (Table 2).
A-349821 demonstrated low affinity at all of these sites.
Since A-349821 fulfilled our requirement of in-vitro
potency and selectivity, it was further evaluated in
models of in-vitro functional activity. In vitro func-
tional antagonism was demonstrated in assays in which
inhibition of forskolin-stimulated cyclic AMP forma-
tion could be inhibited by (R)-a-methylhistamine, and
reversed by H3 antagonists.8 At cloned human and rat
H3 receptors, compound A6 blocked the H3 agonist
with pA2 values of 8.67ꢀ0.25 and 8.71ꢀ0.20, consistent
with similar affinities for these two receptors in radio-
ligand binding assays. A-349821 was tested for H3
receptor antagonist activity in an assay with K+-evoked
depolarization-induced release of [3H]-histamine from
The resulting products were purified using high
throughput-HPLC-MS techniques, and assayed in a
binding experiment using human cloned H3 and rat
cortex H3 receptors. Data from Table 1 indicate a fairly
well defined pharmacophore. While the lead 2 had good
affinity for human and rat H3R, several other substitu-
tions altering various physicochemical properties of the
molecule showed better binding (i.e., morpholine amide:
A6; 4-methylpiperidine amide B6 or N,N- diethylamide
G6).
Overall, the amide portion can tolerate wide structural
alterations but the basic site seems to be more restric-
tive, favoring small substituted pyrrolidines such as
(R,R)-dimethylpyrrolidine. From the above studies we
selected A-349821 (i.e., A6) based on its high affinity
and selectivity for human and rat H3 receptors. Com-
Table 1. Binding affinitiesa (pKi) at human cloned and rat cortical H3
receptors
Compdb hH3 rH3 Compd hH3 rH3 Compd hH3 rH3
A1
A2
A3
A4
A5
A6
A7
B1
B2
B3
B4
B5
B6
B7
C1c
C2
C3
7.49 6.89 C4
8.62 8.05 C5
8.26 7.56 C6
8.21 7.49 C7
8.14 8.06 D1
9.31 8.78 D2
7.74 7.28 D3
6.74 6.32 D4
8.46 8.08 D5
8.41 7.53 D6
8.16 7.51 D7
7.97 7.68 E1
9.22 8.53 E2
7.63 7.15 E3
ND ND E4
8.52 7.89 E5
8.54 7.73 E6
8.19 7.48 E7
8.44 7.99 F1c
9.16 8.29 F2
7.39 6.75 F3
8.01 7.37 F4
8.67 8.14 F5
8.19 7.67 F6
8.08 7.59 F7
8.43 8.55 G1
9.11 8.99 G2c
7.61 6.95 G3
6.64 6.66 G4
8.29 7.86 G5
8.36 7.76 G6
7.95 7.24 G7
7.43 6.94
ND ND
8.21 7.79
8.22 7.69
8.09 7.54
8.68 8.42
9.07 8.55
7.41 6.87
6.96 6.39
ND ND
8.16 7.55
8.09 7.37
8.32 8.04
9.11 8.69
7.79 7.01
8.14 7.38
8.95 8.18
8.33 8.44
9.01 8.38
1
2
aValues were estimated from at least three separate competition
experiments (SEM < 0.08).
bSatisfactory 1H NMR, MS spectra were obtained for all new com-
pounds. Compounds were tested as TFAsalts.
cLost during purification.
Figure 1.

R. Faghih et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1325–1328
Table 2. Binding affinitiesa (pKi) at human biogenic amine receptors and transporters
1327
Compd
hD4.2
5.01
hM1
5.79
hM2
6.03
hM3
5.78
ha2C10
UPTK-NE
5.01
UPTK- 5HT
5.45
UPTK-DA
5.31
A-349821b
5.79
aValues were estimated from at least three separate competition experiments (SEMꢃ0.14).
bCompound was tested as l-tartaric acid salt.
rat synaptosomes9 with pKb of 9.23ꢀ0.16. The com-
pound also blocked (R)-a-methylhistamine-induced
inhibition of electrical field-stimulation induced twitch
responses in the isolated guinea pig ileum with a pA2
value of 9.47ꢀ0.56.
In summary, we have discovered highly potent ligands
for both human and rat H3 receptors, with several
exemplary compounds showing some of the highest
affinity for human H3 receptors reported to date.12 The
high potency of some of these compounds (e.g., A6 or
A-349821) for human receptors, coupled with other
favorable physiological and pharmacodynamic proper-
ties make these compounds prime candidates for clinical
studies in various CNS disorders.
To demonstrate functional antagonism at the H3 recep-
tor in vivo, we employed a previously characterized
mouse dipsogenia model in which pronounced drinking,
elicited acutely in response to the H3 receptor agonist
(R)-a-methylhistamine, can be attenuated by pre-
administration of H3 receptor blockers10 (Fig. 2).
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A-349821 had no effect on basal drinking response
when administered 5 min prior to vehicle instead of (R)-
a-methylhistamine.
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