4-[6-(2-Aminoethyl)naphthalen-2-yl]benzonitriles are potent histamine H3 receptor antagonists with high CNS penetration

Article abstract of DOI:10.1016/j.bmcl.2006.11.073

4-[6-(2-Tertiaryaminoethyl)naphthalen-2-yl]benzonitriles are conformationally constrained histamine H₃ receptor antagonists with high potency and selectivity. The analogs were designed around a naphthalene core, with the goal of enhancing lipop

Full text of DOI:10.1016/j.bmcl.2006.11.073

Bioorganic & Medicinal Chemistry Letters 17 (2007) 1443–1446
4-[6-(2-Aminoethyl)naphthalen-2-yl]benzonitriles are potent
histamine H3 receptor antagonists with high CNS penetration
Lawrence A. Black,a,* Diana L. Nersesian,a Padam Sharma,b,ꢀ Yi-Yin Ku,b
Youssef L. Bennani,a,ꢁ Kennan C. Marsh,c Thomas R. Miller,a Timothy A. Esbenshade,a
Arthur A. Hancocka and Marlon Cowarta
aNeuroscience Research, GPRD, Abbott Laboratories, Abbott Park, IL 60064, USA
bProcess Research, GPRD, Abbott Laboratories, North Chicago, IL 60064, USA
cExploratory Science, GPRD, Abbott Laboratories, Abbott Park, IL 60064, USA
Received 16 October 2006; revised 16 November 2006; accepted 29 November 2006
Available online 1 December 2006
Abstract—4-[6-(2-Tertiaryaminoethyl)naphthalen-2-yl]benzonitriles are conformationally constrained histamine H3 receptor antag-
onists with high potency and selectivity. The analogs were designed around a naphthalene core, with the goal of enhancing lipophil-
icity and CNS penetration, as compared to a previously reported benzofuran series. The SAR of the tertiary amine moiety is similar
to that reported for the benzofuran series, with analogs bearing a 2-methylpyrrolidine substituent possessing the greatest rat and
human H3 receptor binding affinities.
Ó 2006 Elsevier Ltd. All rights reserved.
Histamine H3 receptors (H3R) are constitutively active,
located on presynaptic nerve terminals, and modulate
the release of the neurotransmitters histamine, acetyl-
choline, dopamine, serotonin, and glutamate.1 Activa-
tion of H3R by the endogenous ligand, histamine (1),
reduces neurotransmitter release, while antagonism of
the H3R leads to enhanced neurotransmitter release.2
This enhanced neurotransmitter release is thought to
be responsible for the reported efficacy observed in ani-
mal models where improvements in cognition,3 atten-
tion,3 wakefulness,4 nasal congestion,5 and in some
cases an anti-obesity effect6 have been observed upon
administration of H3R antagonists. This desirable pro-
file suggests that H3R antagonists have potential to treat
human diseases such as attention-deficit disorder, Alz-
heimer’s disease, schizophrenia, rhinitis, and obesity.
To date, several H3R antagonists have reportedly en-
tered clinical trials and research continues in search of
a H3R antagonist suitable for human use.7
Several selective H3R antagonists have been described in
the literature, including early imidazole-based agents
such as ciproxifan8 (2) and thioperamide9 (3), as well
as later non-imidazole structures such as UCL-219010
(4), A-33144011 (5), JNJ-520785212 (6), and ABT-23913
(7). Many non-imidazole H3R antagonists share a com-
mon structural element: a tertiary amine appended to an
aromatic ring via a four-atom linker, typically the
NH2
N
N
1
H
O
O
S
N
N
H
N
N
O
2
N
N
3
H
H
CN
CN
N
O
N
N
O
4
5
Me2N
N
Keywords: Histamine H3 receptor antagonists; Naphthalene; High
CNS penetration.
*
Corresponding author. Tel.: +1 847 938 6560; fax: +1 847 937
9195; e-mail: larry.a.black@abbott.com
O
O
N
ꢀ
Present address: Bristol-Myers Squibb, New Brunswick, NJ 08903,
USA.
6
7
ꢁ
Figure 1. Structures of histamine (1), imidazole-based H3 antagonists
(2 and 3), and non-imidazole H3 antagonists (4–7).
Present address: Vertex Pharmaceuticals, Cambridge, MA 02139,
USA.
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.11.073

1444
L. A. Black et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1443–1446
tion by ring fusion and replacement of oxygen by car-
CN
bon. Relative to the flexible analog 8, we envisioned
that the more rigid naphthalenes might retain or en-
hance the H3R selectivity and the favorable drug-like
characteristics seen in the earlier benzofuran series.
More importantly, a key motivation for incorporation
of the naphthalene moiety was a belief that the higher
lipophilicity relative to the benzofuran series (Fig. 2)
would increase drug distribution to the brain, potentially
resulting in improved access to H3Rs in the CNS, there-
by boosting efficacy relative to peripherally mediated
side effects. Indeed, in rats one hour after a 5 mg/kg iv
dose, the ratio of brain concentration to plasma concen-
tration for naphthalene 10 was determined to be twice
that of benzofuran 7 (Fig. 2).
N
N
O
8
human H3 Ki = 0.22 nM
rat
H3 Ki = 1.96 nM
CN
N
O
N
O
7
6
CLog P:5.149
human H3 Ki = 0.63 nM
N
C
brain/Cplasma = 34
human H3 Ki = 0.45 nM
rat
H3 Ki = 3.22 nM
CN
The synthesis of the naphthalene-based H3R antago-
nists began with commercially available ester 11, which
was reduced to the benzylic alcohol 12 with LAH
(Fig. 3). Treatment of 12 with thionyl chloride pro-
duced 13, which was reacted with NaCN to give the
acetonitrile 14. Sulfuric acid-catalyzed hydrolysis yield-
ed the acetic acid 15, which upon borane–THF reduc-
tion provided the ethanol 16. Suzuki coupling of 16
with 4-cyanophenylboronic acid gave 17, which was
transformed into the corresponding mesylate 18. Final
products (10, 19–37) were obtained after 18 was react-
ed with the appropriate amines in the presence of
Cs2CO3.
N
N
9
10
human H3 Ki = 1.60 nM
CLog P:5.763
brain/Cplasma = 72
human H3 Ki = 0.24 nM
rat H3 Ki = 2.48 nM
C
Figure 2. Comparison of H3R antagonists with fully flexible propyloxy
links to H3R antagonists with more rigid, extended conformation
links. (ClogP calculated in ChemDrawTM 9.0, CambridgeSoft).
propyloxy group (see 4–6, Fig. 1).7d With ABT-239 (7),
the highly flexible propyloxy link was partially rigidified
in an extended conformation by incorporating the oxy-
gen and the proximal carbon into a furan ring fusion to
the pharmacophore benzene, producing a benzofuran.
This conformationally restricted derivative retains most
of the high binding affinity possessed by the related flex-
ible analog 8 (Fig. 2), while potentially providing a more
drug-like profile.14 Another reported variation on this
theme involved replacement of the oxygen and proximal
methylene of 6 with an acetylene to again provide a
more conformationally restricted analog, 9,15 with simi-
lar potency to the parent. This latter example also indi-
cated that the oxygen atom in the link is not absolutely
essential for high H3R binding affinity.
Structure–activity relationships (SAR) for the amines
surveyed are summarized by the data presented in
Table 1. Good potency at rat as well as human receptors
was desirable, since the majority of behavioral models
were conducted with rats. While all examples displayed
superior binding affinity at the cloned human H3R rela-
tive to the rat cortex H3R, we were gratified to find several
compounds (10, 19, 20, 21, 27, 28, and 33) with high
potency at the rat H3R (Ki < 15 nM). Similar to the amine
SAR reported for the benzofuran series,7f the pyrrolidine
21, the 2-methylpyrrolidines (R: 10, S: 19, and racemate
20), the (2S)-hydroxymethylpyrrolidine 27, and the
(2S)-fluoromethylpyrrolidine 28 possessed the greatest
potency in the naphthyl derivatives studied. Importantly,
the naphthalene analogs were found to be generally more
potent than the corresponding benzofurans.
In this work, we report on the synthesis and amine SAR
of a new series of naphthalene-based H3R antagonists
that combines aspects of these two concepts—rigidifica-
Br
a
Br
Br
Br
Br
b
c
f
HO
Cl
MeO2C
NC
11
14
13
12
Br
d
e
HO2C
HO
16
15
CN
CN
CN
g
h
MsO
R1R2N
HO
18
17
10, 19-37
Figure 3. Synthesis of the 4-[6-(2-tertiaryaminoethyl)naphthalen-2-yl]benzonitrile H3R antagonists. (a) LAH, THF, ꢀ10 °C, 95%; (b) SOCl2, ZnCl2,
dioxane, ꢀ10 °C, 99%; (c) NaCN, CH3CN, H2O, reflux, 97%; (d) conc. H2SO4, AcOH, H2O, reflux, 93%; (e) BH3 Æ THF, THF, ꢀ15 °C, 96%; (f) 4-CN-
C6H4B(OH)2, PdCl2(PPh3)2, K3PO4, i-PrOH, H2O, 65 °C, 73%; (g) CH3SO2Cl, Et3N, CH2Cl2, 93%; (h) R1R2NH, Cs2CO3, CH3CN, 50 °C, 20–60%.

L. A. Black et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1443–1446
1445
Table 1. In vitro SAR of amine derivatives in human and rat H3R binding affinity assays
CN
R1R2N
R1R2N
Human H3
Rat H3
a
b
Compound
Kic (nM)
pKi SEM
Kic (nM)
pKi SEM
10
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
(2R)-Methylpyrrolidined
(2S)-Methylpyrrolidinee
( 2)-Methylpyrrolidine
Pyrrolidine
0.24 [0.45]
0.12
9.62 0.06
9.92 0.23
9.75 0.12
9.31 0.16
8.48 0.11
8.06 0.16
7.56 0.07
6.56 0.05
8.54 0.02
9.36 0.16
9.09 0.13
7.70 0.18
8.81 0.10
8.06 0.12
8.58 0.14
9.07 0.11
8.68 0.19
8.96 0.18
8.34 0.12
7.98 0.34
2.48 [3.22]
3.47
8.61 0.09
8.46 0.10
8.91 0.17
8.19 0.16
7.18 0.07
7.47 0.14
6.63 0.29
6.33 0.21
7.37 0.25
7.96 0.11
8.01 0.12
7.00 0.27
7.51 0.17
6.85 0.09
7.34 0.29
7.90 0.16
7.59 0.20
7.56 0.16
7.52 0.03
6.34 0.26
0.18 [0.95]
0.49 [4.26]
3.31
1.24 [6.46]
6.42 [46.8]
66.1
3-Pyrroline
(2R)-Ethylpyrrolidinef
( 2)-Isopropylpyrrolidine
( 2)-Isobutylpyrrolidine
(2R)-Hydroxymethylpyrrolidine
(2S)-Hydroxymethylpyrrolidine
(2S)-Fluoromethylpyrrolidineg
(3R)-Dimethylaminopyrrolidine
(3R)-Hydroxypyrrolidine
(2R)-Methylpiperidine
Dimethylamine
8.61
27.3
33.7
233
273
465
2.89 [17.8]
0.44 [2.24]
0.81
42.8 [166]
11.0 [25.7]
9.77
20.1 [15.8]
1.56 [8.91]
8.71
100 [63.1]
30.9 [95.5]
141
2.65
0.84
45.3
12.5
Diethylamine
Methylpropylamine
2.09
1.09
25.7
27.9
tert-Butylmethylamine
Ethylisopropylamine
2-Methylaminoethanol
4.62
10.5
30.3
457
Binding affinities determined by displacement of 3H N-a-methylhistamine tested in:
a Membranes from cloned human H3R expressed in C6 cells.
b Rat cortical membranes. The number of independent pKi determinations was P3 for all compounds.
c Bracketed Ki values show published data for the corresponding benzofuran derivatives.
d For synthesis, see Ref. 13d or by fractional recrystallization of L-tartrate salt.
e For synthesis, use preceding method starting with (2R)-hydroxymethylpyrrolidine.
f For synthesis, see Ref. 16.
g Prepared by DAST fluorination of N-Boc-(2S)-hydroxymethylpyrrolidine and subsequent HCl-induced deprotection.
Table 2. Rat pharmacokinetic data
Compound
iv (1 mg/kg)
po (1 mg/kg)
t1/2 (h)
Vb (L/kg)
AUC0–1 (ng h/mL)
Clb (L/h kg)
Cmax (ng/mL)
t1/2 (h)
AUC0–1(ng h/mL)
F (%)
7
10
5.3
6.9
12
6
673
1640
1.5
0.6
29
48
5.2
6.5
349
890
53
55
The naphthyl analog 10 possessed the best overall pro-
file in this series of compounds. This compound is highly
selective, with a binding affinity over a thousand times
more potent at the human H3R relative to the human
histamine H1, H2, and H4 receptors. In addition to high-
er CNS distribution than the benzofuran analog 7
(ABT-239), 10 displayed improved potency in binding
assays and a similar pharmacokinetic profile (Table 2).
potencies, higher lipophilicity, and similar amine SAR.
Finally, in the specific case of the naphthalene 10, the
desired higher brain/plasma concentration ratio relative
to the benzofuran 7 was achieved while maintaining a
similar PK profile.
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