Benzylamine histamine H3 antagonists and serotonin reuptake inhibitors

Article abstract of DOI:10.1016/j.bmcl.2007.06.061

The design, synthesis, and in vitro activity of a series of novel 5-ethynyl-2-aryloxybenzylamine-based histamine H₃ ligands that are also serotonin reuptake transporters is described.

Full text of DOI:10.1016/j.bmcl.2007.06.061

Bioorganic & Medicinal Chemistry Letters 17 (2007) 4799–4803
Benzylamine histamine H3 antagonists and serotonin
reuptake inhibitors
Michael A. Letavic,* Emily M. Stocking, Ann J. Barbier, Pascal Bonaventure,
Jamin D. Boggs, Brian Lord, Kirsten L. Miller, Sandy J. Wilson and Nicholas I. Carruthers
Johnson & Johnson Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA
Received 18 May 2007; accepted 18 June 2007
Available online 26 June 2007
Abstract—The design, synthesis, and in vitro activity of a series of novel 5-ethynyl-2-aryloxybenzylamine-based histamine H3
ligands that are also serotonin reuptake transporters is described.
Ó 2007 Elsevier Ltd. All rights reserved.
Selective serotonin reuptake inhibitors (SSRIs), including
fluoxetine and sertraline, are the most frequently pre-
scribed drugs for depression, a major health issue that
affects millions of people.1 However, there are numerous
problems with SSRI therapy. SSRIs typically have a slow
onset of action (up to 4 weeks) and also often fail to
improve the cognitive impairment and fatigue that is
observed with many patients even as mood improves.2,3
For these reasons, antidepressants with improved efficacy
would represent an important new therapy.
physical properties and decrease structural complexity
while maintaining the high affinity for the H3 receptor
and serotonin transporter observed with 1–3. Toward
this end we hypothesized that it might be possible to
remove C-3 of the tetrahydroisoquinoline ring of 2 to
make benzyl amine compounds such as 4. It is likely that
C-4 of the tetrahydroisoquinoline could then be replaced
by a variety of linkers (Y) to the aryl group; for this
study we chose an oxygen linker since replacing C-4 with
an oxygen would remove the chiral center and was
expected to help lower the logD of the resulting mole-
cules. We were also encouraged by the fact that related
aryloxybenzyl amines have previously been reported to
have serotonin reuptake activity.12
One possible approach to address some of the issues asso-
ciated with SSRI therapy is to combine serotonin reup-
take inhibitor activity with histamine H3 antagonist
activity in a single molecule. This appears to be a viable
tactic since it is known that histamine H3 receptor antag-
onists improve cognition4 and increase wakefulness5,6 in
preclinical models. An added benefit is that histamine
H3 antagonists show these activities without undesired
nonspecific stimulant effects.7 As part of our efforts to pre-
pare dual activity compounds we recently reported sev-
eral series of serotonin reuptake inhibitors that are also
high affinity histamine H3 antagonists, including 1,8
2,9,10 and 3.11 We now report data for some aryloxy ben-
zylamine-based compounds that are also potent hista-
mine H3 antagonists and serotonin reuptake inhibitors.
O
O
F
4
3
N
N
N
N 2
O
O
1
1, hH3 Ki= 0.7 nM
2, hH3 Ki= 4.0 nM
hSERT Ki= 3.3 nM
hSERT Ki= 2.7 nM
Cl
O
Cl
Goals for this project included modifying the structure
of our earlier compounds (i.e., 2) in order to improve
Y
R
R
N
N
N
H
N
Keywords: Histamine H3; Serotonin reuptake inhibitors; Benzyl
amines.
N
O
Linker-X
*
Corresponding author. E-mail: mletavic@prdus.jnj.com
Present address: EnVivo Pharmaceuticals, 480 Arsenal Street,
Building 1, Watertown, MA 02472, USA.
3, hH3 Ki= 7 nM
hSERT Ki= 26 nM
4
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.06.061

4800
M. A. Letavic et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4799–4803
A variety of histamine H3 pharmacophores have been
reported during the past several years,13 including com-
pounds 5,14 6,15 and 716 from our group. For the pur-
poses of this study we chose to focus on the piperidine
alkyne H3 pharmacophore present in 7 because we
thought that this would be preferable to the masked
hydroquinone compounds that would result from the
installation of a piperidinepropyloxy- or piperidinealk-
oxy-group into the benzyl amines.
Alternatively, 11 was coupled with but-3-yn-1-ol in a
palladium mediated reaction to give the corresponding
alcohol which was subsequently converted to the mesy-
late 13. The mesylate was then displaced with a variety
of amines (R1R2N) and finally deprotected to give 12.
In some instances, the amines were further functional-
ized via reductive amination (12t, 12u) or alkylation
(12w) prior to deprotection.
S
S
O
N
O
O
N
N
N
O
O
N
O
H
N
H
N
5; hH3 Ki= 0.6 nM
6; hH3 Ki= 2.1 nM
O
Br
15; hH3 Ki=423+ 61 nM
hSERT Ki=3.4+ 0.4 nM
rSERT Ki=1.8+ 0.7 nM
14; hH3 Ki=9000+ 700 nM
hSERT Ki= 1.7+ 0.3 nM
rSERT Ki=0.5+ 0.1 nM
N
N
7; hH3 Ki= 1.3 nM
S
S
S
S
N
N
N
N
The compounds needed for this study were readily pre-
pared in five steps from 5-bromo-2-fluorobenzaldehyde
8 by reaction with a variety of phenols, followed by
reductive amination with methylamine and protection
as the Boc amine (Scheme 1).
N
O
O
H
N
O
H
N
H
N
16; hH3 Ki=9.7+ 1.6 nM 17; hH3 Ki=5.2+ 0.2 nM 18; hH3 Ki=4.7+ 0.6 nM
hSERT Ki=1.9+ 0.2 nM hSERT Ki=1.4+ 0.1 nM hSERT Ki=2.0+ 0.2 nM
rSERT Ki=0.9+ 0.2 nM rSERT Ki=0.4+ 0.1 nM rSERT Ki=0.6+ 0.2 nM
Subsequent palladium mediated coupling of the arylbr-
omide with a fully elaborated alkyne and deprotection
of the benzyl amine provided the desired compounds
12 in acceptable overall yields.
Compound 15 was prepared in a similar manner starting
from 4-bromo-2-fluorobenzaldehyde, and compounds
16–18 were prepared as the result of catalytic hydroge-
nation of the corresponding compounds 12.
R3
R3
O
O
F
O
H
N
(a)
(b)
Biological data for compounds 12 are shown in Table
1. All of the compounds shown have high affinity for
the human and rat serotonin transporter. This was
not surprising, considering that the R3 groups utilized
for this study were the better groups from our previous
work.8–11 A variety of histamine H3 pharmacophores
were used in this work and the H3 affinity varies for
these compounds. For the alkynes 12, compounds
12v and 12w are poor ligands as are the piperazine
12q and the diazepine 12x. Compound 14, which has
no H3 pharmacophore attached, also has no significant
H3 affinity, however it is a high affinity serotonin reup-
take inhibitor. In addition, the alkyne isomer 15 has
significantly lower affinity for the H3 receptor than
12b. The affinities of compounds 16–18 were compara-
ble to the alkynes at both targets. We also verified that
a number of the compounds in Table 1 are histamine
H3 antagonists at the human receptor (pA2’s 7.89–
9.10).
H
H
Br
Br
Br
O
9
8
10
R3
R3
O
O
(d,e)
R2
H
N
(c)
R1
N
N
Br
Boc
12
11
R3
(d, f)
(g then h or i, e)
O
OMs
N
Boc
13
Scheme 1. Synthesis of 5-ethynyl-2-aryloxybenzylamines. Reagents
and conditions: (a) K2CO3, ArOH, DMF, 90 °C, 20 h, 51–97%; (b)
40% aq MeNH2, MeOH, 0 °C, 20 min, then NaBH4, 0 °C, 0.5 h, then
23 °C, 18 h, 83–97%; (c) di-tert-butyl dicarbonate, DCM, 23 °C, 1 h,
96–100%; (d) various alkynes, Ph3P, CuI, (Ph3P)2PdCl2, DMF,
Et2NH, 100 °C, 1–3 h; (e) trifluoroacetic acid, DCM, 23 °C, 1 h, 13–
71% for two steps; (f) MsCl, Et3N, H3CCN, 0–23 °C, 2 h, 91–100%; (g)
R1R2NH, Et3N, DMF/MeOH, microwave 150 °C, 25 min, 18–34%;
(h) formaldehyde, NaBH(OAc)3, EtOH, 23 °C, 16 h, 65%; (i) NaH, 2-
bromopropane, DMF, 50 °C, 1 h, then 23 °C, 16 h, 16%.
Several of the compounds were tested for affinity at the
human norepinephrine (NET) and dopamine (DAT)
transporters. These data are shown in Table 2. The com-
pounds tested were P100-fold selective over these two
important transporters as compared to the human
SERT.

M. A. Letavic et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4799–4803
4801
Table 1. Binding data for the rat and human serotonin reuptake transporters and for the human H3 receptor for compounds 12
b
Compound
R1R2N–
R3
Rat SERT Kia (nM)
Human SERT Kia (nM)
Human H3 Kia (nM)
Human H3 pA2
12a
4-MeS
0.7( 0.1)
0.7( 0.1)
1.7( 0.2)
8.61
N
O
12b
12c
12d
12e
12f
12g
12h
12i
4-MeS
0.9( 0.1)
2.4( 0.7)
1.8( 0.7)
1.1( 0.5)
11( 2)
0.8( 0.1)
1.8( 0.2)
1.9( 0.3)
1.2( 0.1)
30( 10)
2.7( 0.8)
17( 1)
11( 2)
7.95(n = 2)
N
O
3-Cl, 4-Cl
3-Me, 4-MeS
4-Cl
11( 3)
N
O
11( 3)
N
O
7.0( 0.7)
5.7( 0.6)
7.3( 0.8)
13( 2)
7.97
8.14
7.90
7.89
8.45
8.58
8.78
N
O
H
N
O
4-F3C
2.0(n = 2)
7.3( 1.5)
10( 1.5)
3.0( 1.2)
3.4( 1.0)
0.9( 0.1)
5.7( 0.2)
0.5( 0.1)
0.6( 0.1)
2.1( 0.1)
2.0( 0.2)
N
O
3-F3C, 4-Cl
3-F
N
O
24( 5)
3.0( 0.0)
3.0( 0.0)
6.0( 1.9)
5.4( 2.2)
13( 5)
N
O
12j
3-Cl
7.3( 1.6)
3.6( 0.4)
2.5( 0.5)
6.7(n = 1)
13( 1)
N
O
12k
12l
2-Cl, 4-F
4-MeS
N
S
N
S
12m
12n
12o
12p
12q
3-Cl, 4-Cl
4-MeS
N
i
-Pr
N
31( 4)
N
F
F
4-MeS
0.9(n = 2)
27( 9)
6.0( 3.1)
14( 1)
8.12
N
N
3-Cl, 4-Cl
4-MeS
N
3.5( 0.4)
52( 2)
N
N
H
12r
12s
12t
12u
4-MeS
0.3( 0.1)
1.8( 0.1)
1.3( 0.5)
6.4( 1.9)
12( 2)
17( 6)
N
3-Cl, 4-Cl
4-MeS
1.4( 0.3)
1.1( 0.1)
5.9( 2.7)
17( 4)
H
N
N
6.1( 0.8)
9.7( 1.8)
9.10
3-Cl, 4-Cl
(continued on next page)

4802
M. A. Letavic et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4799–4803
Table 1 (continued)
R1R2N–
R3
Rat SERT Kia (nM)
Human SERT Kia (nM)
Human H3 Kia (nM)
Human H3 pA2
b
Compound
HN
12v
4-MeS
0.4( 0.1)
1.3( 0.1)
864( 380)
N
O
i
-Pr
N
N
12w
4-MeS
4-MeS
1.0( 0.0)
0.7( 0.1)
2.9( 0.6)
1.2( 0.2)
3.6( 1.0)
2.2( 0.6)
1867( 708)
93( 19)
N
O
i-Pr
12x
NH
Fluoxetine
7300( 1100)
a Values are means of at least three experiments in triplicate, SEM is in parentheses.
b Unless indicated, this is the result of a single experiment.
Table 2. Binding data for human NET and DAT
In conclusion, we have prepared a new series of benzyl
amine-based histamine H3 antagonists with serotonin
reuptake activity. The compounds have suitable selec-
tivity over human NET and DAT, and select com-
pounds have good exposure in the brain following
oral administration in rat. These characteristics should
allow further pharmacological profiling of these
compounds.
Compound
Human NET Kia (nM)
Human DAT Kia (nM)
12b
12d
12o
12t
290
240
96
700
1000
190
250
400
a Values are for one experiment, in triplicate.
Table 3. Plasma and brain concentrations in rat
References and notes
Compound
Plasma concentration/brain concentration
(lM)
1. Jane-Llopis, E.; Hosman, C.; Jenkins, R.; Anderson, P.
Br. J. Psychiatry; J. Mental Sci. 2003, 183, 384.
2. Nierenberg, A. A.; Keefe, B. R.; Leslie, V. C.; Alpert, J.
E.; Pava, J. A.; Worthington, J. J., 3rd; Rosenbaum, J. F.;
Fava, M. J. Clin. Psychiatry 1999, 60, 221.
3. Fava, G. A.; Fabbri, S.; Sonino, N. Prog. Neuro-Psycho-
pharmacol. Biol. Psych. 2002, 26, 1019.
4. Witkin, J. M.; Nelson, D. L. Pharmacol. Ther. 2004, 103,
1.
5. Monti, J. M.; Jantos, H.; Boussard, M.; Altier, H.;
Orellana, C.; Olivera, S. Eur. J. Pharmacol. 1991, 205,
283.
6. Monti, J. M.; Jantos, H.; Ponzoni, A.; Monti, D.
Neuropsychopharmacology 1996, 15, 31.
1 h
3 h
6 h
12e
12g
12h
12i
0.068/1.38
0.24/1.77
0.053/0.37
0.11/0.82
0.18/2.37
0.030/0.27
0.045/0.087
0.023/0.044
0.017/0.12
0.039/0.20
0.040/1.70
0.31/4.65
0.12/1.86
0.091/1.42
0.23/5.13
0.018/0.44
0.36/0.36
0.008/0.063
0.032/0.32
0.024/0.22
0.028/1.66
0.15/5.40
0.11/3.56
0.048/1.87
0.27/10.1
0.008/0.40
0.25/0.010
0.010/0.13
0.027/0.52
0.012/0.24
12j
12k
12l
12o
12r
12t
7. Barbier, A. J.; Berridge, C.; Dugovic, C.; Laposky, A. D.;
Wilson, S. J.; Boggs, J.; Aluisio, L.; Lord, B.; Mazur, C.;
Pudiak, C. M.; Langlois, X.; Xiao, W.; Apodaca, R.;
Carruthers, N. I.; Lovenberg, T. W. Br. J. Pharmacol.
2004, 143, 649.
8. Keith, J. M.; Gomez, L. A.; Wolin, R. L.; Barbier, A. J.;
Wilson, S. J.; Boggs, J. D.; Mazur, C.; Frazer, I. C.; Lord,
B.; Aluisio, L.; Lovenberg, T. W.; Carruthers, N. I.
Bioorg. Med. Chem. Lett. 2007, 17, 2603.
9. Keith, J. M.; Gomez, L. A.; Letavic, M. A.; Ly, K. S.;
Jablonowski, J. A.; Seierstad, M.; Barbier, A. J.; Wilson,
S. J.; Boggs, J. D.; Frazer, I. C.; Mazur, C.; Lovenberg, T.
W.; Carruthers, N. I. Bioorg. Med. Chem. Lett. 2007, 17,
702.
10. Letavic, M. A.; Keith, J. M.; Jablonowski, J. A.;
Stocking, E. M.; Gomez, L. A.; Ly, K. S.; Miller, J.
M.; Barbier, A. J.; Bonaventure, P.; Boggs, J. D.; Wilson,
S. J.; Miller, K. L.; Lord, B.; McAllister, H. M.;
Tognarelli, D. J.; Wu, J.; Abad, M. C.; Schubert, C.;
Lovenberg, T. W.; Carruthers, N. I. Bioorg. Med. Chem.
Lett. 2007, 17, 1047.
As stated earlier, one of the main goals of this medicinal
chemistry effort was to design molecules that have phys-
ical properties consistent with good absorption and dis-
tribution into the brain. In order to screen compounds
quickly, we dosed compounds (po at 10 mg/kg) in rats
and the resulting plasma and brain concentrations were
measured at three time points (1, 3, and 6 h). This gave
preliminary information on the extent of exposure in the
brain and also gave a crude assessment of overall bio-
availability. Table 3 shows plasma and brain levels in
rat for compounds tested in this screen. Most of the
compounds tested appear to readily penetrate the brain
and several have very good brain levels (>1 lM) follow-
ing oral administration. Exceptions are 12l and 12o,
which both have rather low brain levels. Many of the
compounds have a high brain to plasma ratio (>10 in
some cases), indicating that the compounds are highly
distributed into the tissue.

M. A. Letavic et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4799–4803
4803
11. Letavic, M. A.; Keith, J. M.; Ly, K. S.; Barbier, A. J.;
Boggs, J. D.; Wilson, S. J.; Lord, B.; Lovenberg, T. W.;
Carruthers, N. I. Bioorg. Med. Chem. Lett. 2007, 17, 2566.
12. Adam, M. D.; Andrews, M. D.; Elliot, M. L.; Gymer, G.
E.; Hepworth, D.; Howard, H. R., Jr.; Middleton, D. S.;
Stobie, A. PCT Int. Appl., WO 2002018333 A1, 2002.
13. Letavic, M. A.; Barbier, A. J.; Dvorak, C. A.; Carruthers,
N. I. Prog. Med. Chem. 2006, 44, 181.
14. Apodaca, R.; Dvorak, C. A.; Xiao, W.; Barbier, A. J.;
Boggs, J. D.; Wilson, S. J.; Lovenberg, T. W.; Carruthers,
N. I. J. Med. Chem. 2003, 46, 3938.
15. Dvorak, C. A.; Apodaca, R.; Barbier, A. J.; Berridge, C.
W.; Wilson, S. J.; Boggs, J. D.; Xiao, W.; Lovenberg, T.
W.; Carruthers, N. I. J. Med. Chem. 2005, 48, 2229.
16. Apodaca, Richard; Xiao, Wei; Jablonoski, Jill A. PCT Int.
Appl., WO 2003050099 A1, 2003.