Pyrrolidino-tetrahydroisoquinolines bearing pendant heterocycles as potent dual H3 antagonist and serotonin transporter inhibitors

Article abstract of DOI:10.1016/j.bmcl.2007.03.043

A series of novel and potent 6-heteroaryl-pyrrolidino-tetrahydroisoquinolines with dual histamine H₃ antagonist/serotonin transporter inhibitor activity is described. In vitro and in vivo data are discussed.

Full text of DOI:10.1016/j.bmcl.2007.03.043

Bioorganic & Medicinal Chemistry Letters 17 (2007) 4374–4377
Pyrrolidino-tetrahydroisoquinolines bearing pendant heterocycles
as potent dual H3 antagonist and serotonin transporter inhibitors
John M. Keith,* Leslie A. Gomez, Ann J. Barbier, Sandy J. Wilson, Jamin D. Boggs,
Brian Lord, Curt Mazur, Leah Aluisio, Timothy W. Lovenberg and
Nicholas I. Carruthers
Johnson & Johnson Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, La Jolla, CA 92121, USA
Received 14 February 2007; revised 12 March 2007; accepted 13 March 2007
Available online 16 March 2007
Abstract—A series of novel and potent 6-heteroaryl-pyrrolidino-tetrahydroisoquinolines with dual histamine H3 antagonist/seroto-
nin transporter inhibitor activity is described. In vitro and in vivo data are discussed.
Ó 2007 Elsevier Ltd. All rights reserved.
More than 340 million people suffer from depression
worldwide, making it a serious global health issue.1
One of the potentially debilitating symptoms of depres-
sion is fatigue.2 Selective serotonin reuptake inhibitors
(SSRIs) are the most frequently prescribed antidepres-
sant drugs, however, these drugs often fail to improve
the symptom of fatigue even as mood improves.3,4
Some SSRIs even induce fatigue and excessive
sleepiness.5,6
elected to use a pyrrolidino-tetrahydroisoquinoline scaf-
fold, developed as part of an earlier in house anti-
depressant program,11 as a template on which to add
an H3 pharmacophore (Fig. 1A). Pharmacophore mod-
els for the H3 receptor suggest a near linear disposition
(m- or p-) of two tertiary amines separated by a phenylene
and a hydrophobic chain of at least four atoms would
frequently lead to potent H3 antagonists.12 We envi-
sioned attachment of a piperidinylpropyloxy side chain
to the pyrrolidino-tetrahydroisoquinoline scaffold in
such a way as to give a complete H3 pharmacophore
(Fig. 1B).
One possible approach to mitigating the fatigue associ-
ated with depression and/or its treatment is through
the use of a histamine H3 antagonist. Histamine H3
receptor antagonists increase wakefulness7 without
showing non-specific stimulant effects such as stimula-
tion of locomotor activity.8 Thus, the case can be made
that H3 antagonists would be useful adjuncts to antide-
pressant therapy. In the current paper, we describe a
medicinal chemistry effort to synthesize molecules
combining H3 receptor antagonism and blockade of
serotonin reuptake.
In a previous report, we disclosed the SAR of pendant
phenyl ring substituents (R).13 In this paper, we further
explore the SAR of this region through the introduc-
R
N
O
N
One of our strategies for the preparation of dual activity
H3 antagonist/serotonin transporter (SERT) inhibitors
was to introduce an H3 pharmacophore to a known
SERT inhibitor.9,10 In one part of these efforts, we
N
N
N
O
A
JNJ-5207852
hH3 Ki = 0.46 nM
B
Keywords: Serotonin transporter; Histamine H3; Microdialysis.
*
Corresponding author. E-mail: jkeith@prdus.jnj.com
EnVivo Pharmaceuticals, Inc, 480 Arsenal Street, Building 1,
Watertown, MA 02472, USA.
Figure 1. (A) SERT inhibitor template. (B) Dual SERT inhibitor and
H3 antagonist template with the H3 pharmacophore in bold.
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.03.043

J. M. Keith et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4374–4377
4375
tion of aromatic heterocycles as either pendant substit-
uents to the phenyl ring or as phenyl ring replace-
ments. Compounds as in Figure 1B were prepared
according to Scheme 1 and the bromo ketones utilized
in step f were prepared by one of two methods shown
in Scheme 2. Heterocyclic ketones with a protonatable
nitrogen were first treated with 1 equiv of HBr in acetic
acid followed by elemental bromine. Non-basic (to
HBr) heterocyclic ketones were simply brominated in
chloroform, methylene chloride or methanol.
In addition to varying the heteroaryl groups, the side
chain was modified to contain either a piperidine or a
morpholine. The piperidinyl derivatives were generally
more potent, but the morpholine compounds had lower
c log P’s.14 In vitro data for the final products 1a–p are
found in Table 1.
Perusal of Table 1 reveals that these compounds all
have a high affinity for the H3 receptor.15 This should
not be too surprising as the H3 pharmacophore por-
tion of these molecules has not been modified beyond
interchanging piperidine and morpholine, both of
which are known to give high affinity H3 ligands.16
The compounds were shown to be potent antagonists
in a functional assay with pA2’s in the range of 8.5–
10.2. However, the nature of the pendant heteroaryl
strongly influences SERT binding.17,18 Generally, these
compounds exhibited greater potency against rSERT
than the hSERT. Pyrrazolo-phenyl and imidazolophe-
nyl derivatives (1a–b) were reasonably well tolerated
by the SERTs. Of the pyridyl derivatives (1c–g), the
3-pyridyl compounds were the most potent. Introduc-
tion of an additional ring nitrogen to give a pyrazine
(1h) resulted in a significant loss of SERT potency.
The most potent compounds were the thienyl deriva-
tives (1i–l), maintaining excellent activity at both the
rat and human SERTs. Thiazoles, pyrazoles, and imi-
dazopyridines were all much less potent against the
SERTs.
X
N
(a,b,c)
(d)
OEt
OEt
HO
O
O
O
X
X
N
N
H
N
(e)
(f)
N
O
O
X
N
X
N
Compound 1d was studied in a mouse brain to plas-
ma ratio experiment.19 After ip administration
(10 mg/kg), 1d achieved a maximal plasma concen-
tration of 1.43 lM after 15 min, and a maximal
brain concentration of 0.92 lM after 2 h. Mean res-
idence time in the plasma was 6.57 h and 31.29 h in
the brain. The blood–brain barrier (BBB) coefficient
was 0.75.20
Ar
Ar
O
(g)
(h)
N
N
O
O
X
N
Ar
Compound 1d was screened against a panel of other tar-
gets (receptors, ion channels, transporters, etc.) and
those revealing significant affinity (>50% at 1 lM) were
retested and Ki’s determined. Other targets of interest in-
cluded the dopamine transporter (DAT; Ki = 107 nM),
norepinephrine transporter (NET; Ki = 460 nM), and
the j opioid receptor (Ki = 74 nM).
( ) 1
N
O
Scheme 1. Reagents and conditions: (a) 1-bromo-3-chloropropane,
3 equiv K2CO3, acetone, reflux, 2 d, 92%; (b) 3.5 equiv NaI, acetone,
reflux, 2 d, 98%; (c) 1.3 equiv piperidine or morpholine, 3 equiv
K2CO3, EtOH, 60 °C, 2 d, 87%; (d) i—2 equiv N-vinylpyrrolidinone,
1.4 equiv NaH, THF rt, reflux; 2 h; ii—6 N HCl reflux, 24 h, 72%; (e)
LiAlH4, THF, 24 h, rt, 88%; (f) bromo-ketone, Et3N, THF, 30 min,
80–99%; (g) MSA, rtÀ80 °C, 1–6 h (temperature and time depend on R);
(h) NaCNBH3, HCl, MeOH, bromocresol green, pH 4.5–5.5, 30 min–
1 h, 15–70%.
The BBB data as well as the DAT activity
prompted us to study 1d via in vivo microdialysis
coupled with HPLC-electrochemical detection in an
effort to assess the effects of 1d on the extracellular
concentration of serotonin (5-HT) and dopamine
(DA) in the frontal cortex of the rat brain.21 Within
4 h of dosing 1d (3 mg/kg sc) the 5-HT and DA lev-
els had increased 300% and 500% over basal levels,
respectively. The increases in neurotransmitter con-
centrations were sustained for the duration of the
experiment (21 h).
O
O
a or b
Br
Het
Het
Scheme 2. Het, aromatic heterocycle; (a) for basic heterocycles:
1 equiv HBr (48%), 0.9 M HOAc, 1.1 equiv Br2, 0–75 °C, 1–4 h; (b)
for non-basic heterocycles: 0.14 M in 5:2 Et2O/CHCl3, or 0.14 M in
MeOH, 1 equiv Br2, 0 °C-rt, 18 h, yields typically 70–80% for both
methods.
In conclusion, the described compounds are potent
brain penetrating dual H3 antagonist/SERT inhibitors
with potential utility for treating depression.

4376
J. M. Keith et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4374–4377
Table 1. Binding data for rat and human serotonin reuptake transporters and for the human histamine H3 receptor for compounds 1a–p
Compound 1
X
O
Ar
rSERT Ki (nM)
hSERT Ki (nM)
hH3 Ki (nM)
N
a
6 ( 1.2)
12.3 ( 2.7)
5.3 ( 0.4)
N
b
c
d
e
f
O
CH2
CH2
O
6.7 ( 1.5)
20 ( 6.0)
2 ( 0.7)
16.7 ( 2.0)
66 ( 32)
5.7 ( 1.1)
1 ( 0.7)
N
N
N
N
8.3 ( 1.8)
12.3 ( 2.3)
18.7 ( 2.2)
31.3 ( 0.8)
88 ( 2.6)
2.7 ( 0.8)
6 ( 0.7)
0.8 ( 0.1)
1.6 ( 0.4)
0.8 ( 0.1)
2.7 ( 0.4)
4 ( 0.7)
N
4.3 ( 0.8)
3.3 ( 0.4)
8.3 ( 1.1)
22.7 ( 7.6)
1.2 ( 0.5)
3 ( 0.7)
N
CH2
O
N
N
g
h
i
O
N
S
CH2
O
1.0 ( 0)
S
j
3 ( 0.7)
S
k
l
CH2
O
0.7 ( 0.2)
2 ( 0)
1.3 ( 0.4)
5 ( 0)
0.7 ( 0.2)
3 ( 0.7)
S
N
m
n
o
p
O
6 ( 0)
19.7 ( 0.4)
291 ( 102)
121 ( 27)
119 ( 11.4)
3.7 ( 0.4)
3.3 ( 0.4)
4 ( 0.7)
S
N
S
O
53.3 ( 20)
24.3 ( 9.4)
39 ( 7.8)
O
N
N
H
N
O
2 ( 0)
N
rSERT, rat serotonin transporter; hSERT, human serotonin transporter; hH3, human histamine H3 receptor: numbers in parentheses are the
standard error of the mean (SEM) for each data set: n P 3 for all in vitro data.
Acknowledgments
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Goldberg for a sample of 2-bromo-1-imidazo[1,2-a]pyri-
din-3-yl-ethanone used to make compound 1p.

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4377
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