2-(3,4-Dihydro-1H-isoquinolin-2yl)-pyridines as a novel class of NR1/2B subtype selective NMDA receptor antagonists

Article abstract of DOI:10.1016/S0960-894X(03)00007-6

Recently, we disclosed 4-aminoquinolines as structurally novel NR1/2B subtype selective NMDA receptor antagonists. We would now like to report our findings on structurally related pyridine analogues. The SAR developed in this series resulted in the discovery of high affinity antagonists which are selective (vs α1 and M1 receptors) and active in vivo.

Full text of DOI:10.1016/S0960-894X(03)00007-6

Bioorganic & Medicinal Chemistry Letters 13 (2003) 829–832
2-(3,4-Dihydro-1H-isoquinolin-2yl)-pyridines as a Novel Class of
NR1/2B Subtype Selective NMDA Receptor Antagonists
Bernd Buttelmann,a,* Alexander Alanine,a Anne Bourson,b Ramanjit Gill,b
Marie-Paule Heitz,a Vincent Mutel,b Emmanuel Pinard,a Gerhard Trubeb
and Rene Wylera
aPharma Division, Discovery Chemistry, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland
bPharma Division, Preclinical CNS Research, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland
Received 28 October 2002; revised 5 December 2002; accepted 20 December 2002
Abstract—Recently, we disclosed 4-aminoquinolines as structurally novel NR1/2B subtype selective NMDA receptor antagonists.
We would now like to report our findings on structurally related pyridine analogues. The SAR developed in this series resulted in
the discovery of high affinity antagonists which are selective (vs a1 and M1 receptors) and active in vivo.
# 2003 Elsevier Science Ltd. All rights reserved.
Native NMDA receptors exist as heteromeric assemblies
containing NR1 subunits together with one or more of
the four NR2 subunits (NR2A-D).1,2 They play a key
role in the normal functioning of glutamatergic neuro-
transmission. However, in a variety of acute and
chronic neurodegenerative diseases, overexcitation of
NMDA receptors triggers neuronal cell death.3 Based
on this rationale, NMDA receptor antagonists have
been tested and were found to be active in animal models
of focal and cerebral ischemia.4,5 The clinical usefulness
of first-generation, subtype unselective NMDA antagonists
however is limited by severe side effects (sedation, psycho-
tomimetic behaviour).6 Second generation, NR1/2B sub-
type selective blockers, such as ifenprodil 1,7 CP-101,606
2,8 and Ro-25-6981 3,9 combine neuroprotective potential
with a markedly improved side-effect profile in animal
models10 and clinical trials.11 The increased safety margin
of these compounds has also been attributed to an
activity dependant blockade of NMDA receptors.9,11 This
makes NR1/2B subtype selective blockers potentially
attractive drugs for the treatment of diseases such as
stroke,4 brain trauma.4 Pain,12 Parkinson’s disease13
and depression14 are other potential indications.
ifenprodil 1 (Scheme 1). They are characterized by one
central and usually basic nitrogen flanked by two aro-
matics, one of them substituted by a phenolic hydroxyl
group or a bioisostere thereof.15
As part of a program to discover structurally novel
NR1/2B subtype selective NMDA receptor antagonists,
we have characterized 4-aminoquinolines (e.g., 4) as a
promising new class.16 We hereby want to communicate
our efforts to simplify the bicyclic aminoquinoline core,
which led to the identification of the pyridine analogues
of 4. In this new series unwanted affinities towards a1-
and M1-receptors15 were monitored routinely, thereby
guiding the selectivity optimization (Table 1).
Most NR1/2B subtype selective NMDA receptor
antagonists described so far are structurally related to
*Corresponding author. Tel.: +41-61-688-1351; fax: +41-61-688-
8714; e-mail: bernd.buettelmann@roche.com
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00007-6

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B. Buttelmann et al. / Bioorg. Med. Chem. Lett. 13 (2003) 829–832
¨
Table 1. NMDA affinities of reference compounds
Compd
Ki (nM)a
NMDAb
1c
2c
3
13
11
6
4
3.5
aKi values are the medians of at least two dose–response curves.
bDisplacement of [3H]-RO-25-6981.23
cCompounds were synthesized at Hoffmann-La Roche.
Scheme 1. (a) (1) AcOH, AcOOH, 50 ꢀC; (2) concd HNO3, concd H2SO4,
90 ꢀC; (3) Fe, AcOH, 100 ꢀC; 58% (all steps); (b) CrO3, concd H2SO4,
70 ꢀC; (2) BH3*THF, 70 ꢀC; (3) Fe, AcOH, 100 ꢀC; 26% (all steps).
Chemistry
Key intermediates in the synthesis of this scaffold are
2-halopyridines
5 and 8. Following the reaction
sequence developed by Ochiai17 5o was prepared from 6
(Scheme 1).18 The hydroxy-substituted analogue 5l was
accessible by Cr(VI) mediated oxidation of the methyl-
group in 719 followed by reduction of the carboxylate by
BH3*THF and Bechamp-reduction of the nitro group.
The other 2-halopyridines are either known20À22 or
commercially available.
Scheme 2. (c) (1) 1,2,3,4-Tetrahydroisoquinoline, iPrOH, rt; (2) H2,
Pd/C, MeOH, RT; 29–48% (all steps); (d) 1,2,3,4-tetrahydroisoquino-
line, 130 ꢀC, 24–98%; (e) NBS, AcOH, rt, 33%; (f) acyl chloride, pyr-
idine, 75 ꢀC, 54–100%; (g) LiAlH4, THF, 70 ꢀC; 58–71%; (h) CH2O,
HCOOH, 100 ꢀC, 57%.
3- or 5–NO2-substituted 2-chloropyridines 8 (Scheme 2)
reacted smoothly at room temperature with 1,2,3,4 tet-
rahydroisoquinoline; subsequent hydrogenolysis furn-
ished the desired amino-substituted 9d and 9g. Less
electron deficient 2-bromopyridines 5 required harsher
conditions: Treatment with 2-3 equivalents of 1,2,3,4-
tetrahydroisoquinoline at elevated temperature led to
the desired substitution products 9a, 9c, 9e–f, 9h–o in
acceptable yields. The 2-(3,4-dihydro-1H-isoquinolin-
2yl)-pyridine skeleton could then be modified further:
Unsubstituted 9e was brominated predominantly in the
5-position to furnish 9b. The free NH2-group in 4-posi-
tion (9k, 9m, 9n) could readily be acylated (e.g., 10–12).
LiAlH4 reduction of the obtained amides led to the
desired monoalkylamines (e.g., 13–15), while reaction of 9n
under Eschweiler–Clark conditions furnished dimethyl-
amino-substituted 16. Ethanolamino-substituted 17–19
were readily available by LiAlH4-reduction of the cor-
responding oxalamides (e.g., 12).
(Table 2a). The unsubstituted 2-(3,4-dihydro-1H-iso-
quinolin-2yl)-pyridine 9e was found to exhibit only
marginal affinity. Bromine in position 5 (9b) or 6 (9a)
was anticipated to mimic the lipophilicity of the annu-
lated benzene ring in 4, however led to a significant drop
in affinity. In this regard additional electron-donating
substituents in position 5 (Me in 9c and NH2 in 9d) and
in position 3 (NH2 in 9g) did not improve the affinity.
However, a moderate increase of affinity could be
observed for NH2-substitution in position 6 (9h); interest-
ingly, an additional Me-substituent in position 4 enhances
affinity even further. In line with this observation, elec-
tron-donating substituents in position 4 critically control
receptor binding: Whilst affinity for 4-Me-substituted 9f
is only moderate (Ki=380 nM), it is greatly improved
down to the low nanomolar range with the strongly
electron-donating 4-NH2-substituent (Ki <10 nM for
9j–9o). By keeping the 4-NH2-group constant, additional
alkyl-groups and the weakly electron-withdrawing
hydroxymethyl-function in position 5 and/or 6 are
Results and Discussion
In order to elucidate the structural requirements for in
vitro affinity key substituents were varied systematically

B. Buttelmann et al. / Bioorg. Med. Chem. Lett. 13 (2003) 829–832
¨
831
Table 2a. NMDA affinities of compounds 9a–9o. Influence of pKa
f
Compd
R1
R2
R3
R4
Ki (nM)a
NMDAb
Ki (nM)a
a1
Ki (nM)a
M1
pKa
d
e
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
9n
9o
H
H
H
H
H
H
NH2
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
H
CH3
NH2
NH2
NH2
NH2
NH2
NH2
H
Br
CH3
NH2
H
H
H
H
H
Br
H
H
H
H
H
H
NH2
NH2
15,000
7500
1700
1100
750
380
380
190
110
9
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
2
3
6.5
5.8
6.4
6.6
5.0
6.0
6.5
9.4
9.0
8.1
8.7
8.5
9.0
n.d
n.d
–(CH2)3–
730
730
1700
1000
1200
670
510
2600
1100
870
1900
2500
H
H
CH3
H
CH3
CH2OH
H
H
C2H5
5
4
4
3
H
2
asee Table 1.
bsee Table 1.
dDisplacement of [3H]-prazosin.24
eDisplacement of [3H]-pirenzepine.25
fpKa values were determined using a potentiometric method.26
Nevertheless, 9n reaches 400-fold selectivity (NMDA
versus a1 and M1 affinity), due to its high NMDA affi-
nity (Ki=2 nM). With the aim to further improve on the
selectivity profile we turned our attention towards
varying substituents at the 4-NH2 in 9n (Table 2b). As
expected, acylation (as in 10–12) not only reduces basicity
but also NMDA affinity. Interestingly, oxalamide 12
and carbamate 10 are of comparable basicity, however
12 exhibits a significantly higher NMDA affinity. This is
already an indication of the tolerance of polar func-
tionalities in the periphery of the molecule. Alkylation
of the 4-NH2 leads to more basic analogues (pKa >8)
with significantly enhanced NMDA affinity. Whilst 13
with the large lipophilic benzyl substituent is the com-
pound with weakest NMDA affinity (Ki=150 nM),
reduction of lipophilic bulk leads to compounds with
increased NMDA affinity (and substituted 14: Ki=
19 nM, Me substituted 15: Ki=8 nM, unsubstituted 9n:
Ki=3 nM). In this respect, the dimethyl-analogue 16
tolerated (9j–9o), thus allowing physico-chemical prop-
erties to be modulated. Interestingly, all high affinity
(i.e., Ki <10 nM) compounds are protonated under
physiological conditions (pKa >8). We have also
observed this in the aminoquinoline-series (e.g., 4),16
suggesting that both series follow a similar SAR. At this
stage of the optimization process we turned our efforts
towards increasing selectivity versus unwanted affinities.
As shown in Table 2a, a1 and M1 affinities are hardly
modulated by substituents at the pyridine core (9j–9o).
Table 2b. NMDA affinities of compounds 10–19. Influence of substituents on p-amino
f
Compd
R3
R4
R5
R6
Ki (nM)a
NMDAb
Ki (nM)a
a1
Ki (nM)a
M1
pKa
d
e
10
11
12
13
14
15
16
17
18
19
H
H
H
H
H
H
H
CH3
H
H
H
H
CH3
H
H
H
H
H
CH3
H
C2H5OCO
CH3CO
C2H5OCOCO
PhCH2
CH3
CH3
CH3
CH2CH2OH
CH2CH2OH
CH2CH2OH
H
H
H
H
H
H
CH3
H
H
H
1100
380
260
150
19
8
n.d
n.d
n.d
n.d
1800
430
490
3200
3300
2300
n.d
n.d
n.d
n.d
n.d
1200
150
6500
3800
6100
6.4
6.5
6.2
8.6
8.9
8.8
8.8
9.0
9.2
8.9
8
8
4
2
asee Table 1.
bsee Table 1.
dDisplacement of [3H]-prazosin.24
eDisplacement of [3H]-pirenzepine.25
fpKa values were determined using a potentiometric method.26

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B. Buttelmann et al. / Bioorg. Med. Chem. Lett. 13 (2003) 829–832
¨
Table 3. In vivo potency of selected compounds
References and Notes
Compd
ED50 (mg/kg)a
Sound induced seizures
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3
4
9n
19
13
13
<12
7
13
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aCompounds were administered ip 30 min before testing in DBA/2
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(Ki=8 nM) is in line with its monosubstituted con-
geners. Strikingly, however, when compared to 4-NH2
substituted 9n, 4-alkylamino substituted pyridines 13–16
are characterized by a somewhat reduced NMDA-affi-
nity combined with an increased a1 and M1 affinity.
This situation can be reversed by introduction of
an extra hydroxy functionality in the alkyl side chain.
4-Ethanolamino substituted 19 not only has high
NMDA affinity (Ki=2 nM), but also low a1 and M1
affinity (selectivity >1000). Introduction of additional
methyl substituents to the pyridine core as in 17 and 18
leads to somewhat less selective compounds. However,
when compared to their 4-NH2 substituted analogues
(9k and 9m) a 2–4-fold reduced affinity at a1 and M1
receptors is apparent. Even when the ethanolamino side
chain does not lead to an increase in NMDA affinity, it
helps to increase selectivity.
11. Chazot, P. L. Curr. Opin. Invest. Drugs 2000, 1, 370.
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In vivo activity was measured in mice after ip administra-
tion using the standard sound-induced seizures assay.27
As depicted in Table 3, the 2-(3,4-dihydro-1H-iso-
quinolin-2yl)-pyridines 9n and 19 exhibited in vivo activity
comparable to the reference compounds 2, 3 and 4.
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Conclusion
Starting from the recently described NR1/2B subtype
selective NMDA antagonist 4-aminoquinoline 416 we
have identified
a series of 2-(3,4-dihydro-1H-iso-
quinolin-2yl)-pyridines that follow a similar SAR: The
pyridine must be sufficiently basic and can be further
substituted by electron-donating groups. Para- hydoxy-
alkylamino substituted pyridines combine high affinity
at the NMDA receptor with low muscarinic and adre-
nergic side-effect liabilities.
23. Mutel, V.; Buchy, D.; Klingelschmidt, A.; Messer, J.;
Bleuel, Z.; Kemp, J. A. J. Neurochem. 1998, 70, 2147.
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Eur. J. Pharmacol. 1993, 231, 485.
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Forest Row UK, 1993.
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Boess, F. G.; Sleight, A. J. Naunyn-Schmiedeberg’s Arch.
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Acknowledgements
The skillful technical assistance of B. David and C.
Wunderlin is gratefully acknowledged. The authors wish
to thank W. Arnold and W. Meister for spectroscopic
characterization and Bjorn Wagner for pKa determination.