The design, synthesis and structure-activity relationships of 1-aryl-4-aminoalkylisoquinolines: A novel series of CRF-1 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2007.12.050

The design, synthesis and structure-activity relationships of a novel series of CRF-1 receptor antagonist, the 1-aryl-4-alkylaminoisoquinolines, is described. The effects of substitution on the aromatic ring, the amino group and the isoquinoline core on C

Full text of DOI:10.1016/j.bmcl.2007.12.050

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 891–896
The design, synthesis and structure–activity relationships
of 1-aryl-4-aminoalkylisoquinolines: A novel series
of CRF-1 receptor antagonists
´
Taeyoung Yoon, Stephane De Lombaert, Robbin Brodbeck, Michael Gulianello,
Jayaraman Chandrasekhar, Raymond F. Horvath, Ping Ge, Mark T. Kershaw,
*
´
James E. Krause, John Kehne, Diane Hoffman, Darıo Doller and Kevin J. Hodgetts
Neurogen Corporation, 35 North East Industrial Road, Branford, CT 06405, USA
Received 26 November 2007; revised 18 December 2007; accepted 19 December 2007
Available online 3 January 2008
Abstract—The design, synthesis and structure–activity relationships of a novel series of CRF-1 receptor antagonist, the 1-aryl-4-
alkylaminoisoquinolines, is described. The effects of substitution on the aromatic ring, the amino group and the isoquinoline core
on CRF-1 receptor binding were investigated.
Ó 2007 Elsevier Ltd. All rights reserved.
Corticotropin releasing factor (CRF) is a 41-amino acid
N
peptide that acts as the prime regulator of the hypotha-
lamic–pituitary–adrenal (HPA) stress response.1 A large
body of evidence exists for the hypothesis that over-stim-
ulation of the CRF system may underlie the pathology of
several diverse neuropsychiatric diseases including
depression, anxiety and stress-related disorders.2 CRF
exerts its actions through high-affinity binding to its
receptors CRF-1 and CRF-2, both of which belong to
the class B subfamily of G-protein coupled receptors.3
They are encoded by two separate genes and display dis-
tinct pharmacology and distribution within the CNS and
periphery.4 While, the therapeutic benefits of blocking
the CRF-2 receptor remain to be fully established, evi-
dence exists that antagonism of the CRF-1 receptor pro-
duces anxiolytic and antidepressant effects. Centrally
acting CRF-1 receptor antagonists are therefore expected
to have utility in the treatment of anxiety, depression and
stress-related disorders. The first potent bicyclic CRF-1
antagonist, CP-154,526, was reported in 1996, and in
the ensuing years a large number of small molecule antag-
onists have been disclosed,5 representative examples are
illustrated in Figure 1.6 Potent CRF-1 antagonists
N
N
N
N
N
N
Cl
N
N
N
NH
N
Cl
N
NMe2
Cl
CP-154,526
(topology I)
R121919
(topology I)
NBI 27914
(topology I)
NMe2
N
N
N
S
F
N
N
O
N
N
N
N
OMe
OMe
NGD 98-1
(topology I)
1
SSR125543A
(topology II)
(topology I)
Figure 1. Structures of representative CRF-1 receptor antagonists.
Keywords: CRF-1 receptor antagonist; 1-Aryl-4-aminoalkylisoquino-
line; Depression; Anxiety.
including CP-154,526,7 R121919,8 NBI 27914,9 NGD
98-1,10 the tricycle 1,11 and SSR125543A12 have been
widely studied in animal models of depression and
*
Corresponding author. Tel.: +1 203 488 8201; fax: +1 203 483
7027; e-mail: khodgetts@nrgn.com
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.12.050

892
T. Yoon et al. / Bioorg. Med. Chem. Lett. 18 (2008) 891–896
anxiety and have shown encouraging results. Notable
amongst these, R121919, demonstrated efficacy in treat-
ing depressed patients in an open label phase IIa clinical
trial.13 Clinical development of R121919 was discontin-
ued, due to significant, albeit reversible, elevation of liver
enzymes at high doses. A number of other CRF-1 recep-
tor antagonists are reportedly undergoing clinical trials
at the present time.
Structural features common to most CRF-1 antagonists
include: a core central heterocycle that contains a critical
hydrogen bond acceptor, an out-of-plane pendant aro-
matic ring and a top side-chain filling a largely hydro-
phobic area of the receptor. They have previously been
classified into two topologies based on distinct structural
features.5b In the first topology, which contains the
majority of compounds to have reached advanced pre-
clinical development or clinical stage, the hydrogen
bond acceptor and the pendant aryl substituent are sep-
arated by two atoms (e.g., R121919), while in the second
topology a single intervening atom is present (e.g.,
SSR125543A). We set out to examine the possibility of
identifying a novel series of CRF-1 receptor antagonists
from the relatively underexplored topology II template.
In this paper the design, synthesis and evaluation of the
first bicyclic CRF-1 receptor antagonists from topology
II, the 1-aryl-4-alkylaminoisoquinolines, is described.
Figure 3. Alignment of the low-energy conformers of quinoline 2
(background) and isoquinoline 3 (foreground).
adopts a nearly orthogonal conformation in both series
(Fig. 3).
There was limited literature precedent for the synthesis of
1-aryl-4-aminoisoquinolines16 and the methods devel-
oped for the synthesis of the compounds described in this
study are illustrated in Schemes 1 and 2. The synthesis of
analogues unsubstituted at the 3-position of the isoquin-
oline is outlined in Scheme 1. Nucleophilic alkylation of
isoquinoline (4) with an aryl Grignard in the presence
of ethyl chloroformate proceeded smoothly and gave in
good yield the desired 1,2-dihydroisoquinoline 5. Nitra-
tion of 5 proceeded at the 4-position and gave the 4-ni-
tro-isoquinoline 6 in moderate yield. Deprotection of
the carbamate 6, spontaneous air-oxidation and hydro-
genation of the nitro group gave the 4-amino-isoquino-
line 7 in 35% overall yield. Reductive amination of 7
gave the monoalkyl amine 8 and finally alkylation with
the appropriate alkyl halide gave the dialkylamine 9.
The design strategy was to rearrange the positioning of
the key structural features of a known high-affinity
topology I template to generate a novel series. In such
a way repositioning of the pendant aryl group, the
hydrogen bond acceptor and the 2-methyl group of
the previously reported quinoline 214 led us to consider
the novel isoquinoline 3, which formally belongs to the
topology II class (Fig. 2).
Potential alignments of low-energy conformers of the
CRF-1 antagonist 2 and the proposed template 3 were
first examined to better understand comparisons be-
tween the pharmacophores of the two templates. The
analyses were performed using the Maestro 7.0 software
package from Schrodinger.15 The analysis was encour-
aging and revealed that there was an excellent alignment
between 2 and 3 with respect to all of the key pharmaco-
phore features: the top side chain, the critical hydrogen
bond acceptor and the pendant aromatic ring which
The synthesis of the 3-alkyl-substituted isoquinolines de-
scribed in the study is depicted in Scheme 2. Cyclization
of homophthalic acid (10) with acetic anhydride in pyr-
idine gave 4-acetyl-1,3-isochromandione (11). Treat-
ment of 11 with refluxing ammonium hydroxide gave
an excellent yield of 3-methyl-isoquinolone (12) over
the two steps. Regioselective nitration and subsequent
chlorination in the presence of diethyl aniline gave the
versatile intermediate 1-chloro-4-nitroisoquinoline (13).
The bi-functional isoquinoline 13 could be used to incor-
porate either the 4-amino substituent or the 1-aryl sub-
stituent in the final step of the synthesis. For example,
Suzuki coupling of 13 under standard conditions al-
lowed introduction of the 1-aryl substituent first.
Hydrogenation of the nitro group of 14 then gave the
amine 15 and reductive amination gave the target com-
pound 16. The 1-aryl group could also be introduced in
the final step. Dithionate reduction of the nitro group of
13 gave the amine 17 and reductive amination yielded
the alkylamine 18. Finally, Suzuki coupling with an aryl
lipophilic
region
H-bond
acceptor
N
N
N
3 group shift
N
one-atom
spacer
Cl
Cl
pendant
aryl
Cl
Cl
2 hCRF-1 = 0.9 nM14
3
(topology I)
(topology II)
Figure 2. Design of 1-aryl-4-aminoalkylisoquinolines as potential
CRF-1 receptor antagonists.

T. Yoon et al. / Bioorg. Med. Chem. Lett. 18 (2008) 891–896
893
O2N
a
b
N
Ar
N
Ar
N
EtO2C
EtO2C
5
4
6
c, d
f
e
HN
N
H2N
R
N
Ar
N
Ar
N
Ar
9
8
7
Scheme 1. Reagents and conditions: (a) ArMgBr, THF, 0 °C then ClCO2Et, (70–92%); (b) HNO3, HOAc, 0 °C, (46%); (c) HBr, HOAc, 100 °C, air;
t
(d) Pd/C, H2 (50 psi), HCl, MeOH, (35% over 2 steps); (e) CH3CH2CO2H, NaBH4, 100 °C, (83%); (f) RBr or RI, BuOK, DMSO, rt, (49–78%).
O
a
b
HO2C
CO2H
O
O
O
N
OH
10
11
12
c, d
f
e
H2N
O2N
O2N
N
Ar
N
Ar
N
Cl
15
14
13
g
h
R
R
g
e
N
N
H2N
R
R
N
Ar
N
Cl
N
Cl
16
18
17
Scheme 2. Reagents and conditions: (a) Ac2O, pyridine, rt; (b) NH4OH, 100 °C, (75% over 2 steps); (c) HNO3, 0 °C, (91%); (d) OPCl3, PhNEt2,
95 °C, (72%); (e) ArB(OH)2, 2 M K2CO3, Pd(PPh3)4, PhMe, 85 °C, (31–72%); (f) Pd/C, H2, MeOH, (95%); (g) aldehyde, NaBH(OAc)3, HOAc,
CH2Cl2, rt, (54–69%); (h) Na2S2O4, NH4OH, THF, H2O, (72%).
boronic acid allowed introduction of a variety of aryl
substituents at the 1-position of 16. It should be noted
that coupling of 18 with 2,6-disubstituted aryl boronic
acids was sluggish and additional boronic acid, palla-
dium catalyst and prolonged reaction times were neces-
sary to drive the reaction to completion.
nously expressed in IMR-32 human neuroblastoma
cells.
The effects of the substituents on the 1-aryl group were
investigated first (Table 1). The 4-dipropylamine and
the 3-methyl substituent were kept constant. The first
example, the 2,4-dichloro analogue 3, had a very
encouraging affinity (Ki = 103 nM) which validated our
original design of the isoquinolines as novel, topology
II, CRF-1 receptor ligands, although the ꢀ100-fold loss
in activity relative to the quinoline 2 (Ki = 0.9 nM)14 was
somewhat disappointing. To further understand the
SAR and improve the affinity of the new series, a num-
The compounds described in this study are listed in Ta-
bles 1–5. The affinity of these compounds for the CRF-1
receptor was determined by using a modified version of
the assay described by Grigoriadis and De Souza17 by
examining their competition with 125I-sauvagine at
membrane preparations of CRF-1 receptors endoge-

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T. Yoon et al. / Bioorg. Med. Chem. Lett. 18 (2008) 891–896
Table 1. Effects of the 1-aryl substituent on CRF-1 binding
Table 4. Effects of the 2-aryl substituent on CRF-1 binding
N
N
N
N
Ar
O
R
3, 26a-k
Compound
Ar
—
Ki (nM)
29a-g
CP154526
2
2.77
0.914
103
>10,000
1685
>10,000
962
21
Compound
R
Solubilitya (lg/mL) Ki (nM)
3
2,4-Dichloro
Ph
26j
<0.5
112
105
27
6
265
173
120
524
30
26a
26b
26c
26d
26e
26f
29a
29b
29c
29d
29e
29f
29g
NMe2
Pyrrolidine
Piperidine
2-Chloro
3-Chloro
4-Chloro
N-Methylpiperazine 135
Morpholine NA
2-Methyl-4-chloro
2-Methyl-4-methoxy
2-Ethyl-4-methoxy
2,4-Methoxy
28
36
4-Hydroxypiperidine 125
3-Hydroxypiperidine 131
41
32
26g
26h
26i
42
17
Ki values are means of three independent experiments.
a At pH 5.4.
2-Methoxy-4-difluoromethoxy
2-Methoxy-4,6-dimethyl
2-Methoxy-4,6-ditrifluoromethyl
2,6-Dimethyl-4-methoxy
26j
6
26k
26l
8
26
Ki values are means of three independent experiments.
Table 5. Representative data for compounds 26j and 26k
Compound CRF-1 At T20 Microsomal Solubilitya MlogP
Table 2. Effects of the 3-methyl substituent on CRF-1 binding
Ki (nM) Ki (nM) T1/2 (min)
(lg/mL)
26j
26k
6
8
12
22
4
36
<0.5
<0.5
4.6
5.7
N
R
a At pH 5.4.
N
OMe
ber of substituted aryl groups were subsequently pre-
pared. For optimal CRF-1 binding, previous studies
have suggested that the aryl ring lies out of the plane
of the core heterocycle and the results in the isoquinoline
series are in accord with that model.18 The unsubstituted
phenyl analogue 26a and the 3-chloro analogue 26c were
inactive. However, an ortho substituent forces the aryl
ring to be out of the plane with respect to the isoquino-
line core and the 2-chloro analogue 26b showed modest
26j, 27a-b
Compound
R
Ki (nM)
26j
Me
H
6
49
9
27a
27b
Et
Ki values are means of three independent experiments.
Table 3. Effects of the 4-amino substituent on CRF-1 binding
R1
N
R2
N
OMe
28a-f
Compound
R1
R2
Solubilitya (lg/mL)
Ki (nM)
26j
nPropyl
nPropyl
CH2–cPropyl
H
nPropyl
<0.5
<0.5
<0.5
NA
103
6
28a
28b
28c
28d
28e
28f
CH2–cPropyl
5
CH2–cPropyl
nPropyl
7
165
>10,000
215
1063
H
CH2CH2–pyrrolidine
CH2CH2–pyrrolidine
CH2CH2–imidazole
nPropyl
nPropyl
120
107
Ki values are means of three independent experiments.
a At pH 5.4.

T. Yoon et al. / Bioorg. Med. Chem. Lett. 18 (2008) 891–896
895
affinity (Ki = 1685 nM). The 4-chloro analogue 26d also
showed weak affinity (Ki = 962 nM) which underscores
the importance of para substitution even in the absence
of an ortho substituent. An increase in affinity was ob-
served by combining an ortho and para substituent (ana-
logues 26e–26i) and the addition of a second ortho
substituent, which further hinders the rotation of the
aryl group, gave another boost in affinity. The 2-meth-
oxy-4,6-dimethyl analogue 26j (Ki = 6 nM) was the first
compound with activity below 10 nM in the series and
replacing both methyl groups with a trifluoromethyl
group gave an analogue of similar affinity (26k,
Ki = 8 nM). Switching the 2-methoxy-4-methyl substitu-
ents resulted in a loss of affinity (26l, Ki = 26 nM).
tion in AtT20 cells expressing the CRF-1 receptor19 with
Ki’s of 12 and 22 nM, respectively. These values tracked
well with binding affinity and confirm that 26j and 26k
are functional antagonists at the CRF-1 receptor (Table
5). The rat microsomal half-life of 26j was very short
(T1/2 < 5 min), however, 26k in which both of the aryl
ring methyl groups have been replaced by trifluoro-
methyl had a much longer microsomal half-life (T1/2
=
36 min). The pharmacokinetic properties of 26k were
examined in rat but modest oral exposure and a large
volume of distribution were observed (F = 4.8% at
20 mg/kg, Cmax = 387 ng/mL, Tmax = 0.7 h, T1/2 = 5.4 h,
Cl = 14.5 mL/min/kg and Vd = 13 L/kg). In general,
poor microsomal stability, minimal aqueous solubility
and low oral bioavailability precluded the further assess-
ment of this series.
The effects of substitution at the 3-position of the iso-
quinoline on CRF-1 receptor binding were examined
next (Table 2). The 4-dipropyl amine and the 2-meth-
oxy-4,6-dimethylphenyl group were kept constant to al-
low comparison with the 3-methyl analogue 26j.
Increasing the size of the alkyl group from methyl to
ethyl produced a compound of comparable affinity to
26j (27b, Ki = 9 nM), but replacing the 3-methyl substi-
tuent with hydrogen resulted in a significant loss of affin-
ity (27a, Ki = 49 nM).
In summary, a series of 1-aryl-4-alkylaminoisoquino-
lines has been described having affinity for the CRF-1
receptor. The original hypothesis of transforming a
topology I template into a topology II template proved
to be successful. A number of new synthetic routes were
developed for the synthesis of substituted isoquinolines
which resulted in the identification of several com-
pounds with <10 nM CRF-1 binding affinity. For opti-
mal CRF-1 binding affinity 2,4,6-trisubstitution was
found to be necessary on the aryl ring of this series.
At this stage however, the unacceptable physiochemical
(e.g., high lipophilicity and low aqueous solubility) and
poor pharmacokinetic profiles of the series rendered
them unsuitable for further development. The results
of our continuing efforts to resolve these issues will be
reported in due course.
The next region of the isoquinoline that was investigated
was the 4-amino substituent. To allow comparison to
26j the 3-methyl substituent of the isoquinoline was
fixed and the 2,4-dimethyl-6-methoxyphenyl group was
retained at the 1-position (Table 3). Exchange of one
or both of the npropyl groups by a cpropylmethyl group
gave compounds of similar affinity (28a, Ki = 5 nM and
n
28b, Ki = 7 nM). Replacement of an propyl group by
hydrogen resulted in a large decrease in affinity (28c,
Ki = 165 nM). In an attempt to increase the solubility
of the series, several basic amines were incorporated into
the side chain (28d–28f). The solubility at pH 5.4 was in-
creased in comparison to 26j, however, a substantial loss
in affinity was also observed.
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