2-Arylpyrimidines: Novel CRF-1 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2008.07.063

The design, synthesis and structure-activity relationship studies of a novel series of CRF-1 receptor antagonists, the 2-arylpyrimidines, are described. The effects of substitution on the aromatic ring and the pyrimidine core on CRF-1 receptor binding wer

Full text of DOI:10.1016/j.bmcl.2008.07.063

Bioorganic & Medicinal Chemistry Letters 18 (2008) 4486–4490
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
2-Arylpyrimidines: Novel CRF-1 receptor antagonists
Taeyoung Yoon, Stéphane De Lombaert, Robbin Brodbeck, Michael Gulianello, James E. Krause,
Alan Hutchison, Raymond F. Horvath, Ping Ge, John Kehne, Diane Hoffman, Jayaraman Chandrasekhar,
*
Darío Doller, Kevin J. Hodgetts
Neurogen Corporation, 35 Northeast Industrial Road, Branford, CT 06405, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The design, synthesis and structure–activity relationship studies of a novel series of CRF-1 receptor
antagonists, the 2-arylpyrimidines, are described. The effects of substitution on the aromatic ring and
the pyrimidine core on CRF-1 receptor binding were investigated. A number of compounds with Ki values
below 10 nM and lipophilicity in a minimally acceptable range for a CNS drug (cLogP < 5) were
discovered.
Received 29 May 2008
Revised 13 July 2008
Accepted 14 July 2008
Available online 18 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
CRF-1
Anxiety
Depression
2-Arylpyrimidine
Corticotropin releasing factor (CRF), a 41-amino acid peptide
originally isolated by Vale in 1981 from ovine brain extract, is
the prime regulator of the hypothalamic-pituitary-adrenal (HPA)
stress–response.1 CRF exerts its biological functions through acti-
vation of its receptors CRF-1 and CRF-2, both of which belong to
the class B subfamily of G-protein coupled receptors.2 While the
benefits of blocking the CRF-2 receptor remain uncertain, evidence
from preclinical animal models and early clinical studies suggests
that antagonism of the CRF-1 receptor has the potential to produce
therapeutically useful anxiolytic and antidepressant effects.3 The
first small molecule CRF-1 receptor antagonists disclosed in the
late 1990s, and subsequently well characterized, include CP-
154,5264 and SSR125543A.5 These early analogues were very po-
tent in vitro and demonstrated efficacy in animal models but are
generally highly lipophilic (cLogP > 7) and poorly water soluble.
Clinical development of compounds of this nature has often been
hindered by issues including unattractive pharmacokinetics,
extensive tissue accumulation, undesirably long elimination half-
life, and adverse events. In the ensuing years, efforts have focused
on reducing the lipophilicity of these molecules to values consid-
ered more suitable for a CNS drug (cLogP of between 2 and 5).6
Successful approaches have included the replacement of the
hydrophobic side-chain with a more polar group, for example,
DMP6967 or substitution of the lipophilic pendant phenyl ring by
an amino-heterocycle, for example, R1219198a and MTIP8b (Fig. 1).
Notably, R121919 demonstrated efficacy in treating patients
with depression in an open-label phase IIa clinical trial.9 While this
N
N
N
F
S
N
N
N
OMe
CP-154,526
hCRF-1 Ki = 3 nM
cLogP = 7.1
SSR125543A
hCRF-1 Ki = 2 nM
cLogP = 7.7
OMe
HN
N
OMe
N
N
N
N
N
N
N
N
N
N
Cl
S
N
N
N
OMe
NMe2
O
DMP696
R121919
hCRF-1 Ki = 3 nM
cLogP = 4.8
MTIP
hCRF-1 Ki = 2 nM
hCRF-1 Ki = 0.2 nM
cLogP = 4.9
cLogP = 2.5
Figure 1. Structures of representative CRF-1 receptor antagonists.
strategy provided an antagonist with improved drug-like proper-
ties, R121919 did not progress further into development due to
* Corresponding author. Tel.: +1 2034888201.
E-mail address: kjhodgetts@aol.com (K.J. Hodgetts).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.07.063

T. Yoon et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4486–4490
4487
O2N
N
N
N
a, b, c
N
N
N
OMe
N
OMe
Cl
MeO
N
Ar
N
MeO
2
N
5a-g
4
1 hCRF-1 Ki = 6 nM
cLogP = 7.4
MW = 376
2
d, e
cLogP = 5.5
MW = 327
Figure 2. Design of 2-arylpyrimidines as CRF-1 receptor antagonists.
hepatotoxicity issues. A number of other CRF-1 receptor antago-
nists are reportedly in clinical development at the present time.
We recently described a series of isoquinolines, such as 1, that
demonstrated strong CRF-1 receptor antagonism (Fig. 2).10 The
suboptimal, physicochemical (high lipophilicity and low aqueous
solubility), and poor pharmacokinetic profiles of this series ren-
dered its members unsuitable for further development. To increase
hydrophilicity and improve general pharmacokinetic properties,
we considered replacing the bicyclic quinoline core of 1 with a less
lipophilic, monocyclic core such as the 2-arylpyrimidine 2. The
synthesis and SAR of the 2-arylpyrimidines as CRF-1 receptor
antagonists are described herein.
The synthesis of pyrimidine 2 is outlined in Scheme 1. Reduc-
tive amination of 2-chloro-4-methyl-5-aminopyrimidine (3)11
with propionaldehyde allowed introduction of the di-N-propyl-
amine moiety at C-5. Subsequent Suzuki coupling provided the de-
sired pyrimidine 2 in modest yield. It should be noted that
throughout the course of the study, the coupling of unactivated
2-chloro-pyrimidines with 2,6-disubstituted aryl boronic acids12
was very sluggish, and excess of both boronic acid and palladium
catalyst, and prolonged reaction times were necessary to achieve
even moderate yields of desired product. The unsubstituted pyrim-
idine 2 had an encouraging affinity (Ki = 561 nM) for the CRF-1
receptor,13 despite being considerably less active than the corre-
sponding isoquinoline 1 (Ki = 6 nM).
N
N
N
f
N
4
Ar
Ar
N
N
RO
Cl
7a-d
6
Scheme 2. Reagents and conditions: (a) ArB(OH)2, 2 M K2CO3, Pd(PPh3)4, PhMe,
85 °C (55–77%); (b) H2, Pd/C, EtOH (77–100%) or Na2S2O4, NH4OH, THF, H2O, (68%);
(c) CH3CH2CHO, NaBH(OAc)3, HOAc, CH2Cl2, RT (82%); (d) 5a, cHCl, 100 °C (100%);
(e) POCl3, 90 °C (77%); (f) ROH, NaH, DMSO, 100 °C (57–69%).
idine. The introduction of a small alkoxy substituent at the vacant
ring position on the heterocycle seemed to be an attractive strategy
to fill this pocket. The repulsion between the lone pairs on the oxy-
gen and the adjacent pyrimidine nitrogen appears to further re-
strict the low-energy conformational space, and confer additional
rigidity that was expected to be beneficial.
The readily available 2-chloro-4-methoxy-5-nitro-6-methyl-
pyrimidine (4)15 proved to be a suitable starting material in this re-
gard (Scheme 2). Suzuki coupling of the 5-nitropyrimidine 4 was
considerably more facile than for the 5-aminopyrimidine and gave
moderate to good yields of the corresponding 2-arylpyrimidines.
Hydrogenation of the nitro group followed by reductive alkylation
with an excess of propionaldehyde gave the desired methoxypyr-
imidines 5a–g in good yields. Acidic hydrolysis of 5a (Ar = 2-meth-
oxy-4,6-dimethylphenyl), then treatment with phosphorus
oxychloride yielded the chloro-pyrimidine 6. The chloride was sus-
ceptible to displacement by alkoxides in hot DMSO to provide the
corresponding 4-alkoxypyrimidines 7a–d in moderate yields.
The effects of alkoxy substitution at the 4-position are summa-
rized in Table 1. The 2-methoxy-4,6-dimethylphenyl, 5-dipropyl
amine, and 6-methyl substituents were kept constant to allow
comparison with the unsubstituted pyrimidine 2 (Ki = 561 nM). A
significant increase in affinity was observed upon incorporation
In order to design a strategy to enhance the affinity of 2, the
structures of SSR12543A and 2 were aligned using GASP software,
and local minimum energy conformations were computed.14 Fig-
ure 3 shows a good overlay for the low-energy conformations of
these two compounds, especially at the pendant aryl ring, the cen-
tral hydrogen bond acceptor, and the lipophilic top side-chain. The
key feature lacking in 2 appears to be a group flanking the pyrim-
Table 1
Effects of the 4-substituent on CRF-1 receptor binding
N
H2N
OMe
N
a, b
N
5
N
Cl
N
N
OMe
N
4
N
R
2 hCRF-1 Ki = 561 nM
3
Scheme 1. Reagents and conditions: (a) CH3CH2CHO, NaBH(OAc)3, HOAc, CH2Cl2,
RT (76%); (b) ArB(OH)2, 2M K2CO3, Pd(PPh3)4, PhMe, 85 °C (35%).
2, 5a, 6, 7a-d
Compound
R
Ki (nM)
cLogP
1
2
—
H
6
561
15
33
16
53
>5000
1610
7.4
5.5
6.4
6.2
6.9
7.5
7.3
5.6
5a
6
7a
7b
7c
7d
OMe
Cl
OEt
OnPr
OiPr
OCH2CH2OH
Figure 3. Minimized structures of 2, SSR125543A, and the 4-methoxy pyrimidine
derivative of 2.
Ki values are the mean of 3 independent experiments.

4488
T. Yoon et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4486–4490
R
5
H2N
HN
CH3
N
CH2R
a, b
N
N
6
N
N
a
N
Ar
Ar
N
N
MeO
MeO
N
N
MeO
MeO
9
10a-c
MeO
MeO
Scheme 4. Reagents and conditions: (a) NaNO2, HCl, H2O, 0 °C then KI, reflux (34%);
(b) Pd2(dba)3, PtBu3, PhMe, (17–29%).
5a
8a-d
Scheme 3. Reagents and conditions: (a) LDA, THF, À78 °C then electrophile (52–
Table 4
75%).
Effects of the 5-substituent on CRF-1 receptor binding
R
of the methoxy group at the 4-position (5a, Ki = 15 nM), although
lipophilicity was significantly increased (cLogP = 6.4). The eth-
oxy-analogue 7a was of a similar potency but further increases
in chain length resulted in a loss in affinity (7b), while side-chain
branching led to an inactive compound (7c). To increase hydrophi-
licity, the incorporation of polar functionality into the chain was
investigated (7d) but since this approach resulted in a severe loss
of potency, it was not pursued further.
In terms of affinity, the 4-methoxy substituent appeared opti-
mal and was thus retained in the next series of analogues. Func-
tionalization of the 6-position of the pyrimidine 5a was achieved
by deprotonation with LDA and subsequent trapping with an elec-
trophile. Using this method, a number of 6-substituted analogues
8a–d were prepared in moderate to good yields (Scheme 3).
5
HN
OMe
N
N
MeO
10a-c
Compound
R
Ki (nM)
cLogP
5a
—
15
>10,000
94
6.4
5.3
6.1
6.1
10a
10b
10c
nPropyl
3-Pentyl
CH2C(CH3)3
>10,000
Ki values are the mean of 3 independent experiments.
Table 2
Effects of the 6-substituent on CRF-1 receptor binding
CH2R
6
N
OMe
N
Figure 4. Minimum energy conformation of the dialkoxypyrimidine 12a.
N
MeO
5a, 8a-d
Compound
R
Ki (nM)
cLogP
5a
8a
8b
8c
8d
H
CH3
CH2CH3
CHOHCH3
C(CH3)2OH
15
22
76
1150
604
6.4
7.0
7.5
5.4
5.8
5
O
HO
a, b
N
N
Ar
N
MeO
Cl
N
MeO
12a-c
11
Ki values are the mean of 3 independent experiments.
Scheme 5. Reagents and conditions: (a) PPh3, DEAD, propan-3-ol, THF, RT (72%);
(b) ArB(OH)2, 2 M K2CO3, Pd(PPh3)4, PhMe, 85 °C (35–57%).
Table 3
Effects of the 2-aryl substituent on CRF-1 receptor binding
Table 5
Effects of the 2-aryl substituent of 5-alkoxy pyrimidines on CRF-1 receptor binding
N
N
5
O
N
2
Ar
MeO
5a-g
N
Ar
N
MeO
12a-c
Compound
Ar
Ki (nM)
cLogP
5a
5b
5c
5d
5e
5f
2-Methoxy-4,6-dimethylphenyl
2,4-Dichlorophenyl
2,4-Dimethoxyphenyl
2,6-Dimethoxyphenyl
2,4,6-Trimethylphenyl
15
6.4
7.4
5.8
5.8
7.1
7.7
5.9
Compound Ar
CRF-1 Ki (nM) AtT20 IC50 (nM) cLogP
>10,000
507
277
354
6
1
5g
—
—
6
2
8
9
9
12
1
19
7
7.4
5.9
5.5
5.0
4.5
12a
12b
12c
2-Methoxy-4,6-dimethyl
2,6-Dimethoxy-4-chloro
2,6-Dimethoxy-4
2-Methoxy-4,6-ditrifluoromethylphenyl
2,6-Dimethoxy-4-chlorophenyl
—
5g
2
-difluoromethyl
Ki values are the mean of 3 independent experiments.
IC50 values are the mean of 3 independent experiments.

T. Yoon et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4486–4490
4489
Table 6
Pharmacokinetic profiles of 1, 5g, and 12b in Sprague–Dawley rats (20 mg/kg po and 3 mg/kg iv)
Compound
Solubility (
l
g/mL)a
F (%)
Cmax (ng/mL)
Tmax (h)
T1/2 (h)
Cl (mL/min/kg)
Vd (L/kg)
1
5g
12b
<0.5
27
28
5
2
6
387
210
194
0.7
0.6
1.8
5.4
2.8
8.3
14.5
21
13.6
13
12
14
a
Determined in 0.1 N HCl.
The CRF-1 receptor binding affinities of these 6-substituted ana-
logues are summarized in Table 2. A small increase in chain size
(8a) afforded a compound of similar potency to 5a but further in-
creases in chain length (8b) led to a decrease in affinity. The intro-
duction of secondary (8c) and tertiary (8d) alcohol functionality
resulted in a decrease in activity.
important to determine the functional activity of these compounds
at the CRF-1 receptor. Compounds 5a, 12a, and 12b were found to
inhibit sauvagine-stimulated cAMP accumulation in AtT20 cells
expressing the CRF-1 receptor18 with IC50s that correlated well
with binding affinity, thereby supporting that these compounds
are indeed functional antagonists at the CRF-1 receptor.
A number of substituted 2-aryl analogues of the 4-methoxypyr-
imidines were prepared (Schemes 2 and 5a–g) and their CRF-1
receptor binding affinities are shown in Table 3. To achieve maxi-
mal CRF-1 binding affinity in the isoquinoline10 series a 2,4,6-tri-
substitution on the aryl ring was required. This also proved to be
the case in the pyrimidine series.16 Replacing the 2-methoxy-4,6-
dimethylphenyl (5a, Ki = 15 nM) by 2,4-dichlorophenyl (5b) led
to a complete loss in activity. Likewise, only modest affinity was
found for the 2,4- and 2,6-dimethoxyphenyl analogues (5c and
5d). Reverting to 2,4,6-trisubstitution and replacing the 2-methoxy
group of 5a with methyl (5e, Ki = 354 nM) resulted in a consider-
able loss in affinity, underscoring the importance of the 2-methoxy
substituent in this series. Reintroduction of the 2-methoxy and
replacement of both methyl groups with trifluoromethyl groups
gave an increase in affinity (5f, Ki = 6 nM) but also lipophilicity
(cLogP = 7.7). In an attempt to increase the hydrophilicity, while
retaining the potency of 5f, the trifluoromethyl groups were re-
placed by less lipophilic substituents such as a second ortho-meth-
oxy and a para-chloro. The resulting compound, 5g, had excellent
CRF-1 receptor binding affinity (Ki = 2 nM) and lower lipophilicity
(cLogP = 5.9).
The pharmacokinetic properties of the 5-aminoalkyl pyrimidine
5g and the 5-alkoxy analogue 12b were examined (Table 6). Disap-
pointingly, despite lower lipophilicity and increased solubility rel-
ative to the isoquinoline 1, both 5g and 12b exhibited moderate
oral exposure in rats. The low-to-moderate clearance values sug-
gest that the poor exposure was not due to metabolic liabilities,
leaving limited absorption as a potential culprit.
In summary, we have described our efforts to overcome the lia-
bilities of our recently described series of isoquinolines (e.g., 1) as
CRF-1 receptor antagonists. Their poor physicochemical properties
(high lipophilicity, cLogP > 7) contributed to unacceptable pharma-
cokinetic profiles. Our strategy to increase hydrophilicity invoked
the replacement of the bicyclic quinoline with a less lipophilic,
monocyclic pyrimidine core (DcLogP = 1.9 between these two
cores). Optimization of this new series with regard to CRF-1 recep-
tor binding affinity and reduced lipophilicity led to the identifica-
tion of compounds with Ki values below 10 nM and lipophilicity
in a minimally acceptable range for a CNS drug (cLogP < 5). How-
ever, the improvements in lipophilicity within this series did not
translate into increased oral bioavailability, therefore hindering
the progression of these otherwise potent antagonists. The results
of our efforts to resolve these issues will be reported in due course.
A limited number of secondary amines were also investigated at
the 5-position. The 5-aminopyrimidine 9 was converted to the cor-
responding 5-iodopyrimidine and subsequent Buchwald amination
gave the 5-aminopyrimidines 10a–c in low yields (Scheme 4).
The modifications to the 5-position are summarized in Table 4.
A complete loss in activity was observed following removal of a
References and notes
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a-branched alkyl ether. The calculated
minimum energy conformation of a representative (e.g., 12a,
Fig. 4) indicates that the combination of lone pair and steric inter-
actions may place the alkyl chain in the desired lipophilic pocket.
The 5-(3-pentyloxy) analogues 12a–c were prepared as out-
lined in Scheme 5. Mitsunobu reaction of the known pyrimidine
1117 with propan-3-ol and subsequent Suzuki coupling with a
2,4,6-trisubstituted aryl boronic acid gave the desired 2-aryl-5-alk-
oxypyrimidines 12a–c in modest overall yields.
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are summarized in Table 5. The 2-methoxy-4,6-dimethylphenyl
analogue 12a displayed excellent affinity (Ki = 8 nM), compared
to the corresponding 3-pentyl amine 10b (Ki = 94 nM), and signif-
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the parent isoquinoline series, such as 1. The effects of a second
ortho-methoxy substituent on the aryl ring were then investigated
and the 2,6-dimethoxy-4-chloro analogue 12b and the 4-difluoro-
methyl analogue 12c had similar affinities to 12a but also a re-
duced lipophilicity (cLogP 6 5). At this point, it became
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a modified version of the assay described by
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Kim, K.-I.; Liu, Z.; Moran, T.; Webb, T. R.; Whitten, J. P.; Xie, Y. F.; McCarthy, J. R.
J. Med. Chem. 1996, 39, 4358;; (b) Hodge, C. N.; Aldrich, P. E.; Wasserman, Z. R.;
Fernandez, C. H.; Nemeth, G. A.; Arvanitis, A.; Cheeseman, R. S.; Chorvat, R. J.;
Ciganek, E.; Christos, T. E.; Gilligan, P. J.; Krenitsky, P.; Scholfield, E.; Strucely, P.
J. Med. Chem. 1999, 42, 819.
12. 2,4,6-Trimethylphenyl boronic acid was commercially available. 2-Methoxy-
4,6-substituted aryl boronic acids were prepared by ortho-lithiation of the
corresponding anisole, quenching with trimethyl borate and acid hydrolysis:
B(OH)2
OMe
X
OMe
X = Me, Y = Me
X
a, b, c
X = CF3, Y = CF3
X = OMe, Y = Cl
X = OMe, Y = CHF2
Y
Y
17. Dohmori, R.; Yoshimura, R.; Kitahara, S.; Tanaka, Y.; Naito, T. Chem. Pharm. Bull.
1970, 18, 1908.
18. Chaki, S.; Okuyama, S.; Nakazato, A.; Kumagai, T.; Okubo, T.; Ikeda, Y.;
Oshida, Y.; Hamajima, Y.; Tomisawa, K. Eur. J. Pharmacol. 1999, 371,
205.
Reagents and (a) nBuLi, TMEDA, Et2O, 0 °C to RT; (b) (MeO)3B, À78 °C to RT; (c)
2 M HCl.