Aminopyrazine CB1 receptor inverse agonists

Article abstract of DOI:10.1016/j.bmcl.2008.04.022

A series of 5,6-diaryl-2-amino-pyrazines were prepared and found to have antagonist-like properties at the CB1 receptor. Subsequent SAR studies optimized both receptor potency and drug-like properties including solubility and Cytochrome-P450 inhibition potential. Optimized compounds were demonstrated to be inverse agonists and compared in vivo with rimonabant for their ability to inhibit food intake, to occupy central CB1 receptors and to influence hormonal markers associated with obesity.

Full text of DOI:10.1016/j.bmcl.2008.04.022

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 3376–3381
Aminopyrazine CB1 receptor inverse agonists
David J. Wustrow,* George D. Maynard, Jun Yuan, He Zhao, Jianmin Mao, Qin Guo,
Mark Kershaw, Jack Hammer, Robbin M. Brodbeck, Kristen E. Near, Dan Zhou,
David S. Beers, Bertrand L. Chenard, James E. Krause and Alan J. Hutchison
Neurogen Corporation, 35 Northeast Industrial Road, Branford CT 06405, USA
Received 15 February 2008; revised 9 April 2008; accepted 10 April 2008
Available online 13 April 2008
Abstract—A series of 5,6-diaryl-2-amino-pyrazines were prepared and found to have antagonist-like properties at the CB1 receptor.
Subsequent SAR studies optimized both receptor potency and drug-like properties including solubility and Cytochrome-P450 inhi-
bition potential. Optimized compounds were demonstrated to be inverse agonists and compared in vivo with rimonabant for their
ability to inhibit food intake, to occupy central CB1 receptors and to influence hormonal markers associated with obesity.
Ó 2008 Elsevier Ltd. All rights reserved.
The endocannabinoid system plays an important role in
many physiological processes.1 Key components of this
system are CB1 receptors which are highly expressed in
the central nervous system (CNS) and under certain
conditions in peripheral tissues. Inverse agonists at
CB1 receptors have been shown either clinically or pre-
clinically, to decrease food intake,2 influence energy uti-
lization via glucose metabolism,3 inhibit nicotine
craving,4 or other drug seeking behavior,5 or block the
fibrosis,6 cardiomyopathy,7 and hypotension8 associated
with liver cirrhosis. Most of these findings were enabled
by the availability of the selective CB1 inverse agonist
rimonabant (SR 141716A, 1)9 currently marketed as
an antiobesity agent in Europe or its close derivative
AM251 (2) (see Fig. 1).10 Subsequently several medicinal
chemistry strategies have been utilized to discover addi-
tional CB1 antagonists/inverse agonists with improved
chemical, physical, and pharmacokinetic properties.11
ping strategy that led to the discovery of the pyrazine
analogue 5 was disclosed.14 An analysis of structures 3
and 4 suggested that in addition to flexibility with regard
to the core positioning of the two aryl moieties, there is
also some flexibility around the position and nature of
the hydrazide functionality found in rimonabant (1).
As part of a program to prepare pyrazine CB1 antago-
nists with improved properties we undertook studies to
determine if the amide functionality adjacent to a pyra-
zine core was a requirement for activity or if it could be
either transposed to another position or replaced en-
tirely. Herein, we describe these studies.
The syntheses used for the preparation of target com-
pounds are outlined in Schemes 1–3. Reacting 2,6-
dichloropyrazine (6) with amines 7a or 7b followed by
regiospecific NBS bromination gave pyrazines 8a–b .
Aryl or heteroaryl functionality could be readily intro-
duced by sequential Suzuki reactions in a regioselective
manner to give the diaryl-pyrazines 9a–j listed in Table 1.
In a similar way dichloropyrazine 6 could be reacted
with thiomorpholine 10. The product was brominated
with NBS and the thio group oxidized with mCPBA
to give 11. Compound 11 was subjected to sequential
Suzuki conditions to give compound 12 (Scheme 2).
One strategy that has proven to be successful for the dis-
covery of novel CB1 inverse agonists is the introduction
of alternatives to the pyrazole core found in rimona-
bant. Such a strategy was employed in the discovery of
SLV319 (3)12 and taranabant (4)13 which are both cur-
rently undergoing clinical trials. Recently a scaffold hop-
Alternatively, Suzuki coupling could be carried out first
as shown in Scheme 3. 2-Chloro-6-aminopyrazine (13)
was reacted with pyridyl-boronic acid 1415 and the
resulting 6-(pyrid-4-yl)pyrazine was brominated giving
compound 15. This was smoothly reacted with
Keywords: Cannabinoid; Rat obesity model; Brain level; CB1 inverse
agonist; Ex vivo receptor occupancy.
*
Corresponding author. Tel.: +1 203 315 3031; fax: +1 203 481 5290;
e-mail addresses: dwustrow@nrgn.com; d.wustrow@comcast.net
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.04.022

D. J. Wustrow et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3376–3381
3377
NH2
Cl
O
NH
O
O
N
N
S
B(OH)2
Cl
Cl
N
N
H
N
N
N
a,b
c,d
Br
NH2
N
N
Cl
N
+
N
X
N
N
Cl
13
14
15
Cl
Cl
SLV319 (3)
Cl
X = Cl rimonabant (1)
X = I AM251 (2)
N
NHBOC
N
CF3
+
e,f
N
O
HN
Cl
H
N
F3C
N
O
N
N
H
N
NC
O
N
16
17
Cl
H
N
R
Cl
Cl
(5)
N
O
taranabant (4)
N
18a R = Methyl
18b R = Ethyl
N
Figure 1. Selected CB1 Inverse Agonists.
18c R = Isopropyl
Cl
F3C
N
CONH2
18a-c
n
NHEt
Cl
N
CONH2
NHEt
N
N
a,b
n
Scheme 3. Reagents for the synthesis of 18a-c: (a) K2CO3, Pd(PPh3)4,
H2O, dioxane, 31%; (b) NBS, CHCl3, 66%; (c) 4-trifluoromethylphenyl
boronic acid, Pd(PPh3)4, Na2CO3, 43%, H2O, dioxane; (d) NaNO2,
HCl, CuCl, 82%; (e) DMA, DMSO, KF 85%, (f) i—TFA, CH2Cl2,
16 h; ii—RCOCl, DIEA, CH2Cl2, 88–93%.
N
n
N
Br
HN
Cl
Cl
n
6
7a n=1
7b n=0
8a n=1
8b n=0
CONH2
NHEt
The resulting Boc derivative was deprotected under
acidic conditions and the resulting amine was acylated
to give the desired targets 18a–c.
n
N
c,d
N
n
N
Ar1
Ar2
9a-j
The compounds prepared were tested for their ability to
inhibit GTPc 35S binding induced by the cannabinoid
receptor agonist CP-55,940 in Sf9 membrane prepara-
tions expressing the hCB1 receptor along with Gai2,
Gb1, and Gc2 G-proteins. In addition to seeking com-
pounds with good potency we desired compounds with
improved solubility compared to rimonabant. To this
end, a high throughput solubility assay was also used
to guide SAR studies as shown in Table 2.
Scheme 1. Reagents for the syntheses of 9a–j: (a) K2CO3, CH3CN,
31–97%; (b) NBS, CHCl3 , 70–80%; (c) Ar1B(OH)2, Pd(PPh3)4,
Na2CO3, H2O, dioxane,75–90%; (d) Ar2B(OH)2, Pd(PPh3)4, Na2CO3,
H2O, dioxane, 40–77%.
SO2
SO2
N
N
S
N
a,b
c,d
N
Initial studies with pyrazines 9a–c having chlorophenyl
substituents possessed excellent CB1 receptor potency
(Ki <2 nM), however, these compounds showed little
or no aqueous solubility in the high-throughput solubil-
ity assay. In order to find agents with improved aqueous
solubility, a variety of aryl substituents were examined
to find those that would impart both good potency
inherent in compounds 9a–c and have increased aque-
ous solubility.
6 +
HN
N
N
Br
Cl
11
Cl
F3C
10
N
12
Scheme 2. Reagents for the synthesis of 12: (a) K2CO3, CH3CN; (b)
i—NBS, CHCl3, 46%; ii—m-CPBA, CH2Cl2, 36%; (c) 4-trifluorometh-
ylphenyl boronic acid, Pd(PPh3)4, Na2CO3, H2O, dioxane, 76%; (d) 3-
chloro-4-pyridyl-boronic acid, Pd(PPh3)4, Na2CO3, H2O, dioxane,
50%.
Replacement of the 4-chloro substituent on the aryl ring
at the 5 position of 9c with an ethoxy substituent re-
sulted in 9d which is almost 10-fold weaker in hCB1 po-
tency. Somewhat surprisingly however, the introduction
of oxygen functionality into the para position of the phe-
nyl ring at the 6 position of the pyrazine ring (compound
9e) resulted in a substantial restoration of CB1 potency.
While this did not improve solubility it did suggest that
4-trifluoromethylphenyl boronic acid and subsequently
the 2-amino group was converted to the chloro deriva-
tive 16 using Sandmeyer conditions. Compound 16
was reacted with Boc-protected 4-aminopiperidine 17.

3378
D. J. Wustrow et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3376–3381
Table 1. Substitution of aminopyrazines 9a–j
Compound Ar1 Ar2
potency while retaining improved aqueous solubility
compared to the initial chlorophenyl derivatives in the
series.
n
9a
9b
9c
9d
9e
9f
4-Chlorophenyl
2,4-Dichlorophenyl
2,4-Dichlorophenyl
2-Chlorophenyl
2-Chlorophenyl
4-Ethoxyphenyl
4-Cyanophenyl
4-Pyridyl
1
1
1
1
1
1
1
1
1
0
4-Fluorophenyl
4-Chlorophenyl
4-Ethoxyphenyl
4-Ethoxyphenyl
4-Chlorophenyl
4-Chlorophenyl
4-Chlorophenyl
Despite having good potency and acceptable solubility
properties, 9h was found to inhibit CYP3A4 as evi-
denced by its ability to block the metabolism of midaz-
olam in human liver microsomes when co-incubated at a
concentration of 5 lM (Table 2). However, it was found
that substitution of the chlorine in the para position of
the 5-phenyl ring of 9h with a trifluoromethyl moiety re-
sulted in compound (9i) with excellent potency, accept-
able solubility and no evidence for CYP3A4 inhibition.
With aryl rings identified that imparted excellent hCB1
potency and good drug-like properties to the aminopyr-
azine template, additional 2-aza substituents on the pyr-
azine ring were explored. In an effort to reduce
molecular weight and decrease lipophilicity the azetidine
analogue of 9i was prepared. This compound (9j)
showed similar potency and somewhat increased aque-
ous solubility while demonstrating a low potential for
inhibiting CYP3A4.
9g
9h
9i
3-Chloro-4-pyridyl
4-Trifluoromethylphenyl 3-Chloro-4-pyridyl
4-Trifluoromethylphenyl 3-Chloro-4-pyridyl
9j
Table 2. hCB1 antagonist potency, solubility, and CYP 3A4 inhibitory
potential for 1, 9a–j , 12, and 18a–c
Compound
hCB1 GTPcS
Inhibition Kia
(nM)
Solubilityb
% Inhib.
CYP3A4
at 5 lMc
(lg/mL)
9a
9b
9c
9d
9e
9f
0.91
1.75
1.66
14.96
2.84
32.33
9.81
0.67
0.87
1.2
0
<5
20.5
9.7
10
0
1.25
1.2
0
The activity of thiomorpholine dioxide 12 suggested
that one or both the sulfone oxygens could act as a
hydrogen bond acceptor in a similar position to the
amide carbonyl oxygen in analogue 9. Like the best
analogues such as 9j, compound 12 displayed good po-
tency as a hCB1 inverse agonist combined with accept-
able solubility. Subsequent studies revealed that 12 had
no CYP3A4 inhibition liability. To further explore the
flexibility of substitution at the 1-amino position, ana-
logues 18a–c were evaluated for their potency at the
hCB1 receptor. In this series it was determined that
as the size and lipophilicity of the acyl substituent in-
creased so did binding affinity. The isobutyric amide
18c was found to have outstanding potency at the
hCB1 receptor and retained a measurable level of aque-
ous solubility.
<5
—
36
9g
9h
9i
74.9
21.83
25.5
38
71
54
<5
<5
<5
<5
11
9j
12
18a
18b
18c
1
0.83
1.97
0.8
23
53
24
0.24
0.43
4.5
0.3
<5
<5
a The antagonist mode Ki value is generated in the presence of the
hCB1R agonist CP-55,940.
b Solubility was assessed by introducing 10 mM DMSO stock solutions
directly into a pH 7.4 buffer solution at a concentration of 250 lM. A
standard plate was created at the same concentration in DMSO.
Precipitation from the solutions was removed by filtration. Analyses
were carried out using a single point calibration based on UV
detector peak areas.
Having identified novel pyrazines with potent hCB1
inhibitory activity and improved solubility properties
compared to rimonabant, we were motivated to fur-
ther evaluate the properties of 9j, 12, and 18c. These
three compounds demonstrated hCB1 inverse agonist
activity by decreasing GTPcS levels below those ob-
served in the basal state of the Sf9 membrane prepa-
ration expressing hCB1 receptor plus G-proteins.
The IC50s in this assay are listed in Table 3. These
c CYP3A4 inhibition was assessed by measuring inhibition of midaz-
olam metabolism in human liver microsomes in the presence of test
compounds.
the 4-position of the aryl ring in the 6 position of the
pyrazine was an area tolerant of polar functionality.
To further explore the effect of hydrogen bond accepting
functionality at the para position of the phenyl ring at
the 6 position of the pyrazine ring, the cyano derivative
9f was prepared. While 9f had decreased hCB1 potency,
this compound had improved aqueous solubility sug-
gesting that investigation of alternative hydrogen bond
accepting functionality at this position was warranted.
To this end a 4-pyridinyl ring was introduced at the 6-
position of the pyrazine core resulting in compound 9g
which had sub 10 nM potency and improved aqueous
solubility compared to many of the biphenyl derivatives.
Further enhancement of the CB1 potency was achieved
by addition of a 3-chloro substituent to the pyridine ring
(9h) which gave a nearly 15-fold improvement in hCB1
Table 3. Further in vitro characterization of selected compounds
Compound
hCB1 Inv.
hCB2 GTPcS
inhibition Kib
(nM)
rCB1 GTPcS
inhibition Kib
(nM)
a
agonist IC50
(nM)
9j
3.07
4.2
>50,000
1900
4945
2.06
0.83
0.41
0.31
12
18c
1
0.54
1.35
815
a Ability to block constitutive activity in Sf9 membrane preparations
expressing hCB1 receptor.
b Both the hCB2 and rCB1 assays are virtually identical with the
exception of the amino acid sequence of the receptor used to infect
the Sf9 cells.

D. J. Wustrow et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3376–3381
3379
26
compounds also had greater than 2000-fold functional
24
22
20
18
16
14
12
10
8
selectivity for the hCB1 receptor compared to their
potency at inhibiting GTPcS interactions stimulated
by CP-55,940 at hCB2 receptors. The compounds also
showed appreciable functional inhibitory potency at
the rat CB1 receptor. The compounds were initially
evaluated in vivo for their anorectic potential in an
overnight feeding model in diet-induced obesity
(DIO) rats. After a single oral dose of 5 mg/kg food
intake was evaluated for 24 h and compared to vehi-
cle-treated controls. As shown in Table 4 all three
compounds significantly decreased food intake with
compounds 12 and 18c causing a similar or slightly
greater decrease than that observed with after a
5 mg/kg oral dose of rimonabant (1).
**
**
**
*
***
**
***
***
*
***
***
***
Vehicle n=10
Compound 18c 1mpk QD n=10
Compound 18c 5mpk QD n=10
Compound 1 5mpk QD n=10
***
6
4
***
0
1
2
3
4
5
6
7
8
9
10
12 13 14 15 16 17 18
*p<0.05 vs.Vehicle
11
TIME (days)
Figure 2. Food intake in subchronic DIO study.
Compound 18c and rimonabant (1) were studied in an
ex vivo receptor occupancy assay to understand their
relative abilities to access and bind to rat brain CB1
receptors after oral administration. First the relative
binding affinities of 18c and 1 were determined in a
rat cerebellum membrane preparation using [3H]CP-
55940 as the radioligand. These studies revealed that
rimonabant (1) had a higher binding affinity (Ki
1.1 nM) than 18c (Ki 4.4 nM) in this assay. Compounds
18c and 1 were next evaluated in an oral dose response
ex vivo study that assessed occupancy of brain CB1
receptor sites 3 h after oral administration of the indi-
vidual compounds. Both compounds prevent labeling
of cerebellar homogenates with [3H]CP-55,940, by
occupying the hCB1 receptor after oral administration
with 18c and 1 having ID50 values of 0.3 and 0.5 mg/
kg, respectively.
leveled out by the end of the study (Fig. 3). The magni-
tude of effect on food intake and percentage of weight
loss relative to control animals was similar between
the group of animals dosed with 1 mg/kg of 18c and
5 mg/kg of rimonabant (1). The group dosed with
5 mg/kg of 18c showed a greater decrease in food intake
and approximately twice the weight loss on a percentage
basis compared to the group of animals dosed with
5 mg/kg 1. (Table 5).
After the completion of the 18th dose, plasma and brain
levels of compounds were assessed at Tmax (1 h for 1; 2 h
for 18c) and 17 h after the last dose (Table 6). These data
suggest that roughly similar brain levels were achieved
with the 5 mg/kg dose of 1 and the 1 mg/kg dose of
18c. Compared to the 5 mg/kg dose of 1, the 5 mg/kg
dose of 18c achieved a higher brain concentration which
may account for the enhanced effect on food intake and
Because 18c possessed oral activity and potency similar
to rimonabant (1) in both the overnight feeding and
receptor occupancy studies, the compounds were com-
pared in an 18 day subchronic food intake study in
DIO rats. Over the course of the study animals (10 per
group) were dosed (po, qd) with 1 or 5 mg/kg of 18c
or 5 mg/kg of 1. Rats were monitored for both food in-
take and body weight relative to a control group of ani-
mals receiving only vehicle. In addition changes to
hormonal markers related to changes in obesity were
measured in both the drug-treated and control animal
groups.
3
2
1
0
-1
-2
-3
-4
-5
-6
-7
-4.1%
-4.8%
-8
-8.5%
-9
-10
-11
-12
Compound 18c 1mpk QD n=10
Compound 18c 5mpk QD n=10
Compound 1 5mpk QD n=10
The inhibition of food intake was greatest in the first
part of the study with the food intake reduction ob-
served with 5 mg/kg of 18c remaining statistically signif-
icant throughout the course of the study (Fig. 2).
Similarly the decreases in percentage of body weight in
the treated groups relative to the control group were lar-
ger at the beginning of the study but appeared to have
0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19
TIME (days)
Figure 3. Percent of body weight versus vehicle in a subchronic DIO
study.
Table 5. Cumulative decreases in food intake and percentage of body
weight in the subchronic DIO study
Table 4. Overnight food intake inhibition study in DIO rats
Compound
Dose
(mg/kg)
Cumulative food
intake % reduction
versus vehicle
Percentage of
body weight
versus vehicle
Compound
Dose PO mpk
Overnight DIO %
inhib. food intake
9j
10
10
5
58
71
80
73
18c
18c
1
1
5
5
18.8
27.6
13.8
4.8
8.5
4.1
12
18c
1
5

3380
D. J. Wustrow et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3376–3381
20.0
15.0
10.0
5.0
weight loss in these animals. This finding is also consis-
tent with the lower oral ID50 observed for 18c compared
to 1 in the rat brain RO study despite 18c being about
fourfold weaker in receptor affinity (see Table 6).
Pre-treatment
Post-treatment
*
*
*
On the day immediately prior to the start of the rat DIO
feeding study and at the end of the 18th day of the study,
the animals were tail-bled after a 8–10 h fast. Blood lev-
els of glucose, insulin, and leptin were measured in the
drug-treated and vehicle-treated groups. The groups of
animals treated with 18c and 1 showed a statistically sig-
nificant decrease in blood glucose level (Fig. 4). Statisti-
cally significant decreases in insulin levels were also
observed in all groups treated with either 18c or 1
but not the vehicle-treated group (Fig. 5). The amount
of decrease in each of the drug-treated groups showed
similarly trending dose responses to that of inhibition
of food intake and weight loss. Analysis of blood leptin
levels revealed that both group of animals treated with
18c had significant, dose dependent decreases in leptin
levels, while those in the rimonabant-treated group
showed a slightly smaller reduction in leptin levels
(Fig. 6).
0.0
Vehicle
Compound 18c Compound 18c
1mpk 5mpk
Compound 1
5mpk
*p<0.01 vs. pre-treatment
Figure 6. Fasting blood leptin levels.
In summary a class of novel pyrazine CB1 receptor in-
verse agonists was prepared. Simultaneous optimization
of functional CB1 receptor potency, solubility, and
CYP3A4 inhibition parameters rapidly led to the discov-
ery of selective CB1 inverse agonists with good drug-like
properties. Optimized compounds in the series such as
18c had similar or better in vivo properties compared
to the marketed antiobesity agent rimonabant in feeding
and CB1 receptor occupancy studies. After dosing for
18 days, 1 mg/kg of 18c had similar effects to 5 mg/kg
of rimonabant (1) both in terms of inhibition of food in-
take and weight loss, while 5 mg/kg of 18c caused
approximately twice the amount of weight loss com-
pared to animals treated with 5 mg/kg of rimonabant
(1). Animals treated with the potent CB1 inverse agonist
18c showed statistically significant reductions in glucose,
insulin and leptin levels over the course of the sub-
chronic study. Taken together these studies suggest that
a compound such as 18c could be a useful treatment in
certain overweight and diabetic populations.
Table 6. Plasma and brain levels after 19th Dose
Compound Dose
Tmax plasma/brain 17 h plasma/brain
levels (ng/mL)
(mg/kg) levels (ng/mL)
18c
18c
1
1
5
5
121/235
346/630
34.9/318
44.2/110
142/253
3/65
110
105
100
95
Acknowledgments
Andrzej Kieltyka performed the ex vivo receptor occu-
pancy experiments. Yung Lee and Danielle Lord partic-
ipated in the PK study.
90
#
#
85
References and notes
#
80
Vehicle n=10
Compound 18c 1mpk QD n=10
Compound 18c 5mpk QD n=10
Compound 1 5mpk QD n=10
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0
17
Number of Days Dosed
# p<0.05 vs pre-treatment
Figure 4. Fasting blood glucose levels.
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Pre-treatment
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2.0
1.5
1.0
0.5
0.0
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*
*
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Compound 18c
1mpk
Compound 18c
5mpk
Compound 1
5mpk
*p<0.001 vs. pre-treatment
´
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