Identification of a novel benzimidazole derivative as a highly potent NPY Y5 receptor antagonist with an anti-obesity profile

Article abstract of DOI:10.1016/j.bmcl.2012.11.005

Optimization of HTS hit 1 for NPY Y5 receptor binding affinity, CYP450 inhibition, solubility and metabolic stability led to the identification of some orally available oxygen-linker derivatives for in vivo study. Among them, derivative 4i inhibited food intake induced by the NPY Y5 selective agonist, and chronic oral administration of 4i in DIO mice caused a dose-dependent reduction of body weight gain.

Full text of DOI:10.1016/j.bmcl.2012.11.005

Bioorganic & Medicinal Chemistry Letters 23 (2013) 90–95
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Bioorganic & Medicinal Chemistry Letters
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Identification of a novel benzimidazole derivative as a highly potent NPY
Y5 receptor antagonist with an anti-obesity profile
Yuusuke Tamura a, , Kyouhei Hayashi a, Naoki Omori a, Yuji Nishiura a, Kana Watanabe a,
⇑
Nobuyuki Tanaka a, Masahiko Fujioka a, Naoki Kouyama a, Akira Yukimasa a, Yukari Tanaka b,
Takeshi Chiba c, Hideki Tanioka a, Hirohide Nambu a, Hideo Yukioka a, Hiroki Sato a, Takayuki Okuno a
a Medicinal Research Laboratories, Shionogi & Co., Ltd, 1-1, Futabacho 3-chome, Toyonaka, Osaka 561-0825, Japan
b Drug Developmental Research Laboratories, Shionogi & Co., Ltd, 1-1, Futabacho 3-chome, Toyonaka, Osaka 561-0825, Japan
c Innovative Drug Discovery Research Laboratories, Shionogi & Co., Ltd, 1-1, Futabacho 3-chome, Toyonaka, Osaka 561-0825, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Optimization of HTS hit 1 for NPY Y5 receptor binding affinity, CYP450 inhibition, solubility and meta-
bolic stability led to the identification of some orally available oxygen-linker derivatives for in vivo study.
Among them, derivative 4i inhibited food intake induced by the NPY Y5 selective agonist, and chronic oral
administration of 4i in DIO mice caused a dose-dependent reduction of body weight gain.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 27 September 2012
Revised 29 October 2012
Accepted 2 November 2012
Available online 10 November 2012
Keywords:
Obesity
NPY Y5 receptor antagonist
GPCR
Benzimidazole
Gauche effect
Neuropeptide Y (NPY) is a 36-amino acid peptide1 which is
widely distributed in the central2–4 and peripheral nervous sys-
tems.5–7 The biological effects of NPY are mediated through its
interaction with five G-protein coupled receptors (Y1, Y2, Y4, Y5
and Y6).8 Among them, the Y5 receptor is thought to play a key role
in the central regulation of food intake and energy balance,9–12
suggesting the possibility of NPY Y5 antagonists being effective
as anti-obesity drugs. Recently, two NPY Y5 antagonists, MK-
0577 and Velneperit in Figure 1, showed modest but significant
suppression of body weight gain in human clinical trials.13,14
Previously, we carried out optimization of HTS hit 1, mainly
focused on modification at the C-2 position of the benzimidazole
core. Elimination of the flexible and metabolically liable –S–CH2–
part and utilization of pyridone and morpholine rings led to
identification of novel NPY Y5 receptor antagonists 2b and 2c,
respectively.15 Although pyridone 2b exhibited high affinity at
the NPY Y5 receptor with attractive in vitro ADME profiles, it suf-
fered from poor bioavailability. While morpholine 2c was orally
active for suppression of food intake induced by a NPY Y5 selective
agonist, its chronic oral administration (25 mg/kg bid) to diet-
induced obese (DIO) mice did not cause reduction of body weight
gain. With regard to brain penetration, morpholine 2c showed
marginal brain exposure presumably due to the presence of a gua-
nidine-like substructure, which would have a negative effect on
in vivo efficacy.16 Lipophilicity is known to be an important param-
eter governing brain penetration and a guanidine-like substructure
show the lowest CLogP value (Fig. 2).17 Therefore, we sought to
eliminate this liability by replacing the nitrogen-linker with a sul-
fur-, oxygen- or carbon-linker. In this letter, we describe the design
and identification of a novel and orally available NPY Y5 receptor
antagonist, which has significant anti-obesity effects in DIO mice
The syntheses of benzimidazole derivatives 3a–d and 4a–k
bearing a sulfur- or oxygen-linker at the C-2 position are shown
in Scheme 1 together with their intermediates. These derivatives
were synthesized through the coupling of thiol or alcohols with
2-chlorobenzimidazole 10, followed by removal of SEM-protection.
To prepare a mixture of 1- and 3-SEM-protected 2-chlorobenzimi-
dazole 10, phenylenediamine 9 was treated with CDI, followed by
chlorination using POCl3 and SEM-protection. To obtain alcohol 13,
ester 12 was reduced using NaBH4. The synthetic routes of deriva-
tive 5–8a are shown in Scheme 2. Carboxylic acid 14 was made to
react with 9 in the presence of HATU and Et3N to produce a mix-
ture of regioisomeric amides. The resulting amides were subse-
quently cyclized in acetic acid to obtain 5a. The benzyl position
18
of 5a was oxidized with SeO2 to afford 6a, which was followed
by deoxofluorination using deoxofluor to give 7a. As for the syn-
thesis of 8a, carboxylic acid 16 was prepared through phase
⇑
Corresponding author. Tel.: +81 6 6331 6247; fax: +81 6 6332 6385.
E-mail address: yuusuke.tamura@shionogi.co.jp (Y. Tamura).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.11.005

Y. Tamura et al. / Bioorg. Med. Chem. Lett. 23 (2013) 90–95
91
O
CF3
N
O
Y5 IC50 : 4.6 nM
N
N
N
H
N
N
CYP inhibition : clean
Solubility (pH = 6.8) : 1.6 µg/ml
O O
S
F
H
O
N
H
MK-0577
Velneperit
O
O O
S
O O
S
Ph
N
N
N
S
O
N
N
H
Cl
H
1
2a
Y5 IC50 : 19.8 nM
Y5 IC50 : 0.43 nM
O O
S
O O
S
Ph
O
Ph
N
F3C
N
N
N
O
N
H
N
H
2c
2b
Y5 IC50 : 0.43 nM
Y5 IC50 : 0.29 nM
Figure 1. Structures of velneperit, MK-0577, HTS hit 1 and compound 2a–c.
transfer cycloalkylation with 1,2-dibromoethane19 and hydrolysis
of the nitrile group. Derivative 8a was prepared in a similar man-
ner to 5a.
N
N
N
N
N
S
O
N
H
N
H
N
H
N
H
On the basis of findings from our previous work,15 the initial
structure–activity relationship (SAR) study was conducted by
replacement of the sulfonamide moiety of HTS hit 1 with an
CLogP: 2.28
CLogP: 2.40
CLogP: 2.70
CLogP: 2.36
Figure 2. Lipophilicity.
O O
S
O O
S
O O
S
H
N
a
b, c
NH2
NH2
N
N
O
Cl
SEM
N
H
9
10
O O
S
d, e or f
R
N
HX R
X
N
H
11
X = S or O
g
3, 4
Ph
F
O
Ph
F
HO
HO
F
F
13
12
Scheme 1. Syntheses of 3 and 4. Reagents and conditions: (a) CDI, DMF, rt; (b) POCl3, 120 °C; (c) SEMCl, NaH, DMF, rt; (d) 10, Cs2CO3 or NaH, DMF, 0–50 °C; (e) TBAF, THF,
70 °C; (f) TFA, CH2Cl2, rt, then MeOH; (g) NaBH4, THF, rt.
Ph
Ph
Ph
a, b
c
d
O O
S
HO2C
Ph
N
F
N
H
14
15
O
6a
5a
7a
F
Ph
e, f
HO2C
O O
S
a, b
NC
Ph
Ph
N
N
16
8a
H
Scheme 2. Syntheses of benzimidazole derivatives 5–8a.Reagents and conditions: (a) 9, HATU, Et3N, DMF, 0 °C to rt; (b) AcOH, reflux; (c) SeO2, dioxane, 80 °C; (d) deoxofluor,
THF, 60 °C; (e) 1,2-dibromoetane, BnNEt3Cl, 12 M NaOH aq, THF, rt; (f) concd HCl, AcOH, 100 °C.

92
Y. Tamura et al. / Bioorg. Med. Chem. Lett. 23 (2013) 90–95
Table 1
IC50 values, CYP450 inhibition profiles, solubility and metabolic stabilities of compounds 1 and 3a–d
O O
S
N
R
N
H
3
a
Compds
R
Y5 IC50 (nM)
CYP450 inhibition (
lM) 1A2/2C19/2C9/2D6/3A4
Solubilityb
8.9
(l
M)
hMs/rMsc (%)
6.7/0.19
1
—
19.8
>20/0.4/1.5/11/1.9
3a
3b
12.1
8.9/9.4/12/18/8.8
27.5
49.9
63.7/0.13
88.5/37.9
S
Cl
Cl
80.4
8.9/>20/>20/>20/16
O
Ph
3c
25.0
4.39
14/>20/>20/>20/>20
14/17/>20/>20/>20
>50.0
>50.0
88.1/37.6
97.9/83.8
O
O
Ph
F
3d
F
a
Concentration of the compound that inhibited 50% of total specific binding of 125I-PYY as a ligand to mouse NPY Y5 receptors; obtained from the mean value of two or
more independent assays.
b
Solubility was measured as kinetic solubility using 1% DMSO solution at pH 6.8.
Metabolic stability in human or rat liver microsomes was measured as the percentage of compound remaining after 30 min incubation.
c
Table 2
IC50 values, CYP450 inhibition profiles, solubility and metabolic stabilities of compounds 4a–g
O O
S
R'
N
O
N
H
4
Solubilityb
(
lM)
hMs/rMsc (%)
a
Compds
R0
Y5 IC50 (nM)
CYP450 inhibition (lM) 1A2/2C19/2C9/2D6/3A4
4a
4b
4c
4d
4e
4f
ortho-CF3
meta-CF3
para-CF3
meta-OCF3
para-OCF3
meta-Ph
3190
41.2
98.1
7.11
22.4
9.55
2.82
>20/>20/>20/0.4/>20
>20/>20/>20/0.4/> 20
All >20
>50
>50
>50
>50
>50
4.2
94.1/>99.9
>99.9/88.4
95.2/86.9
97.1/86.2
92.8/91.6
29.1/77.3
>99.9/>99.9
All >20
>20/>20/>20/>20/17
8.3/12/8.4/15/13
11/15/6.9/>20/7.7
4g
para-Ph
2.5
a,b,c
See Table 1.
Table 3
IC50 values, CYP450 inhibition profiles, solubility and metabolic stabilities of compounds 4g and 5–8a
Ph
O O
S
N
L
N
H
a
Compds
L
Y5 IC50 (nM)
CYP450 inhibition (
l
M) 1A2/2C19/2C9/2D6/3A4
Solubilityb
(lM)
hMs/rMsc (%)
4g
5a
2.82
112
11/15/6.9/>20/7.7
>20/10/14/3.5/10
2.5
3.0
>99.9/>99.9
87.6/74.3
O
6a
2.61
All >20
0.3
>99.9/>99.9
O
7a
8a
48.6
608
10/8.4/2.7/4.1/10
11/9.4/3.2/1.2/5.4
0.3
0.5
0.10/78.3
88.5/81.3
F
F
a,b,c
See Table 1.

Y. Tamura et al. / Bioorg. Med. Chem. Lett. 23 (2013) 90–95
93
Table 4
IC50 values, CYP450 inhibition profiles, solubility and metabolic stabilities of compounds 4g–k
O O
S
Ar
N
O
N
H
4
a
Compds
Ar
Y5 IC50 (nM)
CYP450 inhibition (
11/15/6.9/>20/7.7
lM) 1A2/2C19/2C9/2D6/3A4
Solubilityb
2.5
(l
M)
hMs/rMsc (%)
>99.9/>99.9
4g
2.82
4.07
4h
4i
>20/>20/17/>20/>20
17/>20/15/>20/11
>50
99.1/99.3
N
2.92
39.7
98.6/>99.9
N
4j
96.4
3.75
15/>20/>20/>20/11
>20/17/7.3/>20/2.7
45.2
6.1
89.2/>99.9
>99.9/93.8
N
4k
a,b,c
See Table 1.
Table 5
Rat PK profile of 3d, 4d, 4h and 4i (0.5 mg/kg iv, 1.0 mg/kg po)
desirable conformation
lipophilc area
lipophilc area
Ph
Compds CLtot (ml/min/
kg)
AUC (ng hr/
ml)
Cmax (ng/
ml)
BAa
(%)
B/P
ratiob
H-donar
H-donar
3d
4d
4h
4i
5.29
30.7
2.04
2.13
2160
74.8
2880
3630
166
17.9
287
320
68.3
13.5
33.9
46.5
0.58
0.98
0.04
0.14
O O
S
O O
S
N
N
N
N
O
O
N
H
I
II
a
N
H
Bioavailability.
Brain/plasma ratio.
b
Ph
H-acceptor
H-acceptor
lipophilc area
lipophilc area
H-donar
H-donar
Ph
O O
S
H
N
O O
S
H
N
N
O
O
N
N
N
IV
III
Ph
H-acceptor
H-acceptor
are key sites of the Y5 receptor for its interaction with antagonists
Figure 3. Conformational preference for 4j.
ethylsulfonyl group. As shown in Table 1, derivative 3a exhibited
improved solubility and metabolic stability in human liver micro-
somes, however, its metabolic stability in rat liver microsomes was
still low. Introduction of an –O–CH2– linker in place of the –S–CH2–
moiety of 3a led to improvement of metabolic stabilities in both
human and rat liver microsomes to some extent but resulted in
reduction of the Y5 receptor binding affinity. To enhance the bind-
ing affinity, phenethyl ether was utilized in order to place a termi-
nal phenyl group in a similar position to the highly potent
derivative 2c. Although derivative 3c had improved binding affinity
relative to 3b, the Y5 IC50 value was moderate. We hypothesized
that the moderate binding affinity of 3c could arise from the flex-
ible nature of the –O–CH2–CH2– linker. To fix the conformation of
Figure 4. Effect of 4i (12.5 mg/kg) on Y5 agonist-stimulated food intake in diet-
induced obese mice. ⁄⁄p > 0.01 versus Y5 agonist and vehicle treated group. n = 4–7.
the flexible linker, a gauche effect by introduction of fluorine
atoms20 on the benzylic position was considered, which was also
expected to overcome the metabolic liability. As expected, deriva-
tive 3d showed enhanced binding affinity with improved meta-
bolic stabilities.

94
Y. Tamura et al. / Bioorg. Med. Chem. Lett. 23 (2013) 90–95
Figure 5. Effect of chronic oral administration of 4i on body weight gain in diet-induced obese mice. n = 7.
As shown in Table 2, the next SAR study was conducted with
Derivatives 3d and 4i were thus selected for evaluation of
in vivo efficacy and tested in a Y5 selective agonist-induced food
intake model.23 While derivative 4i (12.5 mg/kg po) blocked the in-
crease in food intake in this feeding model (Fig. 4), derivative 3d
(12.5 mg/kg po) was not efficacious in spite of its desirable PK pro-
file. To determine what led to the difference between 3d and 4i, the
cerebrospinal fluid (CSF) concentrations of these compounds were
measured. At 30 min after administration of 3d (0.5 mg/kg iv) and
4i (0.5 mg/kg iv), the CSF concentrations were 1.7 ng/ml and
2.9 ng/ml, respectively. This suggested that the CSF concentration
has a stronger correlation with in vivo efficacy than the B/P ratio.
In addition to the in vivo efficacy stated above, oral administration
of 4i to DIO mice for 21 days caused a dose-dependent reduction
that was significantly different from the control group without
any abnormal behavior (Fig. 5).
phenoxy derivatives that seem to be a moderately flexible and
useful linker. Positional scanning with the CF3 group was investi-
gated and meta- and para-CF3 derivatives had modest binding
affinities. On the basis of this result, additional meta- and para-
substituted derivatives were explored. The most favorable substi-
tution was para-phenyl, followed by meta-OCF3. Interestingly,
while para-phenyl was three-fold more potent than the meta- phe-
nyl, para-OCF3 was less potent than meta- OCF3. To further explore
the highest potent biphenyl derivative 4g, the oxygen linker was
replaced with a –CH2–, –CO–, –CF2– or cyclopropylene substruc-
ture (Table 3). While –CH2–, –CF2– and cyclopropylene derivatives
resulted in significant decreases in the Y5 receptor binding affinity,
the carbonyl derivative 6a retained high binding affinity with
improved CYP450 inhibition profiles but suffered from decreased
solubility, probably due to its rigid structural nature.
Derivative 4g was a highly potent Y5 antagonist with apprecia-
ble metabolic stabilities, but several issues were identified; it had
potent CYP450 inhibition and low solubility which may have been
a consequence of its high lipophilicity or rigid nature. This hypoth-
esis prompted us to incorporate a nitrogen atom into the biphenyl
region of 4g to reduce its lipophilicity. As shown in Table 4, all pyr-
idine derivatives exhibited improved CYP450 inhibition profiles
and high solubility. While derivative 4h and 4i retained Y5 recep-
tor binding affinity, derivative 4j was not tolerated in the target
affinity, probably due to undesirable conformational preference
via intramolecular hydrogen bonding between benzimidazole N–
H and pyridine nitrogen (I and III in Fig. 3). Next, we replaced
the inner phenyl ring of 4g with a cyclohexyl substructure to re-
duce structural planarity and change ADME profiles.21 Cyclohexyl
derivative 4k maintained high binding affinity and metabolic sta-
bilities, but did not show acceptable improvement in the CYP450
inhibition profiles and solubility.
In summary, a series of novel and potent NPY Y5 receptor
antagonists were identified by modification of HTS hit 1. Among
them, derivative 4i exhibited an acceptable PK profile and inhibited
food intake induced by the NPY Y5 selective agonist, which re-
sulted in reduction of body weight gain in DIO mice. Further char-
acterization of this compound will be reported in due course.
Acknowledgments
We thank our colleagues Yasunori Yokota, Yumiko Saito, Kyoko
Kadono, Tohru Mizutare, Naomi Umesako, and Izumi Fujisaka for
support in characterization of the compounds described.
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, , , ,
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