Design, synthesis and identification of novel benzimidazole derivatives as highly potent NPY Y5 receptor antagonists with attractive in vitro ADME profiles

Article abstract of DOI:10.1016/j.bmcl.2012.07.020

Optimization of our HTS hit 1, mainly focused on modification at the C-2 position of the benzimidazole core, is described. Elimination of the flexible and metabolically labile -S-CH₂- part and utilization of less lipophilic pyridone substructur

Full text of DOI:10.1016/j.bmcl.2012.07.020

Bioorganic & Medicinal Chemistry Letters 22 (2012) 5498–5502
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis and identification of novel benzimidazole derivatives as
highly potent NPY Y5 receptor antagonists with attractive in vitro ADME profiles
Yuusuke Tamura a, , Naoki Omori a, Naoki Kouyama a, Yuji Nishiura a, Kyouhei Hayashi a,
⇑
Kana Watanabe a, Yukari Tanaka b, Takeshi Chiba c, 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 our HTS hit 1, mainly focused on modification at the C-2 position of the benzimidazole
core, is described. Elimination of the flexible and metabolically labile –S-CH2– part and utilization of less
lipophilic pyridone substructure led to identification of novel NPY Y5 receptor antagonists 6, which have
low to sub-nanomolar Y5 receptor binding affinity with improved CYP450 inhibition profiles, good solu-
bilities and high metabolic stabilities.
Received 5 June 2012
Revised 29 June 2012
Accepted 6 July 2012
Available online 14 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Obesity
NPY Y5 receptor antagonist
Benzimidazole
Pyridone
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 receptor antagonists being
effective as anti-obesity drugs. Indeed, two Y5 antagonists, MK-
0577 and Velneperit, have advanced to human clinical trials. While
the clinical data of MK-0577 showed modest efficacy,13 Velneperit
induced statistically significant weight loss in obese subjects.14 To
explore for novel Y5 antagonists, we conducted an HTS campaign
of our compound library and selected structurally diverse com-
pounds.15 Among them, benzimidazole 1 (Fig. 1) was one of the
attractive hit compounds. In our previous SAR studies that led to
the identification of Velneperit, we found that the pharmacophore
of the Y5 antagonist consisted of two distinctive substructures, the
SO2 moiety and amidic N–H, as shown in Figure 1.16 Comparison of
the structural features of Velneperit and HTS hit 1 indicated that
compound 1 would possess a pharmacophore similar to Velneperit
and that the terminal lipophilic groups are also important for Y5
receptor binding affinity (Fig. 1). However, while 1 exhibited Y5
antagonistic activity, its profile regarding CYP450 inhibition and
metabolic stability needed to be improved. We hypothesized that
these issues could arise from oxidatively reactive and flexible –S-
CH2– linker of 1. On the basis of this hypothesis, we focused on
the introduction of metabolically stable and rigid aromatic linkers
in place of the –S-CH2– moiety of 1. Here we report our efforts to
identify novel Y5 antagonists endowed with improved CYP450
inhibition profiles, good solubility and high metabolic stabilities.
Schemes 1–3 show general synthetic methods for the benzimid-
azole derivatives and their intermediates. Derivatives 2 were syn-
thesized from commercially available Albendazole (9), which has a
benzimidazole core. The synthesis of derivatives 4–8 commenced
from amidations of carboxylic acids with phenylenediamines and
subsequent cyclocondensation to construct the benzimidazole
core. As shown in Scheme 1, Albendazole (9) was first treated with
m-CPBA to oxidize the n-propylthio group and then subjected to
hydrolysis of the methyl carbamate group, followed by conversion
of the resulting amino group to a bromo group using the Sandmey-
er reaction, to give 2-bromobenzimidazole 10. Bromide 10 and
boronic acids 11 were coupled using Suzuki cross-coupling to syn-
thesize derivatives 2. Scheme 2 shows the preparation of the
phenylenediamines. To prepare 13, nucleophilic aromatic substitu-
tion of chloride 12 with EtSO2Na17 was carried out,18 followed by
hydrogenation of the nitro group in the presence of Pd/C. To obtain
15, the nitro group of 14 was reduced using Na2S2O4. Phenylenedi-
amines 16 and 17 were commercially available. As shown in
Scheme 3, the synthesis of derivatives 4 commenced from 18,
which were phenylated using Suzuki cross-coupling19 to give 19.
Carboxylic acids 19 were made to react with phenylenediamine
⇑
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.2012.07.020

Y. Tamura et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5498–5502
5499
lipophilic group
CF3
O
H-acceptor
N
H
N
O O
Velneperit
S
N
H-donar
H
H-acceptor
lipophilic group
O O
O O
S
R2
S
N
N
N
R1
r
Linke
S
O
N
H
N
H
Cl
flexible and
rigid and
1
metabolically labile linker
metabolically stable linker
H-donar
Y5 IC50 (nM) : 19.8
CYP450 inhibition (µM)
: >20 / 0.4 / 1.5 / 11 / 1.9
1A2 / 2C19 / 2C9 / 2D6 / 3A4
Solubility (µM) : 8.9
In vitro metabolic stability_human / rat (%) : 6.7 / 0.19
Figure 1. Structures of Velneperit and HTS hit 1 and design of novel derivatives.
13 in the presence of HATU and Et3N to produce a mixture of reg-
O O
S
ioisomeric amides. The amides were subsequently cyclized in ace-
tic acid to provide derivatives 4. Pyridine analogues 5 were
prepared in a similar manner to 4. As for syntheses of pyridone
analogues 6 and 7, carboxylic acids 20 were coupled with pheny-
lenediamines (Scheme 1) and then subjected to cyclocondensation
in acetic acid, followed by MOM-protection of the resulting benz-
imidazole N–H, to afford 21. Next, the chloro group at the C-2 posi-
tion of the pyridine moiety of 21 was converted into a benzyloxy
group. Alkylthio (R1S) groups at the C-5 position of the benzimid-
azole core, introduced using cross-coupling reaction,20 were
converted into alkylsulfonyl (R1SO2) groups by oxidation with
m-CPBA. Hydrogenolysis of the benzyl ether was followed by intro-
duction of an additional phenyl group using the Ullmann reac-
tion.21 Finally, removal of the MOM protecting group under
acidic condition provided pyridone analogues 6 and 7. In the case
of analogue 8, the corresponding carboxylic acid 24 was prepared
and a method similar to the above was adopted.
The first approach to resolving the issues of HTS hit 1 was per-
formed by conversion of the –S-CH2– part to a phenyl linker and
introduction of an additional phenyl ring as the R2 group (Fig. 1).
Considering the availability of starting material for the derivative
synthesis, Albendazole (9) was utilized (Scheme 1), in which the
sulfonyl group could be easily furnished at the C-5 position during
synthesis and would be equivalent to the sulfonyl moiety of 1. As
shown in Table 1, positional scanning with the phenyl ring was
investigated and showed a preference for the meta-position. While
the ortho-phenyl 2b lost Y5 receptor binding affinity, the meta-
phenyl 2c had very high binding affinity, which was 1000-fold
more potent than unsubstituted 2a. The para-phenyl 2d showed
single digit nanomolar binding affinity, which was slightly less po-
tent than 2c. On the basis of these observations, additional meta-
substituted derivatives were explored and we found that the most
favorable substitution was phenyl (2c), followed by trifluorometh-
oxy (2f) and trifluoromethyl (2e). These results prompted us to
verify the pharmacophore of the highly potent derivative 2c and
to investigate the corresponding indole analogues 3a and 3b for
their Y5 receptor binding affinity (Fig. 2). Interestingly, compound
3a was approximately 60-fold more potent than 3b, although both
indole analogues had decreased binding affinity relative to 2c. The
moderate potency of 3a and the loss of potency with 3b suggest
that form I would be the preferred binding mode of the possible
tautomer, whose N–H is attached at the para-position to the sulfo-
nyl group. As for in vitro metabolic stabilities, derivative 2c exhib-
ited improved metabolic stabilities in liver microsomes (human
S
N
a, b, c
N
NHCO2Me
Br
N
H
N
H
Albendazole (9)
10
O O
S
R2
R2
d
N
(HO)2B
N
H
2
11
Scheme 1. Representative synthetic routes of analogues 2. Reagents and condi-
tions: (a) m-CPBA, CH2Cl2, 0 °C to rt; (b) 2 N NaOH aq, 85 °C; (c) conc. HCl, NaNO2,
CuBr, 60 °C; (d) 10, Pd(PPh3)4, Cs2CO3, dioxane, H2O, MW(180 °C).
O O
Cl
NH2
NO2
Br
NH2
NH2
a, b
c
S
NH2
NH2
12
14
13
15
16
17
O O
S
NH2
NO2
S
NH2
NH2
S
NH2
NH2
F3C
Scheme 2. Preparation of phenylenediamines 12–17. Reagents and conditions: (a)
EtSO2Na, DMSO, 100 °C; (b) Pd/C, H2, MeOH, rt; (c) Na2S2O4, EtOH, H2O, 60 °C.
68.6%, rat 57.1%) relative to HTS hit 1 (human 6.7%, rat 0.19%).22
In this way, derivative 2c was a highly potent Y5 antagonist with
improved metabolic stabilities, however, there was room for
improvement in the CYP450 inhibition profiles and the solubility.
Initial efforts to improve the CYP450 inhibition profiles and the
solubility of the key compound 2c led to the introduction of a less
lipophilic ethylsulfonyl group in place of an n-propylsulfonyl group
(Table 2). While little or no change was observed in the CYP450
inhibition profiles and the solubility, compound 2g retained high
affinity for the Y5 receptor along with further improved metabolic
stabilities in liver microsomes (human 85.2%, rat 79.1%). Keeping
the ethylsulfonyl group constant, we next turned our attention to
the introduction of different substituents on the central phenyl ring
of 2g to disrupt molecular planarity and change the physicochem-
ical profile.23 As shown in Table 2, relatively bulky substituents,
such as the chloro and methyl groups, at the 20- or 40-position
(4d, 4e, 4g and 4h) were not tolerated, probably due to prevention

5500
Y. Tamura et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5498–5502
O O
S
Ph
R3
Ph
R3
X
a
b, c
N
HO2C
HO2C
R3
X=Cl, Br or I 18
N
H
19
4
Ph
N
O O
S
N
Cl
O
N
Cl
Y
b-d
e-j
R1
N
N
N
HO2C
N
H
MOM
20
6, 7
21
Ph
O
k. l
m, n
N
O
EtO2C
HO2C
CO2Et
22
O
23
O
24
O O
S
Ph
b, c, g
N
N
N
H
O
8
Scheme 3. Representative synthetic routes of analogues 4, 6, 7 and 8. Reagents and conditions: (a) Pd(dtbpf)Cl2, PhB(OH) 2, K2CO3, DMF or EtOH, H2O, rt to 60 °C; (b) 13, 15,
16 or 17, HATU, Et3N, DMF, 0 °C to rt; (c) AcOH, reflux; (d) MOMCl, NaH, DMF, 0 °C; (e) BnOH, NaH, DMF or NMP, 50 to 100 °C; (f) Y = Br: R1SH, Hunig’s base, Pd2(dba)3,
xantphos, dioxane, MW(130 °C); (g) m-CPBA, CH2Cl2, rt; (h) Pd/C, H2, THF, MeOH, rt; (i) CuI, N,N-dimethylglycine, PhBr, K2CO3, DMA, MW(170 °C); (j) 2 N HCl in MeOH, 60 °C;
(k) 1,1-dimethoxy-N,N-dimethylmethanamine, dioxane, rt; (l) ethyl formate, t-BuOK, THF, 0 °C to rt; (m) PhNH2, AcOH, 60 °C; (n) 2 N NaOH aq, MeOH, rt.
Table 1
O O
S
O O
S
H
N
Ph
Ph
IC50 values, CYP450 inhibition profiles and solubilities of 2a–f
O O
N
H
R2
S
N
3a
3b
N
H
Y5 IC50 = 11.6nM
2
609nM
a
Compd R2
Y5 IC50
(nM)
CYP450 inhibition (lM)
1A2/2C19/2C9/2D6/3A4
Solubilityb
M)
.
O O
O O
S
H
(l
S
N
N
N
2a
2b
2c
2d
2e
2f
H
4657
4065
0.43
6.3
44.5
1.9
2.9/13/9.5/>20/>20
>20/>20/4.5/15/11
2.7/19/9.5/>20/6.0
>20/5.9/2.4/15/2.9
0.4/17/7.4/>20/20
1.9/10/5.6/>20/10
>50
23.6
0.50
0.50
2.5
ortho -Ph
meta-Ph
para-Ph
meta-CF3
meta-OCF3
N
II
I
H
which is bioactive form ?
Figure 2. Elucidation of the preferred binding mode.
3.6
a
Concentration of the compound that inhibited 50% of the 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.
of lone pair repulsion between the benzimidazole nitrogen and the
pyridine nitrogen, while the bio-inactive form III or V would be fa-
vored owing to the intramolecular hydrogen bond between the
benzimidazole N–H and the pyridine nitrogen. To test our hypoth-
esis, other pyridine analogues 5b–d, which should have no unde-
sirable intramolecular interaction and retain the high binding
affinities, were explored. Compounds 5b–d maintained similar Y5
receptor affinity for 2g as expected. In addition, the pyridine nitro-
gen of 5c or 5d contributed to solubility presumably because of re-
duced lipophilicity (5c cLogP = 3.53, 5d cLogP = 3.74). These
investigations yielded additional information about the preferred
binding mode. However, pyridine analogues did not show accept-
able improvement in the CYP450 inhibition profiles.
In an attempt to resolve this issue, we next adopted less lipo-
philic pyridone rings as linkers. Dramatic improvement of the
CYP450 inhibition profiles and the solubility without loss of tar-
geted affinity was exhibited by the pyridone analogue 6a
(cLogP = 3.45). While pyridone analogues 7a and 8a also had desir-
able CYP450 profiles, they showed dramatic loss of the Y5 receptor
binding affinity, probably due to a change in the conformational
preference, like pyridine analogue 5a, and prevention of the inter-
action between benzimidazole N–H and the Y5 receptor, as ob-
served for 40-substituted biphenyl derivative 4h.
b
Solubility was measured as kinetic solubility using 1% DMSO solution at pH 6.8.
of the interaction between benzimidazole N–H and the Y5 receptor.
In contrast, all substituents at the 60-position (4c, 4f and 4i) main-
tained excellent binding affinity. However, they did not show
acceptable improvement in the CYP450 inhibition profiles and the
solubility. High lipophilicity due to the biphenyl moiety of deriva-
tive 2g or 4 seemed to be the reason for the CYP450 inhibition
and the low solubility.
To reduce the lipophilicity of 2g (cLogP = 4.94),24 we sought to
incorporate polar functionality into the phenyl linker. One strategy
was insertion of a nitrogen atom to afford pyridine analogues. As
shown in Table 3, the first example was 5a (cLogP = 3.95), which
unfortunately resulted in significant decreases in the Y5 receptor
binding affinity. We could explain the effect of the nitrogen atom
in the pyridine linker of 5a on the binding affinity as follow.
Assuming that the bioactive form was the one described as form
IV in Figure 3 and the pyridine nitrogen indirectly affected the
binding affinity by changing the conformational preference, the de-
creased potency of 5a would be reasonable. In case of 5a, the pro-
posed bioactive form IV would be unfavorable presumably because

Y. Tamura et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5498–5502
5501
Table 2
IC50 values, CYP450 inhibition profiles and solubilities of 2g and 4a–i
O O
S
Ph
6'
R3
2'
4'
N
N
H
4
R3
Y5 IC50 (nM)
CYP450 inhibition (
l
M) 1A2/2C19/2C9/2D6/3A4
Solubilityb
(lM)
a
Compd
2g
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
0.46
2.7
0.4/17/9.9/>20/9.0
1.1/13/7.2/>20/6.6
2.2/19/17/>20/14
3.4/17/9.5/16/5.6
3.0/9.3/4.0/18/3.8
0.4/4.9/7.1/15/5.0
8.5/>20/5.4/18/2.6
7.8/14/4.4/>20/5.2
0.4/4.2/6.8/14/5.9
3.2/18/8.3/>20/5.7
0.90
0.60
0.60
0.20
1.5
0.40
N.D.
3.2
20-F
40-F
60-F
0.54
0.16
40.5
31.1
0.16
21.8
383
20-Cl
40-Cl
60-Cl
20-Me
40-Me
60-Me
0.50
N.D.
0.20
a,b
See Table 1.
Table 3
IC50 values, CYP450 inhibition profiles and solubilities of 5a–d, 6a–d, 7a and 8a
O O
R1
S
Ph
N
Linker
N
H
Compd
R1
Et
Linker
Y5a IC50(nM)
38.9
CYP450 inhibition (
l
M) 1A2/2C19/2C9/2D6/3A4
Solubilityb
4.0
(l
M)
N
5a
0.4/18/14/ 20/7.7
5b
5c
Et
Et
0.55
1.8
1.6/14/10/>20/7.0
6.3/15/9.8/>20/7.8
1.6
N
12.1
N
5d
6a
6b
6c
6d
Et
0.31
1.9
3.4/>20/>20/>20/8.7
All>20
20.3
43.3
9.4
N
N
N
N
N
n-Pr
t-Bu
CF3
O
O
O
O
7.5
All>20
2.5
>20/9.1/7.5/20/5.1
All>20
1.3
CF3CH2
0.29
7.7
O
O
7ac
8a
n-Pr
n-Pr
>1000
579
All>20
All>20
5.5
2.0
N
N
a,b
See Table 1.
HCl salt.
c
We therefore chose pyridone analogue 6a for further optimiza-
nanomolar Y5 receptor binding affinity. It appeared that the bulk-
iness of the b-position of the alkylsulfonyl group contributed to the
binding affinity. In addition, pyridone analogues 6 exhibited high
metabolic stabilities in liver microsomes (6a human 88.5%, rat
78.6%; 6b human 94.2%, rat >99.9%; 6c human 96.0%, rat 92.6%;
6d human 94.7%, rat 93.6%).
In summary, the optimization of HTS hit 1 led to identification
of the highly potent derivative 2c. Modification of 2c gave pyridone
analogues 6 which had low to sub-nanomolar Y5 receptor binding
tion. The influence of the R1 group of the analogue is also shown in
Table 3. Replacement with a t-butyl group led to retention of the
binding affinity and improved CYP450 inhibition profiles with a
slight decrease in the solubility (6b). While trifluoromethyl sulfone
6c resulted in aggravation of the CYP450 profiles and reduction in
solubility, consistent with high lipophilicity (cLogP = 4.50), 2,2,
2-trifluoroethyl sulfone 6d retained desirable CYP450 profiles,
consistent with low lipophilicity (cLogP = 3.18) and showed sub-

5502
Y. Tamura et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5498–5502
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VI
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Figure 3. Proposed active conformation.
affinities with improved CYP450 inhibition profiles, good solubili-
ties and high metabolic stabilities. Further investigations of these
compounds are in progress and will be reported in due course.
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We thank our colleagues Yasunori Yokota, Yumiko Saito, Kyoko
Kadono, Tohru Mizutare, Hirohide Nambu, Hideki Tanioka, Naomi
Umesako, and Izumi Fujisaka for support in the characterization
of the compounds described. We acknowledge Shinya Hisakawa
for synthesis of key intermediates.
23. Ishikawa, M.; Hahimoto, Y. J. Med. Chem. 2011, 54, 1539.
24. ClogP values were estimated with ChemDraw Ultra, version 9.0.
References and notes
1. Tatemoto, K.; Carlquist, M.; Mutt, V. Nature 1982, 296, 659.