Discovery of a novel series of benzimidazole derivatives as diacylglycerol acyltransferase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2012.10.046

A novel series of benzimidazole derivatives was prepared and evaluated for their diacylglycerol acyltransferase (DGAT) inhibitory activity using microsome from rat liver. Among the newly synthesized compounds, furfurylamine containing benzimidazole carboxamide 10j showed the most potent DGAT inhibitory effect (IC₅₀= 4.4 μM) and inhibited triglyceride formation in HepG2 cells. Furthermore, compound 10j reduced body weight gain of Institute of Cancer Research mice on a high-fat diet and decreased levels of total triglyceride, total cholesterol, and LDL-cholesterol in the blood accompanied with a significant increase in HDL-cholesterol level.

Full text of DOI:10.1016/j.bmcl.2012.10.046

Bioorganic & Medicinal Chemistry Letters 22 (2012) 7456–7460
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of a novel series of benzimidazole derivatives as diacylglycerol
acyltransferase inhibitors
Kyeong Lee a, , Ja-Il Goo b, , Hwa Young Jung b, Minkyoung Kim b, Shanthaveerappa K. Boovanahalli a,
b,
Hye Ran Park c, Mun-Ock Kim c, Dong-Hyun Kim d, Hyun Sun Lee c, , Yongseok Choi
⇑
⇑
a College of Pharmacy, Dongguk University-Seoul, Seoul 100-715, Republic of Korea
b College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea
c Chemical Biology Research Center, KRIBB, Ochang, Cheongwon, Chungbuk 363-883, Republic of Korea
d College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of benzimidazole derivatives was prepared and evaluated for their diacylglycerol acyltrans-
ferase (DGAT) inhibitory activity using microsome from rat liver. Among the newly synthesized com-
pounds, furfurylamine containing benzimidazole carboxamide 10j showed the most potent DGAT
Received 31 July 2012
Revised 8 October 2012
Accepted 10 October 2012
Available online 17 October 2012
inhibitory effect (IC50 = 4.4 lM) and inhibited triglyceride formation in HepG2 cells. Furthermore, com-
pound 10j reduced body weight gain of Institute of Cancer Research mice on a high-fat diet and decreased
levels of total triglyceride, total cholesterol, and LDL-cholesterol in the blood accompanied with a signif-
icant increase in HDL-cholesterol level.
Keywords:
Obesity
Type II diabetes
Triglycerides
DGAT
Ó 2012 Elsevier Ltd. All rights reserved.
DGAT inhibitors
Benzimidazole
Triglyceride (TG) synthesis in mammals is important in many
biochemical processes, including lactation, energy storage in adi-
pose tissue, muscle, and assembly of lipoprotein particles in the li-
ver and small intestine. Triglycerides (TG) are essential for normal
physiology. However, excess accumulation of TG in certain organs
and tissues can cause a variety of disorders, such as dyslipidemia,
obesity, insulin resistance, and hepatic steatosis. Based on these as-
pects, inhibition of TG synthesis is considered as an efficient strat-
egy for treatment of obesity and type II diabetes.1,2
TG is produced by two pathways: the major glycerol phosphate
pathway and the minor monoacylglycerol pathway. Diacylglycerol
acyltransferase (DGAT), which catalyzes acyl residue transfer from
acyl-CoA to diacylglycerol (DAG), is the exclusive key enzyme for
the final step common to both pathways.3–5 Accordingly, DGAT
has emerged as an attractive target for the control of obesity and
other related disorders.6 So far, several small molecules including
natural products and synthetic compounds (1–4) have been re-
ported to possess DGAT inhibitory activity (Fig. 1).7–11 Recently,
detailed pharmacological effect of T863 (4) has been reported, in
which T863 caused weight loss and reduction in serum and liver
TG.12 In addition, T863 improved insulin sensitivity and reduced
level of serum cholesterol. These results suggested pharmacologi-
cal relevance of DGAT1 inhibitors for treatment of metabolic
disorders.12
In our search for novel DGAT inhibitors, we have screened our
in-house chemical library using rat microsome based DGAT assay,
which resulted in identification of a benzimidazole-type com-
pound. Herein, we describe synthesis and biological evaluation of
novel benzimidazole derivatives as potential DGAT inhibitors.
A series of benzimidazole carboxamides (10a–o and 16a–c) was
prepared as depicted in Schemes 1 and 2. Reaction of commercially
available adamantyl phenol 5 with ethyl chloroacetate followed by
alkaline hydrolysis furnished compound 7 in good yield. A single-
step ring closure of adamantylphenoxy acetic acid 713 with
methyl-3,4-diaminobezoate in the presence of cyclodehydrating
agent PPSE at 140 °C afforded the benzimidazole ester 8 in 90%
yield. Initial attempts to hydrolyze the ester under basic hydrolysis
conditions using LiOH, KOH, NaOH or LiI resulted in poor yields;
however, successful hydrolysis reaction was achieved in good yield
by employing acetic acid and hydrochloric acid under reflux condi-
tion to provide the corresponding benzimidazole carboxylic acid 9
in considerable yield. Further reaction of 9 with the appropriate
amines using coupling agent HATU in the presence of DIPEA
yielded the amide derivatives 10a–o (50–86%).14
⇑
Corresponding authors.
E-mail addresses: leehs@kribb.re.kr (H.S. Lee), ychoi@korea.ac.kr (Y. Choi).
These authors contributed equally to this work.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.10.046

K. Lee et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7456–7460
7457
O
O
HO
HO
O
O
OH
OH
OH
O
OH
1 (Xanthohumol)
2 (Kurarinone)
O
OH
OH
O
O
NH2
N
N
O
N
O
N
H
N
H
3 (A-922500)
Figure 1. Structures of DGAT inhibitors.
4 (T863)
As shown in Scheme 2, compound 16a–c, in which the adaman-
tyl group was replaced with hydrogen, tert-butyl, and phenyl, were
prepared starting from the corresponding phenols 11a–c. Thus,
reaction of the appropriate phenols 11a–c with ethyl chloroacetate
followed by subsequent hydrolysis under basic conditions afforded
the required aryloxy acetic acids 13a–c. PPSE-mediated cyclization
of the acids 13a–c with methyl-3,4-diaminobezoate furnished re-
lated benzimidazole esters 14a–c in good yield. The resulting es-
ters 14a–c were hydrolyzed to give the acids 15a–c, which were
then coupled with 2-furfurylamine to produce the amides 16a–c,
respectively.
compounds 10k–o. Among these, compounds 10l, 10m, and 10n
having 5-methylfuranyl and tetrahydrofuranyl linkage demon-
strated good inhibitory activities comparable to that of the refer-
ence
1 (IC50 = 11.4 lM, 8.7 lM, and 9.5 lM, respectively).
Compound 10k with 3-methyl furan exhibited 7-fold less potency
than the furan analogue 10j. This suggests that the methyl
group on furan ring is making an unfavorable interaction with
the enzyme. Moreover, replacement of oxygen in furan ring by
sulfur afforded drastically reduced inhibitory activity (10o,
IC50 > 50 lM), suggesting that oxygen atom in the furan ring is
optimal for DGAT inhibition.
The newly synthesized compounds in this study were evaluated
for their inhibitory activities against DGAT (Table 1) as IC50 values
according to the reported method.15 The known DGAT inhibitors 28
and 410 were used as positive controls for comparison. Compound
4 displayed significant DGAT inhibition with an IC50 value of
We then explored the significance of the alkyl group of the
phenoxymethyl moiety at 2-position of the benzimidazole ring
by substituting with tert-butyl, phenyl, and hydrogen (16a–c)
while retaining the furfurylamine moiety in 10j. However, only
tert-butyl derivative showed good inhibitory activity with an IC50
3.1
(IC50 = 10.9
exhibited moderate DGAT inhibitory activity with an IC50 value of
23 M.
Firstly, in order to assess the effect of ester functional group at
5-position of the benzimidazole ring, we compared the inhibitory
activity of the ester 8 with the corresponding acid 9 and its amide
analogues, including free amide 10a, and mono- and di-substituted
amides 10b–e. Of these, pyrrolidine-containing amide 10d
l
M, whereas compound 2 was shown to be moderately active
value of 9.0 lM, indicating that hydrophobic groups such as ada-
mantanyl and t-butyl may be more suitable for the inhibition of
DGAT than aromatic (phenyl) and H.
To examine whether DGAT inhibitory effect in enzyme level
translates into inhibitory effect on TG synthesis in cellular level,
the most active analogue 10j in the series was chosen for further
evaluation. Accordingly, 10j was evaluated for its potential to in-
hibit cellular formation of TG in HepG2 cells. As shown in Ta-
lM). Compound 8 identified from the initial screening
l
ble 2, the HepG2 cells treated with 10 lM of 10j produced far
exhibited improved inhibitory activity (IC50 = 11.3
screening hit 8 and the activity was comparable to that of the
reference compound 2. The isopropyl amide derivative 10c exhib-
l
M) than the
smaller amounts of triglycerides than the control (without any
inhibitor). 10j was measured to inhibit the biosynthesis of TG
by 47% for radio-labeled acetate and 55% for radio-labeled glyc-
erol, respectively. These results revealed that 10j entered the
cells and reduced the cellular formation of TG by inhibiting
DGAT activity.
Encouraged by the enzymatic and cellular level activity of 10j,
we then examined its in vivo efficacy in a diet-induced obesity
(DIO) mouse model, containing normal diet group, high-fat diet
(HFD) group with diet-induced obesity, and HFD group with a drug
as summarized in table 3. On the basis of the control, the HFD
group administered with compound 10j at a dose of 10 mg/kg
was observed to inhibit body weight gain by 73%. The inhibitory
effect of Xenical17 serving as a positive control (orlistat, a lipase
inhibitor) against body weight gain was 88%. A 5-week administration
of 10j greatly decreased body weight without affecting food
intake.
ited moderate inhibitory activity (IC50 = 20 lM) with two-fold less
potency than the reference 2, whereas all of the other derivatives
displayed poor inhibitory activity. Based on these results, we
further evaluated the amide analogue series by preparing
compounds 10f–j. This derivatization resulted in potent DGAT
inhibitors, as represented by compound 10j that demonstrated
appreciably high inhibitory activity (IC50 = 4.4 lM), which was as
potent as the reference compound 4 and more potent than the
reference 2. On the other hand, the pyridinyl methane substituted
amide derivative 10i displayed moderate inhibition with an IC50
value of 20
lM and rest of the compounds 10f–h were found to
be poor inhibitors (IC50 > 50
lM). In view of potent inhibitory
activity of the furfurylamine derivative 10j, we were interested
in exploring the effect of furanyl moiety for DGAT inhibition. Thus,
substitution of furanyl moiety with 3-methylfuran, 5-methylfuran,
tetrahydrofuran, and thiophene was investigated by synthesizing
It was reported that altered lipid absorption by inhibition of
DGAT1 might associate with the improvement in serum lipid

7458
K. Lee et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7456–7460
a)
b)
O
O
O
O
OH
OH
O
5
6
7
H
N
c)
d)
H
N
O
O
N
N
O
OH
O
O
8
9
H
e)
N
O
N
R
10a-o
Compd
R
Compd
10i
R
H
N
NH2
N
10a
N
O
O
O
H
N
10b
10c
10j
O
O
O
O
H
H
N
N
N
N
10k
O
O
O
O
H
N
10d
10l
O
O
H
N
10e
10f
10m
10n
O
O
O
H
H
N
N
O
O
H
N
S
H
N
10g
10h
10o
O
H
N
O
Scheme 1. Synthesis of compounds 10a–o. Reagents: (a) ethyl chloroacetate, K2CO3, DMF, 12 h, r.t., 96%; (b) LiOHÁH2O, THF/H2O, 8 h, r.t., 94%; (c) methyl-3,4-diaminobezoate,
PPSE, 140 °C, 5 h, 90%; (d) AcOH/HCl, reflux, 4 h, 84%; (e) HATU, DIPEA, DMF, R-NH2, 1–12 h, r.t., 50–86%.
profile.12,19 We then measured the levels of total triglyceride, total
cholesterol, low density lipoprotein (LDL)-cholesterol, and high
density lipoprotein (HDL)-cholesterol in DIO mice. As shown in
Table 4, the administration of the compound 10j in DIO mice,
resulted in decreased levels of total TG, total cholesterol, and
didymal fat, and retroperitoneal fat in comparison with HFD mod-
el. The data of 10j was comparable with that of Xenical. Excessive
accumulation of body weight was due to HFD-caused obesity.
These results suggest that the decrease in body weight is mainly
attributed to a reduction of total fat.
LDL-cholesterol in the blood, accompanied by
a
significant
In summary, a novel series of benzimidazole analogues was
identified to possess DGAT inhibitory activities. Among the series,
10j has emerged as the most promising DGAT inhibitor, which also
demonstrated considerable inhibition of cellular TG formation in
HepG2 cells as well as in vivo efficacy.
Taken together, these results merit further investigation toward
the development of preclinical candidates for the treatment of
obesity and metabolic disorders.
increase in HDL-cholesterol. This improvement in serum lipid pro-
file by 10j was consistent with the result of A-922500 (3)12 and
T863 (4).19
After completion of administration, the animals were measured
for their weights of total fat, abdominal fat, epididymal fat, and ret-
roperitoneal fat (Table 5). The animal group with HFD and 10j
showed a significant decrease in all of total fat, abdominal fat, epi-

K. Lee et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7456–7460
7459
O
O
a
b
R
OH
R
O
O
O
OH
11a R=H
12a R=H
13a R=H
11b R=phenyl
12b R=phenyl
13b R=phenyl
11c R=t-butyl
12c R=t-butyl
13c R=t-butyl
O
O
O
N
N
c
OH
d
N
O
N
H
R
R
O
H
14a R=H
15a R=H
14b R=phenyl
15b R=phenyl
15c R=t-butyl
14c R=t-butyl
O
O
N
N
H
e
N
H
R
O
16a R=H
16b R=phenyl
16c R=t-butyl
Scheme 2. Synthesis of compounds 16a–c. Reagents: (a) ethyl chloroacetate, K2CO3, DMF, 12 h, r.t., 93–99%; (b) LiOHÁH2O, THF/H2O, 8 h, r.t., 89–91%; (c) methyl-3,4-
diaminobezoate, PPSE, 140 °C, 5 h, 76–81%; (d) AcOH/HCl, reflux, 4 h, 97–99%; (e) PyBop, DMAP, DMF, 2-furfurylamine, 16 h, r.t., 86–92%.
Table 4
Levels of total TG, total cholesterol, LDL-cholesterol, and HDL-cholesterol in DIO mice
Table 1
treated with 10j and Xenical
DGAT inhibitory activity of the synthesized compounds
a
Compound
IC50
(l
M)a
Compound
IC50 (lM)
Groups/diet
Total TG
(mg/dl)
Total
cholesterol
(mg/dl)
LDL-
cholesterol
(mg/dl)
HDL-
cholesterol
(mg/dl)
8
9
23
10j
10k
10l
10m
10n
10o
16a
16b
16c
2
4.4
>50
>50
>50
20
11.3
27.5
>50
>50
>50
20
25.4
11.4
8.7
Normal diet
HFD
HFD + 10j
46.0 9.89 64.7 10.9
120 11.2 160 13.9
41.8 9.26 73.2 10.9
30.1 8.06
119 14.3
43.6 10.1
20.5 8.99
26.4 2.69
17.4 2.15
21.2 2.19
30.3 1.52
10a
10b
10c
10d
10e
10f
10g
10h
10i
9.5
HFD + Xenical 40.8 6.06 53.8 12.4
>50
>50
>50
9.0
10.9
3.1
Table 5
Weights of total fat, abdominal fat, epididymal fat, and retroperitoneal fat in DIO mice
4
treated with 10j and Xenical
a
The inhibitory effects of compounds on DGAT activity were studied with
Groups/diet
(Tissue weight/body weight) Â 100
microsomes prepared from rat liver by modification of the method reported by
Coleman.15
Total fat
Abdominal
Retroperitoneal
fat
fat + epididymal fat
Normal diet
HFD
HFD + 10j
2.77 1.52
6.75 1.18
4.1 1.03
2.11 1.09
5.34 1.09
3.16 0.84
2.45 1.03
0.66 0.44
1.41 0.29
0.94 0.24
0.75 0.50
Table 2
Inhibition of formation of TG by compound 10j in HepG2 cells16
HFD + Xenical 3.20 1.52
Substrate
[
14C]-TG synthesis, % of controla
Toxicityb
(lM)
Control (DMSO)
10j (l
M)
10
Acknowledgements
3
This research was supported by grants from KRIBB Research Ini-
tiative Program, Basic Science Research Program through the Na-
tional Research Fund from Ministry of Education, Science and
Technology (#2011-0026325), and GRRC (dongguk-2012-B02),
Republic of Korea.
[
[
14C]acetate
14C]glycerol
100 6.2
100 6.2
80.9 2.4
69.5 5.3
53.0 7.8
45.0 4.2
>50
>50
a
The cell-based assay for confirmation of DGAT inhibition was performed in
human hepatocyte HepG2 cells.
b
The cytotoxic effects on HepG2 cells were determined by MTT assay.
Table 3
Inhibition of body weight gain by 10j in DIO mice18
Groups/diet
Body weight (g) (Mean SD)
Week 0
Week 1
Week 2
Week 3
Week 4
Week 5
Normal diet
HFD
HFD + 10j
HFD + Xenical
26.3 1.08
25.3 1.09
25.1 0.99
26.3 1.45
32.2 1.77
35.2 1.57
35.1 1.99
33.6 1.28
36.3 3.83
37.8 3.55
38.9 2.33
37.4 2.02
36.6 3.41
45.9 2.29
40.8 1.75
39.1 0.90
39.1 3.17
49.9 1.24
42.3 1.57
40.0 1.26
39.7 1.20
52.9 1.20
43.2 1.41
41.2 1.60

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K. Lee et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7456–7460
room temperature. The mixture was stirred for 16 h at room temperature and
Supplementary data
then poured into water. The resulting solid was extracted with EtOAc, washed
with brine, aqueous sodium bicarbonate, and water. The organic layer was
dried over anhydrous magnesium sulfate, filtered, and concentrated under
reduced pressure. The resulted crude product was purified by column
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.
10.046.
chromatography
(hexanes/EtOAc, 2:1) to afford 10j as a white solid
(112 mg, 86% yield).
15. Coleman, R. A. Methods Enzymol. 1992, 209, 98.
16. (a) Pommier, A.; Pons, M.; Kocienski, P. J. Org. Chem. 1995, 60, 7334; (b) Cell
culture and viability test: HepG2 cells were obtained from the American Type
Culture Collection (Manassa, VA) and maintained in DMEM medium
(Invitrogen) supplemented with 10% heat-inactivated FBS and 1% penicillin–
streptomycin (Sigma) in 5% CO2 at 37 °C. To test whether 10j has cytotoxic
effects on HepG2 cells, the MTT assay was performed. Cells were seeded in 96-
well plates (2 Â 104 cells/well) and treated with compounds for 48 h. The
absorbance of formazan dye was read using ELISA plate reader at 560 nm.; (c)
Cellular TG formation assay using HepG2 cells: to determine the de novo
synthesized TG, the cells were incubated with DMSO or indicated
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to the guidelines approved by the Animal Experimental Use Committee of the
SLC Company, and every effort was made to minimize the number and any
suffering of the animals used in the experiments. Diet-induced obese mice
were generated using 6-week-old male mice obtained from Japan SLC (Tokyo,
Japan). All animals were housed individually in polyethylene cage with paper-
clean-chips in a room maintained at 23 °C 3 °C under a 12-h light–dark cycle
(lights on from 6:00 am to 6:00 pm) with free access to food and tap water. We
designed our experiments to use 6 mice in each group. This number was
expected to yield a statistical power of N0.8 by Pb0.025 in the parametric
Williams’ test in preliminary analysis of body weight change variations.
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14. Procedure for the synthesis of 2-((4-adamantylphenoxy)methyl)-N-(furan-2-
ylmethyl)-1H-benzo[d]imidazole-5-carboxamide (10j): to
benzimidazole carboxylic acid (0.37 mmol), furfurylamine (54.3 mg,
0.55 mmol), and HATU (0.55 mmol) in DMF was added DIPEA (0.55 mmol) at
a solution of
9