Benzimidazole-carboxamides as potent and bioavailable stearoyl-CoA desaturase (SCD1) inhibitors from ligand-based virtual screening and chemical optimization

Article abstract of DOI:10.1016/j.bmcl.2013.01.030

The discovery of potent benzimidazole stearoyl-CoA desaturase (SCD1) inhibitors by ligand-based virtual screening is described. ROCS 3D-searching gave a favorable chemical motif that was subsequently optimized to arrive at a chemical series of potent and promising SCD1 inhibitors. In particular, compound SAR224 was selected for further pharmacological profiling based on favorable in vitro data. After oral administration to male ZDF rats, this compound significantly decreased the serum fatty acid desaturation index, thus providing conclusive evidence for SCD1 inhibition in vivo by SAR224.

Full text of DOI:10.1016/j.bmcl.2013.01.030

Bioorganic & Medicinal Chemistry Letters 23 (2013) 1817–1822
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Benzimidazole-carboxamides as potent and bioavailable
stearoyl-CoA desaturase (SCD1) inhibitors from ligand-based virtual
screening and chemical optimization
a
a
b,
Hans Matter a, , Gerhard Zoller , Andreas W. Herling , Juan-Antonio Sanchez-Arias
,
⇑
Christophe Philippo c, Claudie Namane c, Markus Kohlmann a, Anja Pfenninger a, Marc D. Voss a
a Sanofi-Aventis Deutschland GmbH, Research and Development, D-65926 Frankfurt am Main, Germany
b Sanofi-Aventis, Research and Development, Avenida de Leganés, 62, 28925 Alcorcón, Madrid, Spain
c Sanofi-Aventis, Research and Development, 1 Avenue Pierre Brossolette, F-91385 Chilly-Mazarin, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The discovery of potent benzimidazole stearoyl-CoA desaturase (SCD1) inhibitors by ligand-based virtual
screening is described. ROCS 3D-searching gave a favorable chemical motif that was subsequently opti-
mized to arrive at a chemical series of potent and promising SCD1 inhibitors. In particular, compound
SAR224 was selected for further pharmacological profiling based on favorable in vitro data. After oral
administration to male ZDF rats, this compound significantly decreased the serum fatty acid desaturation
index, thus providing conclusive evidence for SCD1 inhibition in vivo by SAR224.
Received 19 November 2012
Revised 7 January 2013
Accepted 9 January 2013
Available online 22 January 2013
Keywords:
Benzimidazole
SCD1
Ó 2013 Elsevier Ltd. All rights reserved.
SCD1 inhibition
Diabetes
Enzyme inhibition
Virtual screening
The increasing prevalence of obesity and associated metabolic
disorders such as type 2 diabetes in societies following a Western
lifestyle highlights the necessity to discover new pharmaceutical
solutions for this area.1,2 Recently, elevated activity of stearoyl-
CoA desaturase (SCD1), one of the essential enzymes in lipogenesis,
has been linked to the pathogenesis of obesity, metabolic disorders,
dyslipidemia and type 2 diabetes.3,4 SCD1 is an iron-containing
microsomal enzyme, which catalyzes the formation of a cis-double
bond at the carbon-9 position of saturated fatty acyl-Coenzyme-A
esters, the rate-limiting step in the synthesis of mono-unsaturated
16:1 n-7 and 18:1 n-9 fatty acyl-CoAs.3 SCD1 expression is regu-
lated by different nutritional and pharmacological stimuli.5,6
SCD1-deficient mice were reported to exhibit reduced body weight,
body fat mass, increased oxygen consumption and improved
insulin sensitivity in a glucose tolerance test.7 Therefore substantial
efforts in the pharmaceutical industry have been undertaken to
discover small-molecule SCD1 inhibitors for the treatment of
metabolic disorders.
In a previous publication we reported the discovery and
pharmacological profiling of SAR707 as a promising member of a
class of potent hexahydro-pyrrolopyrrole based SCD1 inhibitors
(Fig. 1).8,9 Our starting point was patent applications from Xenon
Pharmaceuticals10 and Merck Frosst Canada,11 describing chemical
series reported to modulate SCD1 activity, thereby regulating
plasma-lipid levels. Further structure–activity relationship data
for SCD1 inhibitors was also available in reports from Abbott
Laboratories.12,13
Rescaffolding the central piperidine substructure resulted in the
discovery of the hexahydro-pyrrolopyrrole scaffold,9 which subse-
quently was optimized to result in SAR707 with an IC50 value of
0.00848 l
M in a rat liver microsome SCD1 assay.8 In particular, this
compound is characterized by high potency, selectivity and favor-
able properties in enzymatic and cellular assays. In vivo, SAR707
O
O
N
F
F
N
N
N
F
⇑
Corresponding author. Tel.: +49 69 305 84329.
E-mail address: Hans.Matter@sanofi.com (H. Matter).
Current address: Small Molecule Discovery Platform, Center for Applied Medical
Research, University Of Navarra, Pamplona, Spain.
Figure 1. Chemical structure of SAR707.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.01.030

1818
H. Matter et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1817–1822
O
Query
R
N
N
H
N
F
O
H
N
N
F
N
H
N
O
F
O
1: IC50 2.260 µM
R
2a: 3.76 µM
2b: 7.81 µM
2c: 11.80 µM
S
CF3
Virtual Screening
HO
O
N
N
N
H
O
Alignment 2a (grey)
to query 1 (orange)
2d: 5.00 µM
Figure 2. Ligand-based virtual screening. Left: ROCS alignment of hit structure 2a (grey carbons) to query 1 (orange carbons). Right: Chemical structures for hit 2a and
analogs from further iterations.
O
OH
O
O
O
O
O
CF3
CF3
a
b
CF3
SO3Na
4b
4a
3
O
H2N
+
H2N
OH
5
O
O
H
N
H
N
O
S
O
OH
N
Cl
CF3
CF3
H
c
N
N
9m
6
Scheme 1. Synthesis of compound SAR224. Reagents and conditions: (a) AcOH/H2O 80/20, 65 °C, 90 min, 73%; (b) Na2S2O5 (1.3 equiv), DMF, 100 °C, 1 h, 79%; (c) HOBt,
EDCÁHCl, DIEA, DMF, rt, 18 h, 95%.
reduced the serum desaturation index, decreased body weight gain
Table 1
and improved lipid parameters and blood glucose levels in obese
Zucker diabetic fatty rats treated for 4 weeks in a chronic study.8
However, fissures of the eyelid, alopecia and inflammation of the
skin were observed in parallel from day 11 onwards in all animals
treated with the same metabolically active dose.8 Therefore, unfor-
tunately, the benefits of systemic in vivo SCD1 inhibition by this
compound were accompanied by dose-dependent adverse effects.8
This observation prompted us to identify alternative chemo-
types as SCD1 inhibitors. In this publication, we describe the
discovery of potent benzimidazoles using ligand-based virtual
screening, followed by optimization of a favorable motif to arrive
at the potent and promising compound SAR224, suitable for fur-
ther pharmacological profiling.
In vitro SCD1 inhibition for compounds 7a–7fa
O
R
N
N
H
O
N
H
Compd
R
SCD1 IC50
3.70
(lM)
7a
S
Cl
N
Ligand-based virtual screening14 was performed in multiple
iterations guided by experimental data. For the first iteration, the
7b
7c
7d
6.51
16.6
21.6
S
query molecule 110 with an in-house IC50 value of 2.26
lM was
used for a 2D similarity search using UNITY,15 a topological phar-
macophore search using an in-house implementation of CATS,16
and a 3D shape search using ROCS.17 For ROCS, a canonical 3D
geometry served as query; hits were selected using the Combo-
Score. For each method, searching was performed in our corporate
database.
7e
7f
24.9
28.3
All hit lists were combined and filtered by physicochemical
properties. 148 compounds were selected after visual inspection
a
IC50 data were obtained as described in the text and in Refs. 8,9,19.

H. Matter et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1817–1822
1819
Table 2
Table 3
In vitro SCD1 inhibition for compounds 8a–8ga
In vitro SCD1 inhibition for compounds 9a–9qa
1
S
S
R
N
H
N
N
H
Cl
2
R
N
N
H
O
R1 = A
R1 = B
1
R
N
2
Compd
R1
R2
SCD1 IC50
15.8
(
lM)
R
N
N
H
H
N
H
O
O
O
O
O
R1 = C
R1 = D
8a
Compd
R1
R2
SCD1
IC50
(lM)
8b
8c
>100
13.3
Cl
O
9a
9b
9c
9d
9e
9f
A
B
C
D
A
B
C
D
0.115
0.832
0.966
2.72
CF3
O
Cl
O
O
O
O
O
O
O
O
O
O
O
CF3
8d
>100
Cl
CF3 OH
O
8e (rac)
8f
0.082
1.30
2.21
Cl
CF3
O
N
H
N
S
CF3
CF3
CF3
CF3
CF3
CF3
CF3
O
O
0.212
0.142
0.539
0.434
27.2
CF3
O
H
N
Cl
8g
S
a
IC50 data were obtained as described in the text and in Refs. 8,9,19.
and tested for SCD1 inhibition and 31 of these compounds were
found active (21%). From a total of four novel scaffolds, compound
2a (IC50: 3.76 lM) with a benzimidazole-carboxamide scaffold was
9g
9h
9i
regarded as a promising start for further investigation. This struc-
ture resulted from the ROCS search; its alignment (grey carbons)
with the query 1 (orange carbons) is shown in Figure 2 (left).
In a second iteration, 103 analogs of the hits were retrieved by
2D similarity searching (UNITY). A total of 15 compounds were
active after experimental testing (15%). This resulted in the
discovery of further benzimidazole-carboxamide analogs of 2a,
summarized in Figure 2 (right panel). Replacing the thiophene
by benzyl groups resulted in only slightly decreased SCD1 activity
(2b–c). Alkyl-substitution at the imidazole N1 combined with
alkyl instead of aryl-substitution at carbon C2 was also tolerated
by the enzyme (2d).
Ligand-based virtual screening was then continued using addi-
tional actives from in-house investigations and the literature,
which finally resulted in 57 hits for a total of 961 compounds
tested (6%). We then decided to investigate the structure–activity
relationships of novel substituted benzimidazoles with a limited
medicinal chemistry program due to their interesting computed
physicochemical properties (2a: logD7.418: 3.68; MW: 425; ligand
efficiency: 0.24; lipophilic ligand efficiency: 1.74), alignment to
the query molecule 1 (cf. Fig. 2) and chemical attractiveness (cf.
Scheme 1).19
CH3NH–
9j
CH3CH2O–
38.3
N
H
9k
>100
O
O
CF3
CF3
9l
A
B
0.078
0.136
9m
(SAR224)
The synthetic pathway for the preparation of compound series
7–9 is based on the formation of the benzimidazole ring by a
microwave accelerated cyclodehydration from substituted aro-
(continued on next page)

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H. Matter et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1817–1822
Table 3 (continued)
Compd
R1
R2
SCD1
IC50
(lM)
O
O
O
CF3
CF3
9n
9o
9p
D
3.86
4.52
0.099
N
S
N
H
N
H
CF3
F
S
S
H
N
O
N
N
N
F
9q
3.20
O
F
N
H
a
IC50 data were obtained as described in the text and in Refs. 8,9,19.
matic 1,2-diamines and aldehydes. As a representative example,
the preparation of benzimidazole amide SAR224 is depicted in
Scheme 1. The synthesis starts with a mild acidic hydrolysis of
the commercially available dioxolane 3 to unmask the aldehyde
moiety. Subsequent microwave-assisted cyclization of the sodium
bisulfite adduct 4b of benzaldehyde 4a with 3,4-diaminobenzoic
acid 5 provided benzimidazole 6.20 Finally, the carboxylic acid
was amidified with 5-chloro-2-thiophenemethanamine to yield
the targeted SCD1 inhibitor 9m (SAR224).
Table 1 summarizes a set of benzimidazole-carboxamides 7a–7f
with a biphenylether motif on carbon 2 with their corresponding
SCD1 inhibitory potencies [lM]. The IC50 values were evaluated
in a rat liver microsomal assay using 14C-labeled stearic acid, an
8-point concentration range and calculated as previously
described.8,9,19,21 All compounds were tested up to a concentra-
tion of 100
lM. Compounds with an IC50 >30 lM were consid-
ered as ‘inactive’.
We first focused on the role of the amide substituent on the left
side of the scaffold. The SCD1 inhibition is maintained when a chlo-
rine atom is added to the thiophene of 2a (7a: 3.70
the thiophene by a thiazole results in decreased activity by a factor
of 2 (7b: 6.51 M), while aliphatic substitutions consistently lower
the activity, as exemplified by 7d with an isopentyl-substituent
(IC50: 21.6 M).
lM). Replacing
l
l
Next, we studied the influence of the carboxamide linker on
SCD1 activity with a small set of compounds, which are summa-
rized in Table 2. Replacing the carboxamide by a keto-linker in-
cluded in a benzophenone moiety does not improve activity, as
shown for derivatives 8a–8d. Adding a CF3-group at the ortho-
position does not significantly improve activity, as can be seen
by comparing compounds 8a and 8c with IC50 values of 15.8 versus
13.3 lM, respectively.
However, replacing the keto-linker with a hydroxyl-group as in
8e (racemic mixture) results in a significant improvement of activ-
ity (IC50: 0.082 lM). Due to the chirality of this motif and its higher
metabolic lability, this motif was not followed further. Finally, we
introduced an ortho-trifluoromethyl-phenoxy-substituent on this
position of the benzimidazole. The rational of derivatives 8f and
8g was to check if a reversed superposition compared to the
alignment in Figure 2 of the benzimidazole (grey) with the
virtual screening query 1 (orange) could be possible and whether

H. Matter et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1817–1822
1821
a CF3-group would improve binding affinity. While derivatives 8f
and 8g exhibit slightly increased activity with 1.30 and
2.21
pounds (column MLab Keto in Table 4). In contrast CYP2D6 appar-
ently is much less likely to be involved in this metabolization
process, as the addition of the CYP2D6 inhibitor quinidine (column
MLab Quin in Table 4) does not significantly alter the experimen-
tally observed metabolization rates. From the inspection of Table
4, compound 9m exhibited interesting in vitro ADMET and physi-
cochemical properties with moderate human metabolic lability
and still acceptable logD7.4. This compound is the most potent
member of this series in HepG2 and H4IIE cell-based SCD1 assays
a
l
M compared to the original hit, this option was not explored
further with a larger range of R2 substituents, since alternative sub-
stituents combined with the carboxamide linkers lead to signifi-
cantly improved activity (cf. Table 3).
Table 3 summarizes our efforts to investigate the ortho-position
on the distal phenoxy-moiety of the original hit 2a. The ROCS-de-
rived alignment of 2a with the virtual screening query 1 suggests
that inserting the lipophilic substituent of the query 1 at this posi-
tion in our series should be tolerated by the enzyme. We explored
this option combined with different carboxamide substituents (R1
in Table 3). Introducing an ortho-chlorine substituent on the distal
ring with a thiazolyl-substituent attached to the carboxamide
with IC50 values of 0.157 and 0.182 lM (see Table 4), respectively.
It was also potent with respect to ACC phosphorylation. Therefore,
this compound was selected for further investigation and renamed
SAR224.
An in-depth pharmacokinetic and pharmacological character-
ization of SAR224 was performed. All experimental procedures
were conducted in accordance to the German Animal Protection
Law and international animal welfare legislation and rules and per-
formed as previously described.8,9,19 After intravenous administra-
tion of 5 mg/kg SAR224 in solution to male ZDF rats, a low mean
plasma clearance (0.25 L/h/kg), a large volume of distribution
(Vss = 1.7 L/h/kg) and a long half-life (6.5 h) were observed. After
a single oral dose of 30 mg/kg SAR224 in suspension to male ZDF
rats, the mean plasma concentration profile showed a slow
increase from 0.25 to 6 h after administration and a mean Cmax va-
lue of 1950 ng/mL after 4 h. SAR224 showed a long mean apparent
plasma half-life (8.4 h) and a relative bioavailability of 25% (Fig. 3,
Upper). To evaluate the in vivo pharmacological activity of SAR224,
the compound was administered once orally at 30 mg/kg to
8 week-old male ZDF rats, a well-known animal model of obesity
and diabetes. After 6 h the compound significantly decreased the
serum fatty acid desaturation index (À84.4 15.9%) compared to
(R1 = A) results in potent derivatives, for example, 9a (IC50
:
0.115 lM).
The nature of the amine substituent of R1 significantly influ-
ences SCD1 activity. Replacing the thiazole-ring by a chloro-thio-
phene (R1 = B) results in a lower activity (9b: 0.832
lM), while
aliphatic substituents do not improve activity, as demonstrated
by 9c and 9d with IC50 values of 0.966 and 2.72 lM, respectively.
Interestingly this ranking of R1-substituents is not respected if
the ortho-chlorine of substituent R2 is replaced by an ortho-trifluo-
romethyl group. Here the most active compound is obtained with
the chloro-thiophene moiety (R1 = B), 9f (IC50: 0.142
lM) rather
than with the thiazolyl-moiety, 9e (IC50: 0.212 lM). Combining ali-
phatic R1-substituents with ortho-CF3-substituted biarylethers
does not improve activity, as seen by compounds 9g and 9h with
IC50 values of 0.539 and 0.434
carboxamide substituent by a methyl-group significantly affects
activity (9i: 27.2 M), and even more so with a phenylpropyl-
substituent (9k: >100 M). similar decrease in activity is
observed for the corresponding ethyl-ester substitution at position
R1 (9j: 38.3
M).
l
M, respectively. Replacing the R1-
l
l
A
100000
10000
1000
l
Finally we replaced the ortho-substituted biphenylether by
substituted benzophenone-derivatives (9l–9q). Our intention was
to explore the effect of altered hydrogen-bond accepting properties
on SCD1 inhibition by comparing the carbonyl oxygen to the aro-
matic ether-oxygen which cannot play the role of H-bond acceptor.
Once again the most significant influence on activity is observed
with a thiazole-substituent (R1 = A; 9l: 0.078
thiophene (R1 = B; 9m: 0.136
M), while aliphatic substituents at
R1 once more result in decreased SCD1 inhibition (9n: 3.86
M).
lM) and chloro-
l
l
100
i.v.
These favorable motifs in 9l and 9m were further explored by
changing the distance between the aromatic thiazole ring and
the carboxamide linker.
p.o.
10
Removing the methylene-linker from R1 = A reduces activity, as
0
6
12
18
24
TIME (hours)
can be seen by comparing 9l (IC50: 0.078
4.52 M. Removal of the chlorine substituent in 9m has only a
slightly favorable effect on SCD1 inhibition, leading to 9p with an
IC50 value of 0.099 M. Our final investigation in this series was
to reverse the order of the carboxamide linker, resulting in the
much less active compound 9q (3.20 M).
lM) and 9o (IC50:
l
1,4
1,2
1
l
l
*
This systematic SAR investigation had lead to several molecules
that were interesting as potent SCD1 inhibitors, and which were
then profiled in further assays. A summary of additional in vitro
data, giving cellular SCD1 activities in rat H4IIE and human HepG2
liver cell lines, effect on ACC phosphorylation in human HepG2
0,8
0,6
0,4
0,2
0
cells (at 10 lM concentration with in-cell Western immunolabel-
ing),8 ADME and physicochemical properties is provided in Table
4. In general, the entire chemical series is characterized by high
Caco-2 permeability and acceptable to moderate metabolic lability
rates (e.g., column MLab Human reporting the percentage of a com-
pound metabolized). Addition of the CYP3A4/5 inhibitor ketocona-
zole to the metabolic lability assay reveals an important influence
of CYP3A4/5 on the observed metabolic degradation of the com-
lean
obese
SAR224
Figure 3. Upper: Pharmacokinetic parameters of SAR224 following an intravenous
bolus administration of 5 mg/kg SAR224 and following a single oral dose of 30 mg/
kg SAR224 to male obese ZDF rats. Results are means SD (n = 3). Lower: Decreased
serum fatty acid desaturation indices (À84.4 15.9%) by treatment of male obese
ZDF rats with 30 mg/kg SAR224. Results are means SEM (n = 8) and ⁄p <0.05
versus the vehicle-treated, obese controls.

1822
H. Matter et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1817–1822
6. Ntambi, J. M. Prog. Lipid Res. 1995, 34, 139.
vehicle in the obese animals (Fig. 3, lower), thus providing evidence
for SCD1 inhibition in vivo by SAR224.
7. Ntambi, J. M.; Miyazaki, M.; Stoehr, J. P.; Lan, H.; Kendziorski, C. M.; Yandell, B.
S.; Song, Y.; Cohen, P.; Friedman, J. M.; Attie, A. D. Proc. Natl. Acad. Sci. U.S.A.
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8. Voss, M. D.; Zoller, G.; Matter, H.; Herling, A. W.; Biemer-Daub, G.; Pfenninger,
A.; Haag-Diergarten, S.; Keil, S.; Kohlmann, M.; Schmidts, H.-L. Eur. J.
Pharmacol., Submitted for publication.
In conclusion, we have described the identification, design and
structure–activity relationships of a novel series of potent SCD1
inhibitors based on a benzimidazole scaffold. This series was devel-
oped following promising results from a ligand-based virtual
screen. Major parts of the scaffold were then appropriately substi-
tuted to arrive at compounds having high affinity as SCD1 inhibi-
tors and favorable physicochemical and ADMET properties.
Finally SAR224 which showed the most promising in vitro
properties was characterized by in vivo PK and pharmacology
studies, which revealed strong evidence for in vivo SCD1 inhibition
by this molecule with suitable oral bioavailability and half-life.
Hence SAR224 constitutes a promising starting point for further
investigation of SCD1 inhibitors as potential treatments of diabetes
and related diseases.
9. Zoller, G.; Voss, M. D.; Keil, S.; Herling, A.; Matter, H. PCT Int. Appl. 2008,
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Acknowledgments
We would like to thank Petra Selle and Sascha Rauch for their
excellent technical assistance.
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