2-Aryl benzimidazoles: Human SCD1-specific stearoyl coenzyme-A desaturase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2010.09.094

A series of potent, benzimidazole-based SCD inhibitors which demonstrate selectivity for the hSCD1 enzyme over the hSCD5 isoform are described. The compounds possess suitable cellular activity and pharmacokinetic properties which render them capable of inhibiting liver SCD activity in a mouse pharmacodynamic assay. These 2-aryl benzimidazoles may serve as valuable tools for studying selective hSCD1-inhibition.

Full text of DOI:10.1016/j.bmcl.2010.09.094

Bioorganic & Medicinal Chemistry Letters 20 (2010) 6366–6369
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
2-Aryl benzimidazoles: Human SCD1-specific stearoyl coenzyme-A
desaturase inhibitors
⇑
David A. Powell , Yeeman Ramtohul, Marie-Eve Lebrun, Renata Oballa, Sathesh Bhat,
Jean-Pierre Falgueyret, Sebastien Guiral, Zheng Huang, Kathryn Skorey, Paul Tawa, Lei Zhang
Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Québec, Canada H9H 3L1
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of potent, benzimidazole-based SCD inhibitors which demonstrate selectivity for the hSCD1
enzyme over the hSCD5 isoform are described. The compounds possess suitable cellular activity and
pharmacokinetic properties which render them capable of inhibiting liver SCD activity in a mouse phar-
macodynamic assay. These 2-aryl benzimidazoles may serve as valuable tools for studying selective
hSCD1-inhibition.
Received 18 August 2010
Revised 14 September 2010
Accepted 16 September 2010
Available online 19 September 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Stearoyl CoA
Desaturase
SCD
Stearoyl coenzyme-A desaturase (SCD) is an iron containing
atic b-cell death.6a,16 Unfortunately there is no SCD5 equivalent
gene present in rodents,17 but SCD5 is expressed in primates, dogs,
and other higher species.14 To the best of our knowledge, no SCD
inhibitors have been described which are selective for either the
hSCD1 or hSCD5 isozymes.
In light of these findings, we initiated a campaign to identify
SCD inhibitors which are selective for the hSCD1 isoform over
the hSCD5 enzyme. Structurally diverse inhibitors identified from
a previous high-throughput screening campaign using a competi-
tive rat SCD1 (rSCD1)18 scintillation proximity binding assay
(SPA) were further screened against recombinant hSCD1 and
hSCD5 enzymes expressed in Sf9 cells.19 These efforts led to the
identification of a series of modestly potent 2-aryl benzimidazole
inhibitors, which demonstrate complete selectivity for the hSCD1
enzyme over the hSCD5 isoform.
These benzimidazoles are attractive lead compounds whose
modular structure enables rapid analog synthesis (Scheme 1).
Chemistry efforts were initiated with the goal of further improving
the hSCD1 potency and exploring the structure–activity relation-
ship in this series.
Benzimidazole 1, containing a 6-tert-butyl group is representa-
tive of the potency observed in the initial hit series (Table 1).
Initially, we elected to explore modifications at the 6-position of
the benzimidazole scaffold and found the substituent here to be
critical for SCD1 activity. Replacing the tert-butyl group with a pro-
ton 2 or nitrile 3 resulted in complete loss of activity. In contrast,
the sulfonamides 4 and 5 displayed similar rat SCD1 activity as 1.
While the sulfide 6 and sulfoxide 7 analogs were reasonably potent
and selective SCD1 inhibitors, methylsulfone 8 exhibited superior
activity compared to all other 6-substituted derivatives explored.
microsomal enzyme, which catalyzes the formation of a cis-double
bond at the
D
9 position of saturated fatty acyl-coenzyme-A esters.1
The monounsaturated lipid products [mainly palmitoleoyl-CoA
(C16:1) and oleoyl-CoA (C18:1)] are major components of triglycer-
ides, cholesterol esters, and membrane phospholipids. Lipids play a
vital role in the pathology of metabolic disease2 and consequently
SCD dysregulation has been implicated in the development of
dyslipidemia,3 diabetes,4 cancer,5 and other metabolic disorders.6,7
Supporting this hypothesis, rodents deficient in SCD1, either as a
result of gene deletion,8 antisense oligonucleotide (ASO) treatment,9
or pharmacological inhibition,10 are resistant to diet-induced
weight gain, have an improved lipid profile and increased insulin
sensitivity. Not surprisingly, substantial efforts have focused on
the development of small-molecule SCD inhibitors for therapeutic
application against these metabolic disorders.11,12
Human SCD1 (hSCD1) is the prevalent isoform of the enzyme
found in humans, however a second SCD gene, hSCD5 (sometimes
referred to as hSCD2), has also been described.13 This evolution-
arily distinct human SCD5 enzyme possesses 61% sequence iden-
tity to hSCD1 and is highly expressed in the brain and pancreas,
whereas hSCD1 is expressed predominantly in liver and adipose
tissues.13 While little is known about the exact function of hSCD5,
it has been suggested to serve a developmental and/or protective
role.13a,14 Indeed, a mutation in the hSCD5-encoding gene (ACOD4)
has been associated with the congenital deformity, cleft-lip syn-
drome.15 Additionally, SCD-inhibition has been linked to pancre-
⇑
Corresponding author. Tel.: +1 514 428 3098; fax: +1 514 428 4900.
E-mail address: david_powell2@merck.com (D.A. Powell).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.09.094

D. A. Powell et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6366–6369
6367
Table 2
SCD activity and selectivity of D-ring benzimidazole derivatives
Compound
R
Enzyme IC50 (nM)
rSCD1
hSCD1
hSCD5
11
20
24
>10,000
12
13
>20,000
>20,000
—
—
—
—
14
15
304
25
2326
—
>20,000
—
16
17
319
148
—
15
—
>10,000
18
19
396
21
342
30
>20,000
>20,000
Scheme 1. Reagents and conditions: (a) 10 mol % p-TsOH, DMF, air, 80 °C, 2 h; (b)
2.5 equiv TMSCl, DMF, 90 °C, 4 h; (c) sulfinic acid sodium salt (2.0 equiv), 1 equiv
CuOTf, 2 equiv trans 1,2-diaminocyclohexane, DMSO, 130 °C, 2–6 h; (d) 2.5 mol %
[PdBr(t-Bu3P)]2, 2 equiv K3PO4, dioxane/H2O (10:1), 100 °C, microwave, 20 min.
20
21
22
8
3863
4489
336
65
—
255
—
27
—
>20,000
—
>20,000
23
278
—
—
Table 1
SCD activity and selectivity of 6-substituted benzimidazole analogs
24
95
—
—
25
26
>20,000
2473
—
—
4246
>20,000
Compound
R
Enzyme IC50 (nM)
rSCD1
hSCD1
hSCD5
27
28
425
—
—
1
2
3
175
731
>20,000
—
>20,000
>20,000
—
1713
1760
>20,000
>20,000
>20,000
29
30
395
104
1705
—
>20,000
—
4
528
—
—
5
6
7
343
697
472
74
—
>20,000
—
31
32
97
472
231
—
>20,000
—
96
>20,000
IC50s are an average of at least two titrations.
8
9
65
27
>20,000
resulted in only a modest loss of SCD1 potency (33 and 35–37). In
contrast, substitution of the benzimidazole with a benzothiazole
(34) or alkylation at either of the benzimidazole nitrogens (41–
42) resulted in almost complete loss of SCD1 activity. Interestingly,
the isomeric imidazo[1,2-a]pyridine 39 was identified as a highly
potent SCD1 inhibitor, suggesting that a hydrogen bond donor is
not essential for SCD activity.
1248
1308
>20,000
10
401
—
—
IC50s are an average of at least two titrations.
Other sulfones (9–10), including the ethyl and cyclopropyl deriva-
tives are inferior in terms of SCD potency, as compared to 8.
Having established the 6-methyl sulfone substituent as benefi-
cial for hSCD1 potency and selectivity over the hSCD5 isoform,
investigations turned to modifications on the D-ring (Table 2).
A variety of ortho-, meta- and para-substituents were explored at
the terminal D-ring (compounds 11–24). Surprisingly, the unsub-
stituted biaryl derivative 11 exhibited similar potency to fluoro
analog 8. Removal of the D-ring phenyl or replacement with a
bromide (26) resulted in inactivity in the SCD1 enzyme assay.
Heterocyclic D-rings were, for the most part, tolerated in terms
of SCD1 potency (compounds 26–32) however no real improve-
ment was observed as compared to biphenyl analog 8.
Having identified a variety of potent benzimidazole-based SCD1
inhibitors, we proceeded to further profile representative analog 8
and characterize the in vitro and in vivo properties of this class of
inhibitors. Benzimidazole 8 is not an inhibitor of rat or human
D
5-desaturase in an enzyme-based assay (Table 4). This result
demonstrates that the inhibitory activity of 8 is unlikely a result
of perturbation of the essential desaturation co-factors, including
cytochrome b5 or cytochrome b5 reductase.20 In two varying
whole cell assays,21 compound 8 demonstrated micromolar inhibi-
tion of SCD activity. In addition, 8 displays adequate pharmacoki-
netic properties in both mice and dogs (Table 5) with reasonable
exposures and bioavailability to enable in vivo study of SCD1
inhibition.
Finally, variations in the central rings B and C were explored and
their effect on SCD1 potency and selectivity were examined
(Table 3). Incorporation of nitrogen atoms onto the aromatic rings
Gratifyingly, hSCD1-selective inhibitor 8 demonstrated inhibi-
tion of liver SCD activity in a mouse liver pharmacodynamic assay
(Fig. 1).22 Benzimidazole 8 was administered orally at doses of 30

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D. A. Powell et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6366–6369
Table 3
SCD activity and selectivity of benzimidazole derivatives
Figure 1. Male C57Bl6 mice were fed a high sucrose/fat-free diet for 2 days to
induce liver SCD activity. Compound 8 was administered orally in 0.5% Methocel at
7:00 am on day 3. The [1-14C]-stearic acid tracer (40
Ci/kg) was dosed via the
l
jugular vein at 8:00 am and livers were harvested 2 h later. Liver SCD activity was
measured by the ratio of [14C]-oleic acid/[14C]-stearic acid after complete lipid
hydrolysis (mean SEM, n = 5–8/group). The corresponding liver and plasma
concentrations of 8 in mice upon termination (3 h post dosing) are included.
inhibitor MK-8245.23 2-Aryl benzimidazole 8 was found to be com-
petitive with MK-8245 for binding to hSCD1. MK-8245 has been
demonstrated to bind competitively with stearoyl-CoA, the natural
substrate for SCD1.
IC50s are an average of at least two titrations.
Table 4
In conclusion, we have described a series of benzimidazole-
based SCD inhibitors which demonstrate specificity for the hSCD1
enzyme over the hSCD5 isoform. Furthermore, we demonstrate
that these compounds inhibit SCD-activity in vitro in liver-derived
cells and in vivo in a mouse liver PD assay. Given the paucity of
known selective hSCD1-inhibitors, these compounds may serve
as valuable tools to enable further understanding of the specific
role of hSCD1 as compared to hSCD5.
In vitro properties of 2-aryl benzimidazole 8
Assay
IC50 (nM)
Enzymatic
Rat SCD1
65
27
>20,000
>50,000
1325
5169
Human SCD1
Human SCD5
Rat D5Da
Cellular
Human HepG2
Rat Hepatocycteb
IC50s are an average of at least two titrations.
References and notes
a
D
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b
Freshly isolated rat hepatocyctes were utilized.
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(
l
M h)
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