Discovery of thiazolylpyridinone SCD1 inhibitors with preferential liver distribution and reduced mechanism-based adverse effects

Article abstract of DOI:10.1016/j.bmcl.2013.12.035

We discovered a series of novel and potent thiazolylpyridinone-based SCD1 inhibitors based on a 2-aminothiazole HTS hit by replacing the amide bond with a pyridinone moiety. Compound 19 demonstrated good potency against SCD1 in vitro and in vivo. The mouse liver microsomal SCD1 in vitro potency for 19 was improved by more than 240-fold compared to the original HTS hit. Furthermore, 19 demonstrated a dose-dependent reduction of plasma desaturation index with an ED₅₀ of 6.3 mg/kg. Compound 19 demonstrated high liver to plasma and liver to eyelid exposures, indicating preferential liver distribution. The preliminary toxicology study with compound 19 did not demonstrate adverse effects related to SCD1 inhibition, suggesting a wide safety margin with respect to other known SCD1 inhibitors with wider distribution profiles.

Full text of DOI:10.1016/j.bmcl.2013.12.035

Bioorganic & Medicinal Chemistry Letters 24 (2014) 526–531
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of thiazolylpyridinone SCD1 inhibitors with preferential
liver distribution and reduced mechanism-based adverse effects
a
a
a
a
a
Shaoyi Sun a, , Zaihui Zhang , Vandna Raina , Natalia Pokrovskaia , Duanjie Hou , Rostam Namdari ,
⇑
Kuldip Khakh a, Leslie G. Ratkay a, David G. McLaren a, Monica Mork a, Jianmin Fu a, Suzie Ferreira b,
Brian Hubbard b, Michael D. Winther a, Natalie Dales b,
⇑
a Xenon Pharmaceuticals Inc., 3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada
b Novartis Institute for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We discovered a series of novel and potent thiazolylpyridinone-based SCD1 inhibitors based on a
2-aminothiazole HTS hit by replacing the amide bond with a pyridinone moiety. Compound 19 demon-
strated good potency against SCD1 in vitro and in vivo. The mouse liver microsomal SCD1 in vitro potency
for 19 was improved by more than 240-fold compared to the original HTS hit. Furthermore, 19 demon-
strated a dose-dependent reduction of plasma desaturation index with an ED50 of 6.3 mg/kg. Compound
19 demonstrated high liver to plasma and liver to eyelid exposures, indicating preferential liver distribu-
tion. The preliminary toxicology study with compound 19 did not demonstrate adverse effects related to
SCD1 inhibition, suggesting a wide safety margin with respect to other known SCD1 inhibitors with wider
distribution profiles.
Received 8 October 2013
Revised 3 December 2013
Accepted 9 December 2013
Available online 16 December 2013
Keywords:
Stearoyl-CoA desaturase-1
SCD1 inhibitors
Thiazolylpyridinone
Liver selective
Ó 2013 Elsevier Ltd. All rights reserved.
Desaturation index
Obesity and type 2 diabetes are emerging as two major global
health problems of the 21st Century. Evidence published over the
past decade has shown that abnormal lipid metabolism is closely
related to occurrences of metabolic syndrome, obesity, type 2 dia-
betes and dyslipidemia.1,2 One potential target for the treatment of
these diseases, which has recently received great attention in the
scientific community, is stearoyl-CoA desaturase-1 (SCD1, com-
monly known as delta-9 desaturase, D9D). SCD1 catalyzes the de
novo synthesis of monounsaturated fatty acids (MUFA) from satu-
rated fatty acids by introduction of a cis-double bond between car-
bons 9 and 10. The products, mainly oleate and palmitoleate, are
key substrates for the synthesis of triglycerides, wax esters, choles-
terol esters and phospholipids.3 SCD1, with about 85% homology
across all murine SCDs, is the major isoform present in lipogenic
tissues (including liver and adipose tissues) and functions as a
key regulator of lipid and carbohydrate metabolism. SCD1-defi-
cient mice have been shown to be lean and hypermetabolic.4 In
the leptin-deficient model for obesity, mice with an inactive
SCD1 gene were significantly less obese than the ob/ob controls
and had markedly increased energy expenditure; in addition, these
mice had histologically normal livers with significantly reduced
triglyceride storage and VLDL production.4 The main consequences
of SCD1 deficiency are hypothesized to be activation of lipid
oxidation and reduction of triglyceride synthesis and storage.5–7
These beneficial phenotypes are also observed in high fat diet-in-
duced obese (DIO) mice treated with antisense oligonucleotides di-
rected towards SCD1.8,9 In humans, elevated SCD1 activity
positively correlates with high triglyceride levels in familial hyper-
triglyceridemia subjects,10 increased body mass index (BMI) and
high plasma insulin levels.11 Therefore, compounds that inhibit
SCD1 may hold significant therapeutic potential for the treatment
of obesity, type 2 diabetes and other metabolic disorders.
Since we disclosed a series of small molecule SCD1 inhibitors in
2005, such as compound 112,13 (Fig. 1), a number of subsequent
inhibitors have been reported.14–20 Many of these have strikingly
similar structural features. In order to discover additional novel
and structurally distinct SCD1 inhibitors, we conducted a second
high throughput screen which lead to the discovery of a class of
2-aminothiazole-based SCD1 inhibitors with moderate mouse
SCD1 activity (e.g., compound 5, Fig. 2). Due to the labile nature
of the amide bond motif of compound 5, we initially sought
replacements for the 2-position amide. Modification of 5 by the
replacement of the C-2 amide bond with a pyridin-2(1H)-one moi-
ety led to the discovery of compound 6 with greater than 24-fold
increase in activity against mouse SCD1. Compound 6 had poor
activity against human SCD1 as measured by a HepG2 cell assay;
nonetheless, the pyridinone modification provided a good struc-
tural template for further optimization efforts. Herein, we report
⇑
Corresponding authors. Tel.: +1 604 484 3300 (S.S.), +1 617 871 7796 (N.D.).
E-mail addresses: ssun@xenon-pharma.com (S. Sun), natalie.dales@novartis.com
(N. Dales).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.12.035

S. Sun et al. / Bioorg. Med. Chem. Lett. 24 (2014) 526–531
527
O
O
O
O
N
N
CF3
N
N
NH N N
N
NH
N-N
OH
1 (Xenon)
2 (Daiichi Sankyo)
Br
N
N
O
O
N
N
O
F
N
N
NH N N
O
N
HO
F
O
F
4 (Merck)
3 (Abbott)
Figure 1. Selected reported SCD1 inhibitors.
O
O
N
H
N
N
N
NH
N
H
S
S
O
O
5
6
Mouse SCD1 IC50: 141 nM
HepG2 SCD1 IC50: 2578 nM
Mouse SCD1 IC50: 3400 nM
Figure 2. Thiazole-based SCD1 inhibitors discovered at Xenon.
the discovery of a series of novel, potent thiazolylpyridinone SCD1
inhibitors which demonstrate in vivo activity and high liver to
plasma ratios. These results suggest the 4-hydroxy pyridinone
functionality may be a suitable handle for liver-targeting or prefer-
ential liver distribution, and thus may lead to SCD1 inhibitors with
improved safety and tolerability.
The activity data of these pyridin-2(1H)-one analogues is
summarized in Table 1. Methoxyl (compound 9) and cyclopropy-
lethoxyl (compound 10) analogues maintained good potency in
both assays, and metabolic stability in rat liver microsomes was
greatly improved compared to compounds 7 and 8. Compound 9
also demonstrated significantly improved cell permeability. Ana-
logues generated by replacement of the benzyloxyl group with a
Compound 6 (Fig. 2) demonstrated improved SCD1 activity rel-
ative to the original hit compound 5; however, this activity re-
mained modest and likely insufficient to elicit in vivo effects.
Based on our earlier work and knowledge from other scaffolds,
we hypothesized that compound 6 was too conformationally con-
strained and that more flexibility might be required for binding to
the SCD active site. Therefore, we introduced flexible linkers be-
tween the pyridin-2(1H)-one moiety and the terminal phenyl ring.
Indeed, compounds 7 and 8 (Table 1) were roughly 7-fold more po-
tent than compound 6 in the mouse liver microsomal SCD1 assay
and, importantly, these modifications resulted in 50- to 100-fold
increased potency in the HepG2 cell-based SCD1 assay. However,
both compounds showed poor metabolic stability in rat liver
microsomes and poor cell permeability as assessed in Caco-2 cells
(Table 1). Therefore, our initial chemistry effort was focused on
improving metabolic stability and cell permeability.
As outlined in Scheme 1, synthesis of pyridin-2(1H)-one
analogues was achieved via a copper-catalyzed coupling reaction21
between pyridin-2(1H)-ones and N-benzyl-2-bromo-4-methylthi-
azole-5-carboxamide, which were prepared from commercially
available 2-bromo-4-methylthiazole-5-carboxylic acid and benzyl-
amine under standard amide formation conditions. The resulting
analogues were tested in SCD1 assays directly, or further
elaborated to generate final target compounds.
trifluoromethyl group,
a small alkyl or a cycloalkyl group
(compounds 13, 14 and 15) retained potency in the mouse liver
microsomal SCD1 assay, but activity was reduced in the HepG2
cell-based assay. A similar trend was also observed when the
benzyloxyl group was removed to generate the unsubstituted ana-
logue 16. The pyridine moieties (compounds 17 and 18) were not
well tolerated, resulting in decreased mouse liver microsomal
activity. Removal of the benzyl group generated the 4-hydroxyl
analogue 1925 which had good activity, displayed superior meta-
bolic stability (ꢀ100% remaining after a 30 min incubation with
0.5 mg/mL rat liver microsomes), and had good permeability.
Replacement of the oxygen atom with a nitrogen atom resulted
in a decrease in activity. We found that modifications at the
4-position of the pyridinone could provide improved metabolic
stability and cell permeability while maintaining the SCD1
potency.
Given the good in vitro potency in both SCD1 assays, good met-
abolic stability and reasonable cell permeability demonstrated by
compound 19, we then shifted our optimization effort to the C5 po-
sition amide functionality. Analogues were synthesized as outlined
in Scheme 2. Similar to the chemistry described in Scheme 1, a cop-
per-catalyzed coupling reaction between ethyl 2-bromo-4-methyl-
thiazole-5-carboxylate
and
4-(benzyloxy)-pyridin-2(1H)-one
The inhibitory activity of these compounds against SCD1 was
typically assessed by two assays: a mouse liver microsomal assay22
and a human HepG2 cell-based assay.23 Compounds with good po-
tency on SCD1 were also screened against delta-5 (D5D) and delta-
6 desaturase (D6D) to determine their selectivity against these
desaturases. In humans, these two desaturases are involved in
the synthesis of highly unsaturated fatty acids which play crucial
roles in maintaining membrane fluidity; therefore, we felt that
achieving selectivity against D5D and D6D is essential to avoid
undesirable toxicities.24 Active compounds described herein
(HepG2 IC50 <100 nM) did not demonstrate D5D and D6D activity
generated compound 23a. Hydrolysis in the presence of lithium
hydroxide yielded the corresponding acid 23b. Subsequent amide
formation under standard conditions afforded compounds
23c–31c. The final 4-hydroxy compounds 23–31 were obtained
after removal of the benzyl group via hydrogenation.
The SCD1 activity of these 4-hydroxy analogues was assessed
using the same methods as outlined above and the results are sum-
marized in Table 2. Fluorine substitution on the phenyl ring was
well tolerated and maintained potency in both assays (23–26).
Introduction of heteroaryl functionality was not tolerated as dem-
onstrated by compounds 27–30. Cycloalkylalkyl substitution
maintained good potency in the mouse liver microsomal SCD1
at 10 lM.

528
S. Sun et al. / Bioorg. Med. Chem. Lett. 24 (2014) 526–531
Table 1
SAR summary of selected SCD1 inhibitors
N
N
O
R
H
N
S
O
a
a
Compound
R
Mouse SCD1 IC50 (nM)
HepG2 SCD1 IC50 (nM)
Rat liver microsome stabilityb
Permeabilityc (Â10À6 cm/s)
6
7
8
9
Phenyl
Benzyloxyl
Phenethyl
Methoxyl
Cyclopropylethoxyl
(Tetrahydrofuran-2-yl)methoxyl
Thiazol-4-ylmethoxyl
Trifluoromethyl
Methyl
141
25
20
90
40
29
24
24
31
2578
26
50
61
12
17
25
22
64
71
ndd
37
nd
nd
62
nd
nd
nd
100
nd
nd
nd
1/0.2
0.02/0.01
0.6/0.2
15/15
0.05/0.04
nd
11/10
nd
nd
28/22
nd
nd
nd
7/16
nd
10
11
12
13
14
15
16
17
18
19
20
21
22
329
55
1510
191
458
2536
nd
nd
34
nd
nd
Cyclopropyl
H
40
63
Pyridine-2-ylmethoxyl
Pyridine-3-ylmethoxyl
Hydroxyl
Benzylamino
Benzamido
1235
3430
14
155
>10,000
387
nd
nd
NH2
nd
a
b
c
IC50s are an average of at least two independent determinations.
Expressed as % remaining after a 30 min incubation with 0.5 mg/mL rat liver microsomes at 5
Permeability was determined using Caco-2 cells. Data are expressed as Papp(a to b)/Papp(b to a).
lM.
d
nd: not determined.
O
N
N
N
a
b
H
N
H
Br
Br
HO
N
N
OBn
OH
S
S
S
O
O
O
7a
7
7b
c
b
O
O
N
S
N
H
N
H
N
N
N
R'
S
O
O
R' = phenethyl, 8; R' = CF3, 13; R' = CH3, 14;
R'= cyclopropyl, 15; R' = H, 16; R' = NH2, 22
19
when R' = NH2,
e or f
d
O
O
N
N
H
N
H
N
N
N
OR
NHR
S
S
O
O
20, 21
9-12, 17, 18
Scheme 1. Reagents and conditions: (a) EDCI, HOBt, iPr2NEt, benzylamine, DMF; (b) 4-(benzyloxy)pyridin-2(1H)-one, CuI, 8-hydroxyquinoline, K2CO3, DMF, 80 °C; (c) H2, Pd/
C, MeOH; (d) RX, NaH or Cs2CO3, rt to 80 °C, DMF; (e) PhCHO, TFA, Et3SiH, CHCl3; (f) benzoyl chloride, pyridine.
assay, but the potency in the HepG2 cell assay decreased dramat-
ically (compounds 31 and 32). Compounds 19, 23 and 25, the most
active analogs identified, maintained good metabolic stability,
however are potential efflux transporter substrates as indicated
by their Caco-2 Papp(b to a) to Papp(a to b) ratios (Table 2). This
property could be due to the acidic nature of the hydroxyl group
of 4-hydroxypyridinone (pKa 5).
Based on the in vitro potencies and overall properties, we eval-
uated the in vivo effect of compounds 19, 23 and 25 on the plasma
C16:1/C16:0 triglycerides (TG) desaturation indices (DI)26 in an
acute Lewis rat pharmacodynamics (PD) model.27 C16 DI has been
well-documented as biomarkers for SCD1 target engagement.9,28
The results of the C16:1/C16:0 plasma DI are illustrated in Figure 3.
After a single oral administration, compounds 19 and 25 demon-
strated statistically significant reductions of the plasma C16:1/
C16:0 TG DI, by 40% and 26%, respectively, at a 4 h time point.
Compound 23 had only a marginal effect on plasma DI reduction
despite having a similar in vitro profile as the other two com-
pounds tested.
Compound 19, which had the most robust effect in the DI
screening model, was then evaluated in a dose-responsive manner
(2 mg/kg to 10 mg/kg with plasma sampling at the 4 h time point).
The results indicated a dose-related reduction of plasma TG DI
with the ED50 estimated to be 6.2 mg/kg (Fig. 4).
We further investigated the PK/PD relationship of compound
19. In this study27, Lewis rats were dosed orally at 10 mg/kg and
plasma samples were collected at different time points for expo-
sure and plasma DI measurements (Fig. 5). The maximum effect

S. Sun et al. / Bioorg. Med. Chem. Lett. 24 (2014) 526–531
529
O
N
N
a
Br
EtO
N
EtO
OBn
S
S
O
O
b
7a
23a R = Et
23b R = H
O
O
N
N
c
d
H
N
H
N
N
N
OBn
OH
R1
R1
S
S
O
O
23c-31c
23-31
Scheme 2. Reagents and conditions: (a) 4-(benzyloxy)pyridin-2(1H)-one, CuI,
8-hydroxyquinoline, K2CO3, DMF, 80 °C; (b) LiOH, THF, H2O, reflux; (c) EDCI, HOBt,
iPr2NEt, R1NH2, DMF; (d) H2, Pd/C, MeOH.
Figure 3. Effect of compounds 19, 23 and 25 on plasma C16:1/C16:0 TG
desaturation index 4 h after a 5 mg/kg oral dose in Lewis rats. Each bar represents
the mean of at least 4 animals and the error bars represent standard errors of the
mean. ⁄⁄⁄: One-way ANOVA analysis between vehicle group and compound treated
groups with p <0.001.
in reduction of C16:1/C16:0 TG DI of about 65% was achieved at 2 h
post oral administration. The effect was maintained at 8 h post
dose (42% reduction) and at 24 h, the C16:1/C16:0 TG DI had recov-
ered to about 70% of the level of the contemporaneous vehicle
group. Plasma concentrations at the 2 to 8 h time points where
profound DI reduction was observed, were surprisingly low:
0.46 lM at 2 h; 0.37 lM at 4 h; 0.21 lM at 6 h; 0.15 lM at 8 h. This
observation prompted us to investigate the PK/PD relationship. We
hypothesized that tissue distribution, specifically high liver con-
centration of compound 19, could be a contributor to the apparent
disconnection. Since plasma DI serves as a surrogate readout for
liver SCD1 activity, high liver concentrations of compound 19
would explain the robust effect observed on plasma DI.
We evaluated the tissue distribution of compound 19 after
5 days of treatment (qd, PO, 10 mg/kg dose, Lewis rats), assuming
that this duration would be sufficient to achieve steady state.
The concentration of compound 19 in plasma, eyelid and liver
was analyzed 2 h after the last dose (Fig. 6). At this time point,
compound 19 had an exposure of 11,100 nM in liver, 309 nM in
plasma, and 271 nM in eyelid, resulting a liver to plasma ratio of
36, and a liver to eyelid ratio of 41. These data support the hypoth-
esis that compound 19 preferentially distributes to the liver. Also,
at 2 h, the liver concentration of compound 19 was greater than
300-fold over the cell-based IC50, which explains the robust effect
on DI. Liver-selective SCD1 inhibitors could provide significant
advantages in terms of safety, specifically reducing risks for known
adverse effects, such as dry skin and dry eyes, related to the SCD1
Figure 4. Dose response of compound 19 on plasma C16:1/C16:0 TG desaturation
index 4 h after oral dosing in Lewis rats. Each data point represents the mean of at
least 4 animals. The error bars represent the standard errors of the mean.
inhibition in meibomian and sebaceous glands.28,29 Recently, other
liver-selective SCD1 inhibitors have also been reported.20,30–36
To provide an initial safety assessment with respect to the ad-
verse effects associated with SCD1 deficiency, compound 19 was
Table 2
SAR summary of selected SCD1 inhibitors
N
S
N
OH
H
N
R1
O
O
R1
Mouse SCD1 IC50 (nM)
HepG2 SCD1 IC50 (nM)
Rat liver microsome stabilityb
Permeabilityc (Â10À6 cm/s)
a
a
Compound
19
23
24
25
26
27
28
29
30
31
32
Benzyl
4-Fluorobenzyl
3-Fluorobenzyl
14
15
20
18
34
30
137
48
121
nd
>1000
nd
nd
1692
783
100
85
ndd
89
nd
nd
nd
nd
nd
nd
nd
7/16
9/23
nd
9/33
nd
nd
nd
nd
nd
3,4-Difluorobenzyl
4-Fluorophenethyl
Pyridin-3-ylmethyl
Pyridin-4-ylmethyl
(5-Methylpyrazin-2-yl)methyl
Oxazol-2-ylmethyl
Cyclopropylmethyl
Cyclopropylethyl
43
231
103
342
430
49
nd
nd
69
a
b
c
IC50s are an average of at least two independent determinations.
Expressed as% remaining after a 30 min incubation with 0.5 mg/mL rat liver microsomes at 5
The data were determined using Caco-2 cells. Data are expressed as Papp(a to b)/Papp(b to a).
lM.
d
nd: not determined.

530
S. Sun et al. / Bioorg. Med. Chem. Lett. 24 (2014) 526–531
Legendre, Hongjuan Zhao and David Nettleton for their technical
assistance.
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animals and the error bars represent standard errors of the mean.
evaluated in a fourteen-day clinical observation study. In this
study, female Sprague–Dawley rats were dosed orally at 100 mg/
kg once daily for 13 days and the clinical signs, such as red eyes, hair
loss and dry skin were assessed. No SCD1 inhibition related adverse
effects, or any other side effects, were observed over the course of
this study. The plasma exposure of compound 19 on Day 14 was
25
in the Lewis rat model for maximum DI reduction (10 mg/kg,
AUC0–24 h = 1.9 M h) a greater than 14-fold window exists be-
lM h (AUC0–24 h). Comparing this value to the exposure required
l
21. Filipski, K. J.; Kohrt, J. F.; Casimiro-Garcia, A.; Van Huis, C.; Dudley, D. A.; Cody,
W. L.; Bigge, C. F.; Desiraju, S.; Sun, S.; Maiti, S. N.; Jaber, M. R.; Edmunds, J. J.
Tetrahedron Lett. 2006, 47, 7677.
tween PD effects and adverse effects due to SCD1inhibition.
In conclusion, we discovered a series of novel and potent thia-
zolylpyridinone SCD1 inhibitors based on a 2-aminothiazole-based
scaffold identified by HTS. Compound 19 demonstrated good po-
tency against SCD1 in vitro and in vivo. The in vitro potency was im-
proved >240-fold compared to the original HTS hit compound.
Tissue distribution analyses revealed that compound 19 had signif-
icantly higher exposure in liver than in plasma and eyelid. In an ini-
tial safety assessment, compound 19 did not demonstrate adverse
effects related to SCD1 inhibition. Thus, compound 19, perhaps
due to the 4-hydroxypyridinone functionality, provides a new
structural motif which demonstrates preferential liver distribution.
Furthermore, liver-selective SCD1 inhibitors are likely to provide
improved therapeutic indices with respect to known mechanism-
based adverse effects, and thereby may be more suitable molecules
for clinical development in the area of metabolic diseases.
22. Talamo, B. R.; Bloch, K. Anal. Biochem. 1969, 29, 300.
23. The HepG2 assay was a variation of a cell-based assay for desaturases that uses
radiolabeled fatty acids to measure substrate/product ratios. The SCD1 assay
uses radiolabeled stearic acid as the substrate. Antueno, R. J.; Knickle, L. C.;
Smith, H.; Elliot, M. L.; Allen, S. J.; Nwaka, S.; Winther, M. D. FEBS Lett. 2001,
509, 77.
24. Nakamura, M. T.; Nare, T. Y. Annu. Rev. Nutr. 2004, 24, 345.
25. Characterization data for compound 19: 1H NMR (300 MHz, CDCl3) d 11.51 (s br,
1H), 8.76 (t, J = 5.9 Hz, 1H), 8.59 (d, J = 8.0 Hz, 1H), 7.39–7.16 (m, 5H), 6.26 (dd,
J = 8.0, 2.5 Hz, 1H), 5.81 (d, J = 2.5 Hz, 1H), 4.38 (d, J = 5.9 Hz, 2H), 2.53 (s, 3H);
13C NMR (75 MHz, CDCl3) 167.9, 162.0, 161.6, 154.1, 150.2, 139.9, 132.6, 128.7,
127.7, 127.2, 123.6, 104.4, 98.0, 43.1, 17.5; MS (ES+) m/z 342.1 (M+1); HPLC
purity (a/a%): 99.8%.
26. Desaturation indices were calculated from the fatty acid profile of circulating
plasma triglycerides. Lipids were extracted from plasma using the procedure
reported in Folch, J.; Lees, M.; Stanley, G. H. S. J. Biol. Chem. 1957, 226, 497.
27. In this study, the animals were maintained on a high carbohydrate diet for one
week prior to dosing. The formulation was 1% carboxymethyl cellulose (low
viscosity):0.2% Tween 20:98.8% water and doses were given orally at 3 mL/kg.
The animals were dosed orally with SCD1 inhibitors at 5 mg/kg and plasma
samples were collected 4 h after dosing. The plasma lipid profiles were
determined after separation of different lipid species using thin layer
chromatography and lipid analyses by gas chromatography. The
Acknowledgments
We thank Chris Radomski, Pritpaul Samra, Elaine Chang, Caro-
line Hall, Jing Zhong, Joseph Sanghara, Wendy Young, Annick
contemporaneous plasma TG DI of
a satellite vehicle control group was
determined and the effect of compound 19 on plasma TG DI was assessed by

S. Sun et al. / Bioorg. Med. Chem. Lett. 24 (2014) 526–531
531
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