Bicyclic heteroaryl inhibitors of stearoyl-CoA desaturase: From systemic to liver-targeting inhibitors

Article abstract of DOI:10.1016/j.bmcl.2011.08.037

Optimization of a lead thiazole amide MF-152 led to the identification of potent bicyclic heteroaryl SCD1 inhibitors with good mouse pharmacokinetic profiles. In a view to target the liver for efficacy and to avoid SCD1 inhibition in the skin and eyes where adverse effects were previously observed in rodents, representative systemically-distributed SCD1 inhibitors were converted into liver-targeting SCD1 inhibitors.

Full text of DOI:10.1016/j.bmcl.2011.08.037

Bioorganic & Medicinal Chemistry Letters 21 (2011) 5692–5696
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Bicyclic heteroaryl inhibitors of stearoyl-CoA desaturase: From systemic
to liver-targeting inhibitors
Yeeman K. Ramtohul a, , David Powell a, Jean-Philippe Leclerc a, Serge Leger a, Renata Oballa a,
⇑
Cameron Black a, Elise Isabel a, Chun Sing Li a, Sheldon Crane a, Joel Robichaud a, Jocelyne Guay b,
Sébastien Guiral b, Lei Zhang b, Zheng Huang b
a Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Hwy, Kirkland, Quebec, Canada H9H 3L1
b Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Hwy, Kirkland, Quebec, Canada H9H 3L1
a r t i c l e i n f o
a b s t r a c t
Article history:
Optimization of a lead thiazole amide MF-152 led to the identification of potent bicyclic heteroaryl SCD1
inhibitors with good mouse pharmacokinetic profiles. In a view to target the liver for efficacy and to avoid
SCD1 inhibition in the skin and eyes where adverse effects were previously observed in rodents, repre-
sentative systemically-distributed SCD1 inhibitors were converted into liver-targeting SCD1 inhibitors.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 17 June 2011
Revised 5 August 2011
Accepted 5 August 2011
Available online 12 August 2011
Keywords:
Stearoyl-CoA
SCD1 inhibitors
Liver-selective inhibitors
Mouse liver PD
Desaturation index
The stearoyl-CoA desaturase (SCD) is a key enzyme involved in
the regulation of metabolism1 and has been implicated in a num-
ber of metabolic disorders including type II diabetes, obesity and
other metabolic syndrome diseases.2 These claims are supported
by the observation that SCD-null mice display a beneficial meta-
bolic profile, characterized by resistance to high fat diet-induced
obesity, improved insulin sensitivity and reduced body adipos-
ity.3,4 In addition, similar beneficial effects were observed in high
fat diet-induced obese (DIO) mice treated with SCD1 anti-sense oli-
gonucleotide (ASO).5 Moreover, in humans, an elevated SCD activ-
ity is positively correlated with high triglyceride level in familial
hypertriglyceridemia subjects,6 increased body mass index (BMI)
and high plasma insulin levels.7 Thus, inhibition of SCD1 enzyme
represents a promising target for the treatment of these metabolic
disorders.
with about 85% homology across all murine SCDs, is the major iso-
form present in lipogenic tissues (including liver and adipose
tissues).
In humans, there are two additional fatty acyl-CoA specific
desaturases,
D5D and D6D, involved in the biosynthesis of
long-chain polyunsaturated fatty acids which are crucial for cell
signaling.10 Therefore, it is important to identify selective SCD1
inhibitors against these desaturases. A number of reports on small
molecule SCD1 inhibitors have recently been published.11–16 In our
previous communications, we reported a lead thiazole amide
inhibitor MF-15211a (Fig. 1) and demonstrated that the metaboli-
O
N
Metabolically
labile amide
S
N
N
HO
N
O
CF3
O
SCD1 is a microsomal enzyme involved in the initial desatura-
tion of long-chain fatty acyl-coenzyme A esters (LCFA-CoA), pri-
O
S
N
H2N
1
N
N
CF3
rSCD IC50 = 1 nM
marily stearoyl-CoA and palmitoyl-CoA, at the
D9 (C9–C10)
hHepG2 IC50 = 1 nM
position to produce monounsaturated oleoyl-CoA and palmi-
toleoyl-CoA, respectively.8 These monounsaturated LCFA-CoAs,
are major building blocks for de novo lipid synthesis and therefore
are crucial for the lipogenic pathway.9 Four SCD isoforms (SCD1-4)
are present in rodents and two in humans (SCD1 and SCD5). SCD1
MF-152
O
rat SCD IC50 = 106 nM
hHepG2 IC50 = 253 nM
S
N
HN
N
O
CF3
X
X = C or N
2
⇑
Corresponding author.
E-mail address: ramtohul@hotmail.com (Y.K. Ramtohul).
Figure 1. Replacement of the primary amide moiety with an oxadiazole ring and its
modification into a bicyclic ring system.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.08.037

Y. K. Ramtohul et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5692–5696
5693
cally labile primary amide moiety which is hydrolyzed to the cor-
responding acid in vivo can be replaced with a more stable oxadi-
azole ring 1 leading to improved pharmacokinetic profiles.11b
Herein, we wish to report further SAR on the thiazole series to
identify other metabolically stable and structurally novel
pharmacophores.
Another approach we considered to address the amide hydroly-
sis metabolism was to cyclize the primary amide functionality onto
the thiazole ring to generate the bicyclic ring system 2 (Fig. 1) and
at the same time explore other related 6-5 and 5-6 bicyclic ring
systems as shown in Table 1. The synthesis of representative exam-
ples is shown in Scheme 1.17 Reaction of N-cyano-dithioiminocar-
bonate 4 with the CF3-aryl piperidine ether 5 afforded adduct 6
which upon treatment with 2-mercaptoacetamide 7 in the pres-
ence of triethylamine and ammonia furnished the aminothiazole
amide 8. Reaction of 8 with trimethylorthoformate in the presence
of catalytic amount of p-TSA produced the desired bicyclic thiazolo
pyrimidinone 2b. Compounds 3b and 3c can be accessed via a
nucleophilic displacement of the corresponding halo-bicyclic ana-
logs
respectively.
9
and 11,18 with the bromo-aryl piperidine ether 10,
The inhibitory activity of the compounds were assessed against
the SCD1 enzyme in an SCD1-induced rat liver microsomal assay19
and their cellular potency were evaluated in a human HepG2-
based whole cell assay (hHepG2).20 Both the CF3 5 and bromo-aryl
piperidines 10 were used for the SAR and in general the bromo
analogs are more potent than the corresponding CF3 analogs (Table
1, cf. 2k, 3b, and 2l, 3d). As displayed in Table 1, the bicyclic thiaz-
olo pyridinone 2a and thiazolo pyrimidinone 2b are good scaffolds
for the SCD1 enzyme with 2b being ꢀ10-fold more potent in both
the enzymatic and whole cell assays. Substitution at the 5-position
with a methyl is tolerated (2c). As shown previously with com-
pound 1,11b addition of a hydroxyl moiety on the methyl group
of 2c led to a 4-fold improvement in potency (2d). The carbonyl
group in 2b can be substituted for an amino group (2e) with a
modest loss in enzymatic potency relative to 2b and 2c, indicating
that both hydrogen bond donor and acceptor are tolerated at that
position. Removal of the amide functionality in 2f and carbonyl in
2g led to a modest loss in activity. However, replacement of the
pyrimidinone ring with a phenyl ring in 3a led to significant loss
in potency both in the enzymatic and whole cell assays. The thia-
zole ring in 2e can be substituted for an imidazole ring 2h with
no major effect on potency. Reversal of the linkage strategy con-
necting the piperidine via the 5-ring to 6-ring resulted in com-
pounds 2i–l and 3b–d. In contrast to the previous SAR, the
presence of a carbonyl was deleterious to potency (cf. 2i and 2k).
Attachment of the bromo-aryl piperidine ring at the 4-position of
the pyrimidine ring in 3d is slightly more favored over the 2-posi-
tion giving a 3-fold improvement in potency compared to 3b. In
addition, the compounds in Table 1 displayed selectivity for SCD1
Table 1
SAR on the bicyclic ring17
N
O
CF3
N
O
F
Br
HetAr
HetAr
or
2
3
Compound
HetAr
Rat SCD
IC50 (nM)
hHepG2
IC50 (nM)
a
a
O
S
2a
2b
2c
2d
2e
HN
85
7
268
29
N
O
S
N
HN
N
O
S
HN
N
8
59
N
O
S
N
HN
2
16
HO
N
NH2
S
N
56
n.d.
N
N
and do not inhibit the
D5D and D6D desaturases (data not shown).
S
Pharmacokinetic (PK) profiles for selected potent compounds
were determined in C57BL6 mice following oral dosing at 10 mg/
kg in 0.5% methocel as the vehicle. In general, the bicyclic com-
pounds in Table 1 display improved drug exposure compared to
MF-152, for instance, compound 2c gave a whole blood exposure
(AUC0–24h = 30 lM h) compared to MF-152 (AUC0–24h = 11 lM h).
We next examined the tissue distribution of compounds 2c and
2j, 6 h post oral dosing at 10 mg/kg in C57BL6 mice. As illustrated
in Figure 2, the compounds 2c (21.8 lM) and 2j (24.7 lM) display
high liver levels. Since these compounds are readily cell penetrant
(qualitatively based on the low hHepG2 data, vide infra) they are
also systemically distributed and high drug levels were observed
in the peripheral tissues such as the white adipose, skin and the
Harderian glands.
2f
83
54
755
182
N
N
S
N
N
2g
N
NH2
N
N
2h
2i
39
97
162
378
N
N
H
O
N
NH
N
H
N
N
N
HO
2j
38
319
N
H
N
S
As reported previously, systemically distributed SCD1 inhibitors
MF-15211a and 111b developed partial eye closure and progressive
alopecia after ꢀ7 days of drug treatment. We believe that the dry
eyes are a result of a decreased levels of oleate-derived lipids (tri-
glycerides, cholesterol esters, and wax esters) secreted in tears by
the Harderian glands, which are essential for eye lubrication. Sim-
ilarly, a reduction of these lipids levels in the adipose tissues, skin
and/or sebaceous glands may have led to the dry skin and hair loss.
In addition, it was previously demonstrated that SCD1 liver-target-
ing inhibitors that distribute preferentially in the liver (target or-
gan for efficacy) over the peripheral off-target tissues showed
beneficial anti-diabetic and anti-dyslipidemic efficacies with no
3a
477
10,639
N
N
2k
3b
10
3
257
47
N
N
H
N
N
S
N
H2N
3c
1
17
N
N
2l
3d
10
1
48
<39
N
HN
N
a
IC50s are an average of at least two independent titrations.

5694
Y. K. Ramtohul et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5692–5696
NC
N
S
NC
S
HN
O
CF3
N
N
O
CF3
a
b
+
S
NH2
HS
4
5
6
O
7
O
O
S
N
S
H2N
H2N
HN
c
N
O
CF3
N
O
CF3
N
N
8
2b
N
d
N
N
HN
O
F
Br
N
O
Br
+
N
N
N
H
N
Cl
N
N
H
9
3b
10
F
N
S
N
N
N
H2N
e
N
O
F
Br
N
+
10
Cl
S
H2N
11
3c
Scheme 1. Reagents and conditions: (a) EtOH,
D
, quant.; (b) NEt3, ammonia, MeOH, rt, 61–80%; (c) trimethylorthoformate, p-TSA,
D
, 80%; (d) NEt3, 2-methoxyethanol/H2O or
EtOH,
D
, 46%; (e) NEt3, DMF, D, 64–70%.
ter followed by a Mitsunobu reaction with 2-bromo-5-fluorophe-
nol and a subsequent hydrolysis of the methyl ester afforded the
desired compound 16a. Conversion of the amino group of 3c to
the corresponding bromide 17 was achieved by treatment with
tert-butyl nitrite and copper(II) bromide. Displacement of bromide
17 with ethyl glycolate in the presence of sodium hydride followed
by hydrolysis of the ethyl ester afforded the desired glycolate ana-
log 16b. Reaction of pyrimidine 1823 with ethyl isothiocyanatoac-
etate 19 produced the thiazolo pyrimidine analog 20 which upon
reaction with piperidine ether 10 followed by ester hydrolysis fur-
nished the desired amino acetic acid analog 16c.
As shown in Table 2, in contrast to compound 16a, the carbox-
ylic acid analogs 16b and 16c maintain good enzymatic potency
against the rat SCD1 enzyme. In addition to the human HepG2
whole cell assay which lacks the OATP transporters, the com-
pounds were also tested in a rat hepatocyte whole cell assay (rat
Hep.) where the OATP transporters are present. These three assays
can be used in parallel to qualitatively determine if a compound is
actively transported in the hepatocyte cells via the OATP transport-
ers. For instance, compound 16a demonstrates poor hHepG2 activ-
ity (IC50 = 24,345 nM, 91-fold shift vs enzymatic assay) indicating
that this compound has a low passive diffusion rate across the cell
membrane and therefore cannot effectively penetrate the cells to
inhibit the SCD1 enzyme. This was further confirmed by determin-
ing its diffusion rate across LLC-PK1 monolayer cells which gave an
apparent permeability, Papp of 2 Â 10À6 cm/s, showing its poor cell
permeability. Interestingly, the same compound is more potent in
the rat hepatocyte assay (IC50 = 168 nM, 145-fold shift vs hHepG2
assay) indicating that it is actively transported by OATPs into the
hepatocyte cells. Conversely, compounds 16b and 16c are less
shifted in the hHepG2 (7- to 42-fold shift vs enzymatic assay) indi-
cating that their rate of passive diffusion inside the whole cell is
likely higher compared to 16a and the observation that they are
not more potent in the rat hepatocyte (61-fold shift vs hHepG2 as-
say) indicate that these compounds are not efficiently transported
into hepatocyte cells.
X
0.8
30
25
20
15
10
5
2c
2j
X
.1
1
X
3.6
4X
4.
X
7
A
N
0
Figure 2. Tissue distribution of compounds 2c and 2j, 6 h post oral dosing at 10 mg/
kg (0.5% methocel vehicle) in C57BL6 mice fed on a normal chow diet. The fold of
liver/tissue selectivity is shown. Adipose tissue level for 2c was not determined
(NA–not available).
adverse effects.11f With this in mind, we sought to convert the sys-
temic SCD1 inhibitors as defined by core structures 2c and 3c into
liver-targeting inhibitors. The strategy we employed is to attach a
carboxylic acid moiety onto compounds 2c and 3c, which is known
to be recognized and actively transported by the organic anion
transporting polypeptides (OATPs). The OATPs are transporters
that are highly expressed in the liver but not in the off-target tis-
sues where adverse events were observed. Therefore, by making
use of the OATPs transporters, a preferential distribution of the
SCD1 inhibitors to the liver is favored over the undesired periphe-
ral tissues.21
Tissue distribution of compounds 16a–c was obtained 6 h post
oral dosing at 10 mg/kg in C57BL6 mice. As shown in Figure 3,
incorporation of a carboxylic acid moiety on these bicyclic cores
led to a considerable reduction (ꢀ25–60Â) in the liver drug expo-
sures as compared to the systemically distributed inhibitors
(Fig. 2). Interestingly, all three compounds showed a preferential
distribution in the liver over the peripheral adipose, skin tissues
The synthesis of compounds 16a–c is described in Scheme 2.22
The aminothiazole amide 14 was obtained via a similar reaction
pathway as described in Scheme 1, starting from N-cyano-dithioi-
minocarbonate 4 and 4-piperidinol (12). Reaction of thiazole amide
14 with 4-chloro-oxobutanoate in dimethyl succinate afforded the
cyclized bicyclic ester 15. Selective hydrolysis of the piperidinol es-

Y. K. Ramtohul et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5692–5696
5695
O
NC
S
NC
N
S
S
N
H2N
H2N
N
a
+
HN
OH
N
OH
b
N
OH
S
NH2
HS
14
4
12
13
O
O
7
O
O
N
S
N
d, e, f
c
S
N
HN
HN
N
O
N
O
F
Br
MeO
HO
O
N
O
15
16a
MeO2C
N
N
N
N
O
F
Br
g
N
O
Br
N
h, i
N
3c
N
HO
S
O
S
Br
17
16b
O
F
N
H2N
Cl
EtO2C
N
S
j
k, l
N
N
N
O
F
Br
N
+
EtO
C
HN
N
N
HO
S
N
Cl
N
Cl
S
N
O
H
18
20
19
O
16c
Scheme 2. Reagents and conditions: (a) EtOH,
D
, quant.; (b) NEt3, ammonia, MeOH, rt, 62–80% ;(c) 4-chloro-oxobutanoate, dimethyl succinate,
D
, 30–51%; (d) NaOMe
(1.1 equiv), MeOH, rt; (e) DEAD, PPh3, 2-bromo-5-fluorophenol, THF, rt; (f) LiOH, THF/MeOH, 7-11% over three steps; (g) CuBr2, t-BuONO, CH3CN,
D
, 54–61%; (h) ethyl
glycolate, NaH, DMF rt; (i) NaOH, THF/MeOH, 47% over two steps; (j) neat,
D
, used crude; (k) 10, NEt3, 2-methoxyethanol,
D
; (l) NaOH, THF/MeOH, 22% over two steps.
Table 2
Incorporation of carboxylic acid in the bicyclic analogs
N
O
F
Br
HetAr
16
Compound
HetAr
Rat SCD
IC50 (nM)
hHepG2
IC50 (nM)
Rat Hep.
IC50 (nM)
Fold Shift Rat Hep. versus hHepG2
a
a
a
O
N
S
N
HN
16a
266
24,345
168
145
HO
O
N
N
O
HO
O
O
16b
16c
7
4
53
348
158
<1
1
S
N
N
N
S
N
HN
168
HO
a
IC50s are an average of at least two independent titrations.
and Harderian glands, although only 16a was predicted to have a
liver-targeting property based on the high rat Hep. versus hHepG2
shift. However, compounds 16b and 16c which presumably have a
higher passive diffusion rate (qualitatively based on the 61-fold
shift of rat hepatocyte assay vs hHepG2) did indeed accumulate
more drugs in the Harderian glands compared to 16a where the
Harderian gland concentrations were undetectable. Compounds
16a and 16c having acceptable liver to Harderian gland selectivity
were chosen for further in vivo profiling.
The in vivo potencies of 16a and 16c were assessed in a mouse li-
ver PD assay. The compounds were dosed orally in mice fed on a high
carbohydrate diet and after 3 h the SCD1 activity was determined by
measuring the conversion of intravenously administered [1-14C]-
stearic acid tracer to the SCD-derived [1-14C]-oleic acid in liver lip-
ids. Due to the lower liver level of 16a compared to 16c, 16a was
administered at a higher dose of 60 mg/kg versus 30 mg/kg for
16c. As illustrated in Figure 4, 16c gave a robust 72% reduction of li-
ver SCD1 activity desaturation index (ratio of 14C-oleic acid/14C-
stearic acid), however to our surprise compound 16a did not show
any SCD1 inhibition. Although the liver level of 16a (3.3 lM) was
well above its rat hepatocyte whole cell potency (IC50 = 168 nM),
the lack of in vivo efficacy with 16a remains unclear at this time.24
However, based on our experience with other liver-targeting SCD1
inhibitors, we observed that compounds with rat hepatocyte whole
cell IC50 >200 nM and hHepG2 IC50 >15
lM are generally not active
in themouse liver PD assay. The high hHepG2potency (IC50 ꢀ24
l
M)
of compound16a might have been a contributingfactorto the lack of
efficacy. It seems that a fine balance between the rat hepatocyte and

5696
Y. K. Ramtohul et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5692–5696
References and notes
0.8
0.6
0.4
0.2
0.0
1. Dobrzyn, A.; Ntambi, J. M. Prostaglandins Leukot. Essent. Fatty Acids 2005, 73, 35.
2. Dobrzyn, A.; Ntambi, J. M. Obesity Rev. 2005, 6, 169.
16a
16b
16c
3. (a) Miyazaki, M.; Kim, Y.-C.; Gray-Keller, M. P.; Attie, A. D. J. Biol. Chem. 2000,
275, 30132; (b) Miyazaki, M.; Man, W. C.; Ntambi, J. M. J. Nutr. 2001, 131, 2260.
4. Ntambi, J. M.; Miyazaki, M.; Stoehr, J. P.; Lan, H.; Kendziorski, C. M.; Yandell, B.
S.; Song, Y.; Cohn, P.; Friedman, J. M.; Attie, A. D. Proc. Natl. Acad. Sci. U.S.A. 2002,
99, 11482.
5. (a) Jiang, G.; Li, Z.; Liu, F.; Ellsworth, K.; Dallas-Yang, Q.; Wu, M.; Ronan, J.; Esau,
C.; Murphy, C.; Szalkowski, D.; Bergeron, R.; Doebber, T.; Zhang, B. B. J. Clin.
Invest. 2005, 115, 1030; (b) Gutierrez-Juarez, R.; Pocai, A.; Mulas, C.; Ono, H.;
Bhanot, S.; Monia, B. P.; Rossetti, L. J. Clin. Invest. 2006, 116, 1686.
6. Attie, A. D.; Krauss, R. M.; Gray-Keller, M. P.; Brownlie, A.; Miyazaki, M.;
Kastelein, J. J.; Lusis, A. J.; Stalenhoef, A. F.; Stoehr, J. P.; Hayden, M. R.; Ntambi,
J. M. J. Lipid Res. 2002, 43, 1899.
7. Hulver, M. W.; Berggren, J. R.; Carper, M. J.; Miyazaki, M.; Ntambi, J. M.;
Hoffman, E. P.; Thyfault, J. P.; Stevens, R.; Dohm, G. L.; Houmard, J. A.; Muoio, D.
M. Cell Metab. 2005, 2, 251.
8. Enoch, H. G.; Catala, A.; Strittmatter, P. J. Biol. Chem. 1976, 251, 5095.
9. Ntambi, J. M. Prog. Lipid Res. 1995, 34, 139.
3X
21X
X
2X
2
D
31X
41X
73X
403
145X
N
1
10. Nakamura, M. T.; Nara, T. Y. Annu. Rev. Nutr. 2004, 24, 345.
11. (a) Li, C. S.; Belair, L.; Guay, J.; Murgasva, R.; Sturkenboom, W.; Ramtohul, Y. K.;
Zhang, L.; Huang, Z. Bioorg. Med. Chem. Lett. 2009, 19, 5214; (b) Ramtohul, Y. K.;
Black, C.; Chan, C.-C.; Crane, S.; Guay, J.; Guiral, S.; Huang, Z.; Oballa, R.; Xu, L.-
J.; Zhang, L.; Li, C. S. Bioorg. Med. Chem. Lett. 2010, 20, 1593; (c) Leger, S.; Black,
C.; Deschenes, D.; Dolman, S.; Falgueyret, J.-P.; Gagnon, M.; Guiral, S.; Huang,
Z.; Guay, J.; Leblanc, Y.; Li, C.-S.; Masse, F.; Oballa, R.; Zhang, L. Bioorg. Med.
Chem. Lett. 2010, 20, 499; (d) Powell, D. A.; Ramtohul, Y.; Lebrun, M. E.; Oballa,
R.; Bhat, S.; Falgueyret, J. P.; Guiral, S.; Huang, Z.; Skorey, K.; Tawa, P.; Zhang, L.
Bioorg. Med. Chem. Lett 2010, 20, 6366; (e) Isabel, E.; Powell, D. A.; Black, W. C.;
Chan, C. C.; Crane, S.; Gordon, R.; Guay, J.; Guiral, S.; Huang, Z.; Robichaud, J.;
Skorey, K.; Tawa, P.; Xu, L.; Zhang, L.; Oballa, R. Bioorg. Med. Chem. Lett. 2011,
21, 479; (f) Oballa, R. M.; Belair, L.; Black, C.; Bleasby, K.; Chan, C. C.; Desroches,
C.; Du, X.; Gordon, R.; Guay, J.; Guiral, S.; Hafey, M. J.; Hamelin, E.; Huang, Z.;
Kennedy, B.; Lachance, N.; Landry, F.; Li, C. S.; Mancini, J.; Normandin, D.; Pocai,
A.; Powell, D.; Ramtohul, Y.; Skorey, K.; Sturkenboom, W.; Styhler, A.;
Waddleton, D.; Wang, H.; Wong, S.; Xu, L.; Zhang, L. J. Med. Chem. 2011, 54,
5082.
Figure 3. Tissue distribution of compounds 16a, 16b, and 16c, 6 h post oral dosing
at 10 mg/kg (0.5% methocel vehicle) in C57BL6 mice fed on normal chow diet. The
fold of liver/tissue selectivity is shown. ND–not detected.
No inh.
[Liver] = 3.3 µM
[Plasma] = 0.2 µM
1.0
0.8
12. Xin, Z.; Zhao, H.; Serby, M. D.; Liu, B.; Liu, M.; Szczepankiewicz, B. G.; Nelson, L.
T.; Smith, H. T.; Suhar, T. S.; Janis, R. S.; Cao, N.; Camp, H. S.; Collins, C. A.; Sham,
H. L.; Surowy, T. K.; Liu, G. Bioorg. Med. Chem. Lett. 2008, 18, 4298. and
references therein.
13. (a) Winther, M. D. 2nd Annual Drug Development for Diabetes and Obesity,
London, UK, 2008, Jan 17–18; (b) Atkinson, K. A.; Beretta, E. E.; Brown, J. A.;
Castrodad, M.; Chen, Y.; Cosgrove, J. M.; Du, P.; Litchfield, J.; Makowski, M.;
Martin, K.; McLellan, T. J.; Neagu, C.; Perry, D. A.; Piotrowski, D. W.; Steppan, C.
M.; Trilles, R. Bioorg. Med. Chem. Lett. 2011, 21, 1621.
14. Koltun, D. O.; Vasilevich, N. I.; Parkhill, E. Q.; Glushkov, A. I.; Zilbershtein, T. M.;
Mayboroda, E. I.; Boze, M. A.; Cole, A. G.; Henderson, I.; Zautke, N. A.; Brunn, S.
A.; Chu, N.; Hao, J.; Mollova, N.; Leung, K.; Chisholm, J. W.; Zablocki, J. Bioorg.
Med. Chem. Lett. 2009, 19, 3050. and references therein.
0.6
72% inh.
P<0.001
[Liver] = 4.1 µM
[Plasma] = 0.2 µM
0.4
0.2
0.0
15. Uto, Y.; Kiyotsuka, Y.; Ueno, Y.; Miyazawa, Y.; Kurata, H.; Ogata, T.; Deguchi, T.;
Yamada, M.; Watanabe, N.; Konishi, M.; Kurikawa, N.; Takagi, T.; Wakimoto, S.;
Kono, K.; Ohsumi, J. Bioorg. Med. Chem. Lett. 2010, 20, 746. and references
therein.
16. Five initial applications from Xenon (WO2005/011653 to WO 2005/011657)
were published on February 10, 2005. Representative one: Abreo, M.; Chafeev,
M.; Chakka, N.; Chowdhury, S.; Fu, J. -M.; Gschwend, H. W.; Holladay, M. W.;
Hou, D.; Kamboj, R.; Kodumuru, V.; Li, W.; Liu, S.; Raina, V.; Sun, S.; Sviridov, S.;
Winther, M. D.; Zhang, Z. WO2005/011655.
17. For detailed experimental procedures, see: (a) Crane, S. N.; Robichaud, J. S.;
Leger, S.; Ramtohul, Y. K. WO2007/056846; (b) Ramtohul, Y. K. WO2008/
017161.
Figure 4. In vivo SCD1 inhibition of 16a and 16c dosed orally (0.5% methocel
vehicle) in C57BL6 mice fed on a high carbohydrate diet. 14C-stearic acid in 60%
aqueous PEG 200 was administered intravenously at 1 h later and livers were
harvested at 2 h post tracer-dosing. The SCD1 activity index [ratio of 14C-oleic acid
(OA)/14C-stearic acid (SA) in hydrolyzed liver lipids] were measured (n = 5/group).
18. Golec, J. M. C.; Scrowston, R. M. J. Chem. Res. Miniprint. 1988, 1, 326.
19. For Rat microsomal assay conditions, see Li, C. S.; Ramtohul, Y.; Huang, Z.;
Lachance, N. WO2006/130986.
20. Zhang, L.; Ramtohul, Y.; Gagné, S.; Styhler, A.; Guay, J.; Huang, Z. J. Biomol.
Screen. 2010, 15, 169.
21. For a review on OATPs, see: Niemi, M. Pharmacogenomics 2007, 8, 787.
22. For detailed experimental procedures, see (a) Leger, S.; Deschenes, D.; Fortin,
R.; Isabel, E.; Powell, D. WO2008/141455; (b) Ramtohul, Y. K.; Li, C. S.; Leclerc, J.
-P. WO2009/012573.
23. Takahshi, T.; Naito, T.; Inoue, S. Chem. Pharm. Bull. 1958, 6, 334.
24. Plasma protein binding (PPB) for inhibitor 16a was not measured and PPB is
not likely a major contributing factor to the lack of its in vivo efficacy since a
related liver targeting SCD1 inhibitor, MK-8245, containing a carboxylic acid
moiety has very high PPB (>99% in several species) and yet is very efficacious in
the mouse liver PD assay, Ref. 11f In addition, the rat hepatocyte assay was
performed in the presence 10% fetal bovine serum and compound 16a
displayed good whole cell activity.
the hHepG2 whole cell potencies are required for in vivo efficacy in
the mouse liver PD assay.
In summary, we have identified a number of potent systemic
bicyclic heteroaryl SCD1 inhibitors from modification of an initial
lead inhibitor, MF-152.11a Representative systemically-distributed
SCD1 inhibitors were converted into liver-targeting SCD1
inhibitors by incorporation of carboxylic acid functionalities which
have previously been shown to be recognized by the liver OATP
transporters.11f The liver-targeting inhibitor 16c demonstrated a
robust 72% reduction of liver SCD1 activity index in C57BL6 mice.
Further studies are underway to identify more potent bicyclic het-
eroaryl liver-targeting SCD1 inhibitors with good in vivo efficacy.