Nicotinic acids: Liver-targeted SCD inhibitors with preclinical anti-diabetic efficacy

Article abstract of DOI:10.1016/j.bmcl.2011.10.040

An in vitro screening protocol was used to transform a systemically- distributed SCD inhibitor into a liver-targeted compound. Incorporation of a key nicotinic acid moiety enables molecular recognition by OATP transporters, as demonstrated by uptake studi

Full text of DOI:10.1016/j.bmcl.2011.10.040

Bioorganic & Medicinal Chemistry Letters 21 (2011) 7281–7286
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Nicotinic acids: Liver-targeted SCD inhibitors with preclinical
anti-diabetic efficacy
David A. Powell a, , W. Cameron Black a, Kelly Bleasby b, Chi-Chung Chan a, Denis Deschenes a,
⇑
Marc Gagnon a, Rob Gordon a, Jocelyne Guay a, Sebastien Guiral a, Michael J. Hafey b, Zheng Huang a,
Elise Isabel a, Yves Leblanc a, Angela Styhler a, Li-Jing Xu a, Lei Zhang a, Renata M. Oballa a
a Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Québec, Canada H9H 3L1
b Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065-0900, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An in vitro screening protocol was used to transform a systemically-distributed SCD inhibitor into a liver-
targeted compound. Incorporation of a key nicotinic acid moiety enables molecular recognition by OATP
transporters, as demonstrated by uptake studies in transfected cell lines, and likely serves as a critical
component of the observed liver-targeted tissue distribution profile. Preclinical anti-diabetic oGTT effi-
cacy is demonstrated with nicotinic acid-based, liver-targeting SCD inhibitor 10, and studies with a
close-structural analog devoid of SCD1 activity, suggest this efficacy is a result of on-target activity.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 20 September 2011
Revised 11 October 2011
Accepted 11 October 2011
Available online 18 October 2011
Keywords:
Stearoyl coenzyme A
SCD
Liver-targeted
OATP
Nicotinic acid
Variances in biochemical pathways that regulate fatty acid
synthesis (lipogenesis) are associated with the development of
metabolic disorders including obesity and diabetes.1 Stearoyl coen-
zyme-A desaturase (SCD) represents one-such critical enzyme
involved in lipid metabolism.2 It is responsible for the conversion
of saturated fatty ester-CoAs to monounsaturated lipid products,
such as palmitoleoyl-CoA (C16:1) and oleoyl-CoA (C18:1). Human
studies have correlated SCD over-activity to higher plasma triglyc-
eride levels,3 VLDL,4 body mass index and insulin concentrations.5
In addition, rodents deficient in SCD, either as a result of gene dele-
tion,6 antisense oligonucleotide (ASO) treatment7 or pharmacolog-
ical inhibition8,9 are resistance to diet-induced weight gain, have
an improved lipid profile and increased insulin sensitivity.
Unfortunately, in addition to the beneficial metabolic effects ob-
served upon SCD inhibition, chronic preclinical treatment can lead
to skin and eye aberrations.8a,c,10,11 These adverse events have been
linked to mechanism-based depletion of essential lubricating lipids
within these tissues.
organ where the SCD1 enzyme is most highly expressed,2a the
Merck Frosst team embarked on a program to design a liver-
targeted, small-molecule SCD inhibitor. These efforts were recently
disseminated with the disclosure of the liver-targeted SCD inhibi-
tor MK-8245.9 Gratifyingly, MK-8245 demonstrates preclinical
anti-diabetic and liver-lipid efficacy in the absence of skin or eye
adverse events in chronic dosing studies.
The strategy employed in the design of MK-8245 centers on
increasing transport13 into hepatocyte via molecular recognition
by liver-specific organic anion transporting polypeptides
(OATPs).14 A second critical component is to minimize exposures
in off-target tissues and cells associated with adverse events (skin
and eye) by decreasing the extent of passive cell diffusion. In gen-
eral, carboxylic acids are preferred substrates for OATPs, however,
only a few known acid containing molecules have been confirmed
as demonstrating OATP-mediated transport.15 The key structural
element present in MK-8245 which imparts OATP transport is a
tetrazole acetic acid moiety. Herein we describe the use of a similar
liver-targeting strategy which employs a differential and unique
OATP recognition moiety, a nicotinic acid.16 Furthermore, we dem-
onstrate that the preclinical anti-diabetic efficacy observed with
nicotinic acid-based, liver-targeting SCD inhibitors is likely a result
of on-target activity as supported by studies with a close-structural
analog devoid of SCD1 activity.
A paramount challenge in the development of SCD inhibitors for
therapeutic application in humans12 is the attainment of efficacy
without adversely affecting skin and eye function. Recognizing that
de novo lipogenesis occurs primarily in the liver and the liver is the
⇑
Beginning from the previously-described lead compound
Corresponding author. Tel.: +1 215 652 5902.
E-mail address: david_powell2@merck.com (D.A. Powell).
MF-438,10 acidic moieties were introduced onto the molecule with
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.10.040

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D. A. Powell et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7281–7286
maintain SCD1 potency
1.209
2 hours
6 hours
24 hours
Me
(rat SCD1 enzyme assay)
S
N
Add Acidic
Moieties
Plasma
Left Median Liver Lobe
Kidney
0.626
N
O
CF3
reduce passive cellular penetration
N
N
N
0.005
0.032
0.029
(human hepG2 cellular assay)
MF-438
rat SCD1 enz IC50 = 3 nM
increase active transport
4.387
(rat hepatocyte cellular assay)
eDIO mouse oGTT ED50 ≈ 3 mg/kg
5.200
Systemic Tissue Distribution
Liver-targeted Tissue Distribution
6.137
O
O
HO
1.915
N
O
CF3
N
O
CF3
HO
N N
N
N
1
2
0.389
rat SCD1 IC50 > 10,000 nM
rat SCD1 IC50 = 2,680 nM
Harderian glands
0.098
0.005
O
HO
O
N
O
CF3
N
O
CF3
0.170
N
N
HO
N N
3
4
Skin (Shaved) 0.055
rat SCD1 IC50 = 107 nM
hepG2 IC50 = 1113 nM
rat SCD1 IC50 = 105 nM
hepG2 IC50 = 550 nM
0.012
O
0.106
HO
Left Epididymal Fat
0.111
0.045
N
O
CF3
N
N N
5
0.177
rat SCD1 IC50 = 129 nM
hepG2 IC50 > 20,000 nM
Heart
0.333
rat hepatocycte IC50 = 1,300 nM
0.032
Scheme 1. Acid-containing SCD1 inhibitors.
0.010
Brain + cerebellum 0.017
0.005
Table 1
SCD activity of aryl ether-substituted nicotinic acid derivatives
0.000
1.000
2.000
3.000
4.000
5.000
6.000
7.000
Concentration (uM)
Figure 1. Tissue-distribution profile of compound 10 in C57/BL6 mice. Compound
10 was administered orally in 1% Methocel (30 mg/kg, 10 mL/kg) and 2, 6 or 24 h
post dose, mice were sacrificed, tissues were harvested and drug concentrations
were determined by LC–MS analysis using an internal standard, n = 3 mice per time
point.
Compound Aryl ether Enzyme IC50 rat SCD1 (nM)
Cellular IC50
HepG2 Rat hep.
5
6
7
8
129
166
47
>20,000 1300
>10,000 1894
18,259
5080
1644
1000
27
9
15
8264
563
10
11
15
6030
—
175
—
>20,000
IC50s are an average of at least two titrations.
Scheme 2. Synthesis of nicotinic acid compound 10.
the goal of enabling recognition by OATPs (Scheme 1). While highly
potent, MF-438 displays a nonselective (systemic) tissue distribu-
tion profile with no therapeutic margin in preclinical studies.
Introduction of a carboxylic acid moiety directly onto the 6-posi-
tion of the pyridazine ring afforded compound 1 which is devoid
of SCD1 activity. While the corresponding one-carbon homolog 2
does display weak activity against the rat SCD1 enzyme, improved
potency was observed with the benzoic acid derivatives 3 and 4.
These benzoic acid derivatives however, remain highly potent in
the human hepG2 whole cell assay.17 We felt the extent of passive
cellular penetration observed with these compounds was greater
than desired and looked for ways to further increase the polarity
of the molecule to reduce passive cellular penetration. Introduction
of a nitrogen atom onto the benzoic acid moiety afforded the

D. A. Powell et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7281–7286
7283
Table 2
SCD activity and liver-targeting of heterocyclic carboxylate derivatives
a
Compound
Structure
Enzyme IC50 rat SCD1 (nM)
Cellular IC50
Rat hep.
Liver:Hard, ratiob
HepG2
6030
F
O
HO
10
12
13
11
15
15
772
175
—
15:1
—
N
O
F
Br
N
N
N
O
HO
—
N
N
N
O
Br
N
N
N
N
N
N
N
HN
N
11,018
—
—
—
O
CF3
N
F
8
128
780
159
75
—
O
N
N
O
F
Br
Br
HO
N
N
N
N
N
O
20
4:1
HO
O
N
a
IC50s are an average of at least two titrations.
PO dosing at 10 mg/kg in 0.5–1% Methocel in mice, 6 h post-dose (n = 3).
b
Table 3
SCD activity and liver-targeting of central heterocyclic core derivatives
Liver:Hard, ratiob
a
Compound
Structure
Enzyme IC50 rat SCD1 (nM)
Cellular IC50
HepG2
6030
Rat hep.
F
O
HO
10
16
17
18
19
15
77
175
15:1
8:1
12:1
3:1
—
N
N
N
N
N
O
F
Br
Br
Br
Br
Br
N
N
N
O
HO
9422
6715
2412
—
3047
1363
1926
—
N
N
O
F
N
O
HO
69
N
O
F
N
N
N
O
HO
24
O
F
N
O
HO
1221
O
F
N
N
N
O
HO
20
21
20
4466
—
268
1.5:1
—
N
N
N
N
O
O
Br
N
O
HO
8444
—
CF3
N
a
IC50s are an average of at least two titrations.
PO dosing at 10 mg/kg in 0.5–1% Methocel in mice, 6 h post-dose (n = 3).
b
nicotinic acid compound 5, which displays adequate potency
against the rat SCD1 enzyme, is suitably shifted in the hepG2
cellular assay but regains potency in a cellular assay which
contains active OATPs (rat hepatocyte assay).18

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D. A. Powell et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7281–7286
Kidneys are known to express a variety of transporters, including
OATPs.14
100
75
50
25
0
Control
The synthesis of nicotinic acid 10 is outlined in Scheme 2. Key
+ 100μM BSP
(inhibitor of OATP)
steps include a Suzuki–Miyaura cross-coupling21 to install the nic-
otinic acid moiety onto the central pyridazine core and a Mitsun-
obu reaction22 for the attachment of the aryl ether. Other related
analogs described in this manuscript were synthesized using a
similar route.
We next explored modifications to the nicotinic acid moiety and
central heterocyclic core with the aim of improving the SCD1
potency (particularly the cellular potency in rat hepatocytes) and
further increase the liver:Harderian gland ratio in mice. Various
pyridinyl carboxylate derivatives were examined for their effects
on SCD1 potency and liver-targeting (Table 2). These studies re-
vealed nicotinic acid analog 10 to be unique among the heterocyclic
carboxylates examined; other derivatives afforded compounds with
reduced SCD1 potency (12–13) or diminished hepG2:hepatocyte
ratio (14–15). While reasonably potent, compound 14 was not
further profiled due to the similar hepG2 and rat hepatocyte cell
activity.23 Pyridyl acetic acid compound 15 exhibited a reduced
liver:Harderian gland ratio (4:1) as compared to nicotinic acid 10
(15:1). The diminished liver-targeting of compound 15 may be a
function of the reduced hepG2:hepatocyte ratio (10:1) observed in
comparison to 10 (34:1).
MDCKII OATP1B1 OATP1B3 Oatp1b2
Figure 2. Cellular uptake of compound 10 into MDCKII cells and MDCKII cells
stably-transfected with human OATP1B1, human OATP1B3 or rat Oatp1b2. Uptake
of compound 10 was reduced in the presence of OATP inhibitor sulfobromophtha-
lein (BSP) (mean SEM, n = 3).
Table 4
Potencies of compound 10 against SCD enzymes
Compound
Enzyme IC50 (nM)
Mouse SCD1 Human SCD1
Rat SCD1
15
Human SCD5
4
10
9
7
Changes to the central heterocyclic core also resulted in signif-
icant changes to both the SCD1 potency and liver:Harderian gland
ratio (Table 3). A variety of six-membered heterocyclic derivatives
revealed the pivotal role of the heterocyclic nitrogen for SCD1
potency (compare 18 vs 19 or 21). For reasons not understood at
this time, compound 20, which satisfies our in vitro criteria for
the identification of liver-targeting compounds, exhibits a poor
liver:Harderian ratio in vivo. This example highlights the complex
SAR which governs liver-targeting. Despite further investigations,
nicotinic acid analog 10 remained the lead liver-targeting candi-
date within this series and was chosen for further profiling.
Uptake studies performed in MDCKII cell lines stably transfec-
ted with human OATP1B1, OATP1B3 and rat Oatp1b2, demon-
strated 10 to be a substrate of all three transporters (Fig. 2).24
Furthermore this uptake was inhibited in the presence of the
known OATP inhibitor sulfobromophthalein (BSP).25 These results
suggest molecular recognition by OATP transporters is likely
responsible for the uptake of 10 into hepatocytes and the
corresponding liver-targeted tissue distribution profile.
No differences in enzyme potencies were observed between
mouse, rat and human SCD isoforms,26 thereby enabling rodents
to serve as suitable species for pharmacological evaluation
(Table 4). The pharmacokinetics of 10 in mice and rats were ade-
quate; however, the low bioavailability27 and short half-life would
potentially necessitate the use of higher doses in efficacy studies
(Table 5).
Using previously described mouse models, nicotinic acid-based,
liver-targeting SCD inhibitor 10, was further examined in in vivo
target engagement and acute anti-diabetic efficacy studies
(Fig. 3). In addition, the inactive nicotinic acid analog 11 was tested
in these same models to ascertain on- versus off-target effects.
Compound 10 demonstrates dose-proportional inhibition of liver
SCD activity (Fig. 3a, mLPD) up to an oral dose of 100 mg/kg. In
IC50s are an average of at least two titrations.
Having identified an initial lead that satisfied the in vitro
criteria established earlier, we next set out to improve the intrinsic
potency of these nicotinic acid analogs. Based on previously
established structure–activity relationships (SARs)10,19 we first fo-
cused our attention on exploring aromatic ether analogs (Table 1).
Specifically, modifications at the 2-position of the aryl ether were
found to have a positive impact on potency, as demonstrated with
2-halogen derivatives 7 and 8. While the corresponding 2-iodo
analog 8 was more potent in the enzyme assay as compared to
the 2-bromo derivative 7, we favoured the bromo-compound due
to the increased hepG2:hepatocyte ratio (11:1 for 7 vs 5:1 for 8)
which may translate into an improved in vivo liver-targeting
profile. Further substitution with fluorine at the 5-position (9–
10), resulted in potency improvements in both the enzyme and
rat hepatocyte assays. Interestingly, addition of fluorine at the 4
and 6-position of the aromatic ring (11) affords a compound which
is essentially devoid of SCD activity.
Compound 10 displays potent activity against SCD1 in the
enzyme assay, reduced activity in hepG2 cells lacking functional
OATPs and improved potency in cells which contain active trans-
porters. When assessed for liver-targeting by means of a mouse tis-
sue-distribution profile in vivo, compound 10 exhibited higher
drug concentrations in the liver as compared to the other tissues
examined (Fig. 1). Most importantly, the liver:Harderian gland
ratio for compound 10 is 11:1 at 2 h and >50:1 at 6 h.20 We sought
compounds with a liver:Harderian gland ratio of >20:1 at 6 h as
MK-8245 fully inhibited liver SCD activity with minimal inhibition
in Harderian glands at this ratio (21:1 at 6 h in mice).9 Of note, the
kidney concentrations of 10 are similar to those found in the liver.
Table 5
Pharmacokinetics of compound 10
Species
F (%)
t1/2 (h)
AUCp
(l
MÁh)
CLp (mL/min/kg)
Vdss (L/kg)
C57/BL6 mousea
SD rata
8
43
0.4
1.4
0.3
17.8
81
8.6
1.12
0.41
Average values, n = 2.
a
Dose: 10 mg/kg po (1% Methocel); 2 mg/kg iv (60% PEG-200).

D. A. Powell et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7281–7286
7285
Figure 3. Acute in vivo target engagement in liver (mLPD) and glucose clearance tolerance test (oGTT) in mice upon oral dosing of compound 10 (a and b) or compound 11 (c
and d). mLPD assay (a and c): Male C57/Bl6 mice were fed a high sucrose/fat-free diet for 2 days to induce liver SCD activity. Compound was administered orally in 0.5%
Methocel at 7:00 am on day 3. The [1-14C]-stearic acid tracer (40
lCi/kg) was dosed via the 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). oGTT assay (b and d): Male C57/Bl6 mice were fed a
high fat diet (HFD) for at least 14 weeks and had an established obesity state before the study. Mice were fasted overnight for 16 h before being administered an oral dose of
compound in 0.5% Methocel. A glucose challenge was administered orally, 1 h post dosing of compound and blood glucose measurements were taken from mice periodically
for 2 h after glucose challenge (mean SEM, n = 10–15/group). HFD: high fat diet; ND: normal diet; veh: vehicle. The corresponding liver, plasma and whole blood
concentrations in mice at the termination of the experiment (3 h post-dose) are included.
addition, target-engagement in the liver parallels the dose-depen-
dant improvements observed in blood glucose clearance (Fig. 3b).28
In contrast, the structurally similar but SCD1-inactive analog 11
does not inhibit either liver SCD activity nor improve glucose clear-
ance at a dose of 100 mg/kg (Fig. 3c and d), despite achieving sim-
ilar exposures wherein robust efficacy is observed with compound
10. For both compounds, the whole blood exposures in the oGTT
experiment are within two fold of the plasma exposures observed
in the mLPD assay.
References and notes
1. (a) Merino, D. M.; Ma, D. W. L.; Mutch, D. M. Lipids Health Dis. 2010, 9, 63; (b)
Chavez, J. A.; Summers, S. A. Biochim. Biophys. Acta 2010, 1801, 252; (c) Brown, J.
M.; Rudel, L. L. Curr. Opin. Lipidol. 2010, 21, 192; (d) Kusunoki, J.; Kanatani, A.;
Moller, D. E. Endocrine 2006, 29, 91.
2. (a) Ntambi, J. M.; Miyazaki, M. Prog. Lipid Res. 2004, 43, 91; (b) Dobrzyn, A.;
Ntambi, J. M. Obes. Rev. 2005, 6, 169; (c) Enoch, H. G.; Catala, A.; Strittmatter, P.
J. Biol. Chem. 1976, 251, 5095.
3. Attie, A. D.; Krauss, R. M.; Gray-Keller, M. P.; Brownlie, A.; Miyazaki, M.;
Kastelein, J. J.; Lusis, A. J.; Stalenhoef, A. F. H.; Stoehr, J. P.; Hayden, M. R.;
Ntambi, J. M. J. Lipid Res. 2002, 43, 1899.
In conclusion, using our previously described in vitro screening
protocol, we have identified a liver-targeting, nicotinic acid-
derived SCD inhibitor (10) that is efficacious in improving glucose
clearance in a mouse model. Furthermore, studies with a structur-
ally-related, but SCD1-inactive inhibitor 11, demonstrate that the
anti-diabetic efficacy observed is most likely a result of on-target
inhibition. Unfortunately, the short half-life of compound 10 in ro-
dents precluded further chronic studies to confirm the preclinical
therapeutic index. Our studies also highlight the complex SAR that
governs liver-targeting; subtle structural variations in the acid
moiety or adjacent heterocycles can have a significant impact on
tissue-distribution profiles. Overall, the demonstrated molecular
recognition of the nicotinic acid and the confirmed liver-targeted
tissue distribution profile in mice serves to deepen the understand-
ing of known chemical entities for OATP-mediated transport and
liver-targeted delivery.
4. Peter, A.; Cegan, A.; Wagner, S.; Lehmann, R.; Stefan, N.; Königsrainer, A.;
Königsrainer, I.; Häring, H.-U.; Schleicher, E. Clin. Chem. 2009, 55, 2113.
5. 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. Metabol. 2005, 2, 251.
6. (a) 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.
2002, 99, 11482; (b) Miyazaki, M.; Kim, Y.-C.; Gray-Keller, M. P.; Attie, A. D.;
Ntambi, J. M. J. Biol. Chem. 2000, 275, 30132; (c) Cohen, P.; Miyazaki, M.; Socci,
N. D.; Hagge-Greenberg, A.; Liedtke, W.; Soukas, A. A.; Sharma, R.; Hudgins, L.
C.; Ntambi, J. M.; Friedman, J. M. Science 2002, 297, 240.
7. (a) Brown, J. M.; Chung, S.; Sawyer, J. K.; Degirolamo, C.; Alger, H. M.; Nguyen,
T.; Zhu, X.; Duong, M.-N.; Wibley, A. L.; Shah, R.; Davis, M. A.; Kelley, K.; Wilson,
M. D.; Kent, C.; Parks, J. S.; Rudel, L. L. Circulation 2008, 118, 1467; (b) Xu, H.;
Wilcox, D.; Nguyen, P.; Voorbach, M.; Smith, H.; Brodjian, S.; Suhar, T.; Reilly, R.
M.; Jacobsen, P. B.; Collins, C. A.; Landschulz, K.; Surowy, T. K. Front. Biosci.
2007, 12, 3781; (c) Gutiérrez-Juárez, R.; Pocai, A.; Mulas, C.; Ono, H.; Bhanot, S.;
Monia, B. P.; Rossetti, L. J. Clin. Invest. 2006, 116, 1686; (d) 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.
8. (a) Ramtohul, Y. K.; Powell, D.; Leclerc, J.-P.; Leger, S.; Oballa, R.; Black, C.;
Isabel, E.; Li, C.-S.; Crane, S.; Robichaud, J.; Guay, J.; Guiral, S.; Zhang, L.; Huang,
Z. Bioorg. Med. Chem. Lett. 2011, 21, 5692; (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; (c) Isabel,
E.; Powell, D. A.; Black, W. C.; Chan, C.-C.; Crane, S.; Gordon, R.; Guay, J.; Guiral,
Acknowledgments
We are thankful to the Merck Banyu diabetes and obesity pro-
ject teams, in particular Dr. Tomoyuki Ohe, who first drew our
attention to the use of nicotinic acids as liver-targeted moieties.

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S.; Huang, Z.; Robichaud, J.; Skorey, K.; Tawa, P.; Xu, L.; Zhang, L.; Oballa, R.
19. (a) Uto, Y.; Ueno, Y.; Kiyotsuka, Y.; Miyazawa, Y.; Kurata, H.; Ogata, T.; Yamada,
M.; Deguchi, T.; Konishi, M.; Takagi, T.; Wakimoto, S.; Ohsumi, J. Eur. J. Med.
Chem. 2010, 45, 4788; (b) 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; (c) Xin, Z.;
Zhao, H.; Serby, M. D.; Liu, B.; Liu, M.; Szczepankiewicz, B. G.; Nelson, L. T. J.;
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; (d) Liu, G.;
Lynch, J. K.; Freeman, J.; Liu, B.; Xin, Z.; Zhao, H.; Serby, M. D.; Kym, P. R.; Suhar,
T. S.; Smith, H. T.; Cao, N.; Yang, R.; Janis, R. S.; Krauser, J. A.; Cepa, S. P.; Beno, D.
W. A.; Sham, H. L.; Collins, C. A.; Surowy, T. K.; Camp, H. S. J. Med. Chem. 2007,
50, 3086.
20. The liver:Harderian gland ratio was used as a measure of the degree of liver-
targeting of a compound. For a more complete discussion, see Ref. 9
21. (a) Slagt, V. F.; de Vries, A. H. M.; de Vries, J. G.; Kellogg, R. M. Org. Process Res.
Dev. 2010, 14, 30; (b) Leblanc, Y.; Cérat, P. Synth. Commun. 2008, 38, 2775; (c)
Kudo, N.; Perseghini, M.; Fu, G. C. Angew. Chem. Int. Ed. 2006, 45, 1282.
22. For recent review articles on the Mitsunobu reaction, see: (a) Swamy, K. C. K.;
Kumar, N. N. B.; Balaraman, E.; Kumar, K. V. P. P. Chem. Rev. 2009, 109, 2551; (b)
But, T. Y. S.; Toy, P. H. Chem. Asian J. 2007, 2, 1340.
Bioorg. Med. Chem. Lett. 2011, 21, 479; (d) 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; (e) Issandou, M.; Bouillot, A.; Brusq, J.-
M.; Forest, M.-C.; Grillot, D.; Guillard, R.; Martin, S.; Michiels, C.; Sulpice, T.;
Daugan, A. Eur. J. Pharmacol. 2009, 618, 28; (f) 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; (g) Koltun, D. O.; Zilbershtein, T. M.; Migulin, V.
A.; Vasilevich, N. I.; Parkhill, E. Q.; Glushkov, A. I.; McGregor, M. J.; Brunn, S. A.;
Chu, N.; Hao, J.; Mollova, N.; Leung, K.; Chisholm, J. W.; Zablocki, J. Bioorg. Med.
Chem. Lett. 2009, 19, 4070.
9. Oballa, R. M.; Belair, L.; Black, W. 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. A.; Ramtohul, Y. K.; Skorey, K.; Sørensen, D.; Sturkenboom, W.;
Styhler, A.; Waddleton, D. M.; Wang, H.; Wong, S.; Xu, L.; Zhang, L. J. Med. Chem.
2011, 54, 5082.
10. Léger, S.; Black, C.; Deschenes, D.; Dolman, S.; Falgueyret, J.-P.; Gagnon, M.;
Guiral, S.; Huang, Z.; Guay, J.; Leblanc, Y.; Li, C.-S.; Massé, F.; Oballa, R.; Zhang,
L. Bioorg. Med. Chem. Lett. 2010, 20, 499.
11. In addition, skin and eye abnormalities have been documented in SCD1À/À
mice, see Ref. 6b and (a) Binczek, E.; Jenke, B.; Holz, B.; Günter, R. H.; Thevis,
M.; Stoffel, W. Biol. Chem. 2007, 388, 405; (b) Miyazaki, M.; Man, W. C.; Ntambi,
J. M. J. Nutr. 2001, 131, 2260.
23. As a tissue-distribution analysis was not conducted, we cannot conclusively
state that this compound would not display a liver-targeted tissue-distribution
profile. However, in our experience, most compounds which display a liver-
targeted profile have a hepG2:hepatocyte ratio which is >10:1.
24. Vectorial transport studies across doubly-transfected MDCK II cell monolayers
expressing both OATP1B1 or OATP1B3 and MRP2 on basal and apical
12. For reviews of small molecule SCD inhibitors, see: (a) Dobrzyn, P.; Dobrzyn, A.
Expert Opin. Ther. Patents 2010, 20, 849; (b) Liu, G. Curr. Top. Med. Chem. 2010,
10, 419; (c) Liu, G. Expert Opin. Ther. Patents 2009, 19, 1169.
13. (a) Shitara, Y.; Horie, T.; Sugiyama, Y. Eur. J. Pharm. Sci. 2006, 27, 425; (b) Ho, R.
H.; Kim, R. B. Clin. Pharmacol. Ther. 2005, 78, 260.
membranes demonstrate compound 10 is a substrate of MRP2 efflux
proteins (data not shown).
14. (a) Fahrmayr, C.; Fromm, M. F.; König, J. Drug. Metab. Rev. 2010, 42, 380; (b)
Smith, N. F.; Figg, W. D.; Sparreboom, A. Expert Opin. Drug Metab. Toxicol. 2005,
1, 429.
15. For a list of compounds which are substrates of OATPs, see Ref. 14
16. Recently, nicotinic acid (niacin) has been shown to be actively transported into
human liver cells, see: Said, H. M.; Nabokina, S. M.; Balamurugan, K.;
Mohammed, Z. M.; Urbina, C.; Kashyap, M. L. Am. J. Physiol. Cell Physiol. 2007,
293, C1773. and references within.
17. Zhang, L.; Ramtohul, Y.; Gagné, S.; Styler, A.; Wang, H.; Guay, J.; Huang, Z. J.
Biomol. Screen. 2010, 15, 169.
18. Conditions which describe the fresh rat hepatocyte assay can be found in Ref. 9
A similar rat hepatocyte assay as the one utilized in this manuscript has
recently been described, see: Su, C.; Gullberg1, H.; Simko, H.; Luthman, M.;
Edlund, P.-O.; Lundbäck, T. J. Chromatogr. B 2010, 878, 2427.
25. Konig, J.; Cui, Y.; Nies, A. T.; Keppler, D. A. Am. J. Physiol. Gastrointest. Liver
Physiol. 2000, 278, G156.
26. For a brief description of the hSCD5 assay, see: 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.
27. The bioavailability of liver-targeted compounds is expected to be low; ideally,
the majority of compound absorbed is distributed to the liver with a smaller
fraction entering the circulatory system (F% = plasma bioavailablility).
28. Compound 10 also improved glucose clearance in eDIO mice following
intraperitoneal challenge of glucose (42% and 82% improvement in glucose
clearance at 30 and 100 mg/kg, respectively). This result suggests that the
improvement in glucose clearance upon oral administration of inhibitor 10 is
not due to effects on glucose absorption, see: Ling, R.; Yoshida, M.; Mariano, P.
S. J. Org. Chem. 1996, 61, 4439.