Novel, potent, selective, and metabolically stable stearoyl-CoA desaturase (SCD) inhibitors

Article abstract of DOI:10.1016/j.bmcl.2009.02.019

We identified a series of structurally novel SCD (Δ9 desaturase) inhibitors via high-throughput screening and follow-up SAR studies. Modification of the central bicyclic scaffold has proven key to our potency optimization effort. The most potent analog (8

Full text of DOI:10.1016/j.bmcl.2009.02.019

Bioorganic & Medicinal Chemistry Letters 19 (2009) 2048–2052
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel, potent, selective, and metabolically stable stearoyl-CoA desaturase
(SCD) inhibitors
a
b
b
b
Dmitry O. Koltun a, , Eric Q. Parkhill , Natalya I. Vasilevich , Andrei I. Glushkov , Timur M. Zilbershtein ,
Alexei V. Ivanov b, Andrew G. Cole c, Ian Henderson c, Nathan A. Zautke d, Sandra A. Brunn d,
Nevena Mollova e, Kwan Leung e, Jeffrey W. Chisholm d, Jeff Zablocki a
*
a Department of Medicinal Chemistry, CV Therapeutics, Inc., Palo Alto, CA 94304, USA
b ASINEX Ltd., Moscow 123367, Russia
c Department of Chemistry, Ligand Pharmaceuticals, Inc., Cranbury, NJ 08512, USA
d Department of Pharmacological Sciences, CV Therapeutics, Inc., Palo Alto, CA 94304, USA
e Department of Pre-Clinical Development, CV Therapeutics, Inc., Palo Alto, CA 94304, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We identified a series of structurally novel SCD (D9 desaturase) inhibitors via high-throughput screening
Received 16 December 2008
Revised 31 January 2009
Accepted 3 February 2009
Available online 8 February 2009
and follow-up SAR studies. Modification of the central bicyclic scaffold has proven key to our potency
optimization effort. The most potent analog (8g) had IC50 value of 50 pM in a HEPG2 SCD assay and
has been shown to be metabolically stable and selective against
D5 and D6 desaturases.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Stearoyl CoA
Desaturase
SCD
HEPG2 assay
Microsomal assay
Pteridinone
Stearoyl-CoA desaturases (SCD’s), also known as
D
9 fatty acid
more desirable. As a result the compounds described in this letter
were not designed to be SCD1 isoform selective, but rather to be
tested later for appropriate in vivo pharmacokinetics and
pharmacodynamics.
desaturases are microsomal enzymes that utilize CoA conjugates
of saturated long-chain fatty acids (primarily, stearic acid, and pal-
mitic acid) to introduce a cis-double bond in the C-9 and C-10 po-
sition. The reaction requires molecular O2 and NADH and generates
H2O in the process.1,2 Two isoforms (SCD1 and SCD5, also known as
SCD2) have been identified in humans. SCD1 is primarily found in
liver, adipose and skeletal muscle and is well characterized3 com-
pared to SCD2 which is found primarily in the brain.4 Deletion,
mutation or inhibition of SCD1 in mice and rats results in de-
creased hepatic triglycerides,5–9 resistance to weight gain and
improvements in insulin sensitivity and glucose uptake. Thus,
SCD inhibition may offer a new treatment for obesity, insulin resis-
tance, and diabetes.10–12
D
9 Desaturases are localized to the endoplasmic reticulum and
complexed with cytochrome b5 and cytochrome b5 reductase. This
feature is shared with 5 and 6 desaturases. Therefore, it is crit-
D
D
ical to focus the screening effort on small-molecule inhibitors that
act directly on SCD enzyme itself, and not on cytochrome b5 or
cytochrome b5 reductase. We chose to counterscreen lead mole-
cules against
paradigm.
D5 and D6 desaturases as a part of our discovery
Sterculic acid (1, Fig. 1)14 is a naturally occurring SCD inhibitor.
A large number of small-molecule SCD inhibitors have been pub-
lished to date (e.g., 2–4).15–17 The striking similarities among many
of reported structures underscore the narrow pharmacophoric
space of SCD inhibitors and the difficulty in generating a unique
IP position when using the literature leads.
The development of isoform-selective compounds may be chal-
lenging due to the high homology of SCD1 and SCD2. In addition,
SCD1 inhibition in peripheral tissues like skin and pancreas may
lead to side-effects.7,13 In light of these observations, the develop-
ment of tissue selective, non-brain penetrating compounds may be
We were keen on pursuing an independent approach to discover-
ing new structural series. Using a rat microsomal SCD assay derived
from the literature,14 we performed a screen of approximately 5.2
million unique and proprietary compounds. Initial hits were
* Corresponding author. Tel.: +1 650 384 8581; fax: +1 650 384 7559.
E-mail address: dmitry.koltun@cvt.com (D.O. Koltun).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.02.019

D. O. Koltun et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2048–2052
2049
O
CF3
two methylene units. A number of substituted benzylamines are
tolerated at R2 position, including 3,4-dichlorobenzyl and 3-(tri-
fluoromethyl)benzyl, but the NH is mandatory. Replacement of
the NH with O, S, and N-methyl all resulted in inactive compounds.
Finally, we screened a number of R3 substituents, relying mostly on
commercially available aryl-substituted ketoesters. We found that
the 3-pyridyl (5k, l), 4-chlorophenyl (5n), and 4-methylphenyl (5o)
were the only substituents that, in some cases, match the potency
of the 4-methoxyphenyl substituent. The majority of analogues of
5 did not present a significant improvement over the initial hit 5a.
In the HEPG2 SCD assay, two compounds (5j and 5o) showed sur-
prisingly high potency. Both 5j and 5o possess the combination of a
3-(trifluoromethyl)phenyl group in the R2 position and a CONH2
group (‘reverse amide’) in the R1 position.
N
N
H
N
5
5
Me
CO2 H
Me
N
1
N
Me
Cl
O
2
CF3
O
O
O
H
N
N
Me
N
H
N
N
H
N
O
H N
N
2
3
O
4
Figure 1. Structures of reported SCD Inhibitors.
Next, we turned our attention to the scaffold itself. We decided
to keep the rather unique pyrazin-2(1H)-one ring B of the pteridi-
none system intact and replace the pyrimidine ring A with the 5-
aza isomer of the pyridine ring, resulting in the alternative [6,6]-
bicyclic system 6 (Fig. 2). The synthesis of series 6 compounds
was similar to series 5, employing 2,6-dichloro-3-nitropyridine
(9; X = CH, Y = N) as a starting material (Scheme 1; Method A). At
first, we kept the acetamide and 4-methoxyphenyl moieties in
positions R1 and R3, respectively, and focused on exploring the
effect of the R2 substituent on inhibitory potency in the rat micro-
somal assay. The most interesting compounds were followed up on
in the HEPG2 SCD assay to confirm activity (Table 2).
As a general observation, series 6 presented an improvement
over series 5 for potency of SCD inhibition in both microsomal
and HEPG2 assays. Compound 6a displayed IC50 values of 220 nM
and 81 nM in the microsomal and HEPG2 SCD assays, respectively.
A number of R2 substituents have been tested and resulted in com-
pounds with superior activity relative to 5a in the HEPG2 SCD assay
including 3-chloro-4-fluorophenyl (6e, IC50 47 nM), 3-(trifluoro-
methyl)phenyl (6f, 47 nM), 3,5-bis-(trifluoromethyl)phenyl (6i,
IC50 51 nM), and 4-fluoro-3-(trifluoromethyl)phenyl (6j, IC50
16 nM). A clear trend points towards the preference for lipophilic,
halogenated substituents in the 3- and 4-positions on the aromatic
ring. Of those, the 3-position has a greater tolerance for steric bulk
and greater overall impact on potency in both the microsomal and
followed up using a cell-based HEPG2 SCD assay. We were not sur-
prised to see differences in IC50 values between rat microsomal
and human HEPG2 assays because of differences in species and the
potential for efficacious compounds in the microsomal assay to
not cross the cell membrane or conversely accumulate in the cell
as a result of active transport. We set out to find the compounds with
high inhibitory potency in both assays. We selected hit compounds
5a and 5b (Table 1, IC50 210 nM/410 nM and 2.8 lM/1.67 lM in rat
microsomal/HEPG2 SCD assays) for SAR follow-up. Synthesis of
compounds in series 5 was carried out in 4 steps, starting with com-
mercially available 2,4-dichloro-5-nitropyrimidine (9; X, Y = N;
Scheme 1; Method A). Initially, amination of 9 (X, Y = N) using a pri-
mary amine [R1(CH2)2–NH2] at room temperature allows regioselec-
tive nucleophilic displacement to be conducted at C-4 based on the
increased reactivity of the 4-chloro position. Further amination with
R2CH2–NH2 was conducted at 60 °C overnight to provide 10.18
Reduction of the nitro group was achieved by either a sodium dithi-
onate method or with Raney Nickel.19,20 Final reaction with an
a-
ketoester, followed by cyclization to the pteridinone incorporated
the R3 substituent.21
Through expansion of the SAR around series 5 (Table 1) we have
found that the R1 substituent must contain either an amide (pre-
ferred) or a sulfonamide group separated from the scaffold by
Table 1
Structure–activity relationships in pteridinone series 5
N
N
R3
O
N
R2
N
H
N
R1
Substituents
D9 IC50, nM
R1
R2
R3
Rat Mic. SCD
HEPG2 SCD
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
NHAc
3,4-Dichlorophenyl
3,4-Dichlorophenyl
3,4-Dichlorophenyl
3,4-Dichlorophenyl
3,4-Dichlorophenyl
3,4-Dichlorophenyl
3-Chlorophenyl
3-Fluoro-4-chlorophenyl
4-Fluoro-3-chlorophenyl
3-(Trifluoromethyl) phenyl
3,4-Dichlorophenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
3-Pyridyl
210
2800
2800
560
470
177
1300
900
750
145
270
410
1670
n.d.a
>30,000
4000
140
4600
n.d.
n.d.
5.6
250
36
92
NHSO2Me
NHCOEt
NHCOPh
NHCO-3-Thienyl
CONH2
NHAc
NHAc
NHAc
CONH2
NHAc
CONH2
CONH2
CONH2
CONH2
3,4-Dichlorophenyl
3-Pyridyl
3-Pyridyl
4-Chlorophenyl
4-Methylphenyl
513
1890
330
3-(Trifluoromethyl) phenyl
3-(Trifluoromethyl) phenyl
3-(Trifluoromethyl) phenyl
n.d.
9.6
134
A
Not determined.

2050
D. O. Koltun et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2048–2052
Method A
NO2
NO2
NH
N
N
R3
O
a, b
c or d, e
X
X
X
Cl
Y
Cl
R2
N
H
Y
R2
N
H
Y
9
10
R1
R1
5
X=N, Y=N
6a u x aa
- ,
-
X=CH, Y=N
7
X=N, Y=CH
Method B
OMe
OMe
N
N
N
F3C
F3C
f, g
N
H
N
N
O
O
N
H
N
O
11
6v w
,
OEt
O
NHR4
Method C
NO2
F
NO2
NH
N
N
R3
O
b, h
c or d, e
F
R2
N
H
R2
N
H
12
8a d
-
NHAc
R3
NHAc
Method D
NO2
F
N
N
N
R3
O
h, c, e
i
Br
Br
O
R2
N
H
N
13
8e i
-
NHAc
NHAc
Scheme 1. Reagents and conditions: (a) amine, (i-Pr)2NEt, THF, rt, 24 h; (b) amine, (i-Pr)2NEt, THF, 60 °C, 24 h; (c) NH2NH2ÁH2O, Raney Ni, MeOH, 60 °C, 24 h; (d) Na2S2O4,
Na2CO3, dioxane/water 1:1, 100 °C, 24 h; (e) ketoester, EtOH, 2% v/v AcOH, 80 °C, 24 h; (f) LiOHÁH2O, H2O/THF/MeOH, rt, 24 h; (g) amineÁHCl, EDCÁHCl, HOBt, (i-Pr)2NEt, CHCl3,
rt, 24 h; (h) amine, (i-Pr)2NEt, acetonitrile, reflux, 24 h; (i) amine, Pd2(dba)3, BINAP, NaOt-Bu, toluene, microwave, 120 °C, 10 min.
N
B
N
R3
O
N
A
N
R2
N
H
5
R1
N
N
R3
O
N
N
R3
O
N
N
R3
O
N 7
5
N
R2
N
H
R2
N
H
R2
N
H
6
7
8
R1
R1
R1
Figure 2. Structures of reported SCD inhibitors.
the HEPG2 SCD assays. For example, 3-(trifluoromethyl)phenyl
analogue 6f is over 50 times more potent than 4-(trifluoro-
hydrochloride instead, and obtained compound 11 (Scheme 1;
Method B).
methyl)phenyl analogue (6h, IC50 2.5
l
M) in the HEPG2 SCD assay.
The ethyl ester in 11 was hydrolyzed and the resulting carbox-
ylic acid was coupled with methylamine and O-methylhydroxyl-
amine to obtain compounds 6v (R4 = Me) and 6w (R4 = OMe),
respectively.
One interesting exception is the 4-chlorophenyl substituent. Com-
pound 6b turned out to be the most potent analogue in microsomal
assay among the series 6 compounds (IC50 7.8 nM); however, its
HEPG2 activity was somewhat more moderate (IC50 110 nM).
Next, while staying within scaffold 6, we switched to the re-
verse amide group in the R1 position and explored some limited
SAR (Table 3). Compounds 6t and 6u were synthesized by the pre-
viously detailed procedure (R4 = H; Scheme 1; Method A), using b-
alanine amide hydrochloride in the first step. However, for 6v and
6w, the analogous substituted b-alanine amides were not available.
We modified our synthetic approach to utilize b-alanine ethyl ester
We have found that the smallest R4 substituent, hydrogen, is
preferred (6t and u). As observed within series 5, the most potent
analogue in the HEPG2 SCD assay (6u) also possessed a combina-
tion of a 3-(trifluoromethyl)phenyl group in the R2 position in con-
junction with the reverse amide in the R1 position.
In the course of our SAR studies in Series 5, the 4-methoxy-
phenyl substituent at the R3 position resulted in the highest num-
ber of active compounds. Another substituent of interest was 3-

D. O. Koltun et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2048–2052
2051
Table 4
pyridyl. We were interested in the effect the 3-pyridyl substituent
Structure–activity relationships in series 6 (pyridines, 6x–aa)
may have on potency when combined with scaffold 6 (Table 4). We
found that compound 6x was the most potent (IC50 127 nM and
15 nM in the microsomal and HEPG2 SCD assays, respectively)
among all 3-pyridyl analogues.
Next, we turned our attention to the isomeric (7-aza) pyridine
core structure 7 (Fig. 2). Compounds of series 7 were obtained from
2,4-dichloro-5-nitropyridine (9; X = N, Y = CH; Scheme 1; Method
A) which was prepared as described in the literature.22 Compounds
7a and 7b (Table 5) are direct analogues of their isomeric counter-
N
N
N
R2
N
H
N
O
R1
Substituents
R2
D
9 assay, IC50, nM
R1
Rat mic.
HEPG2
Table 2
6x
6y
6z
NHAc
NHAc
NHAc
CONH2
3,4-Dichlorophenyl
127
333
1400
30,000
15
13
120
n.d.
Structure–activity relationships in series 6 (amides, 6a–s)
3-Chloro-4-Fluorophenyl
3-(Trifluoromethyl) phenyl
3-(Trifluoromethyl) phenyl
6aa
OMe
N
R2
N
H
N
N
O
parts (6a and 6x, respectively). Based on this direct comparison the
heterocyclic core 7 does not present any advantages over 6 in
terms of potency of SCD inhibition.
NHAc
Finally, we investigated the effect of the core structure with
fused benzene as Ring A (8,Fig. 2). Compounds of series 8 were pre-
pared by two different methods (Scheme 1; Methods C and D).
Method C is very similar to method A, except 2,4-difluoro-1-nitro-
benzene is used as a starting material and fluoride serves as a leav-
ing group instead of chloride. Method D is centered on coupling
between bromide 13 and amines containing the R2-group under
Buchwald conditions.23 Series 8 (Table 6) provided analogues with
very high potency for SCD inhibition. For example, compound 8g
displayed 0.6 nM potency of SCD inhibition in the microsomal as-
say and 50 pM in the HEPG2 SCD assay—by far the most potent SCD
inhibitor reported to date. The higher potency of some compounds
in cell-based assay was likely due to either species differences or
accumulation of the compound intracellularly.
Substituents
R2
D9 assay, IC50, nM
Rat mic.
HEPG2
6a
6b
6c
6d
6e
6f
6g
6h
6i
3,4-Dichlorophenyl
4-Chlorophenyl
3-Chlorophenyl
2-Chlorophenyl
3-Chloro-4-fluorophenyl
3-(Trifluoromethyl)phenyl
3-(Trifluoromethoxy)phenyl
4-(Trifluoromethyl)phenyl
3,5-bis-(Trifluoromethyl)phenyl
4-Fluoro-3-(trifluoromethyl)phenyl
2-Fluoro-5-(trifluoromethyl)phenyl
220
7.8
81
110
100
n.d.
47
376
549
466
206
260
2050
217
20
47
210
2500
51
6j
6k
16
1480
n.d.
F3C
6l
330
180
n.d.
n.d.
As previously indicated, we were interested in our compounds’
N
selectivity against other desaturases, specifically
determined 5 and
6 selectivity in microsomal assays24 for a
number of representative compounds from each class, and all com-
pounds tested were found to have IC50 values >30 M, ensuring
D5 and D6. We
F3C
Me
N
6m
6n
13,790
>30,000
D
D
l
O
N
100–50,000-fold selectivity windows (Table 7). Another important
characteristic essential for drug development is metabolic stability
in human and rat liver microsomes. Representative compounds
were evaluated in microsomal stability assays and displayed sta-
bility of 50% or greater following a 30 min microsomal incubation.
6o
6p
6q
6r
6s
3-Methylphenyl
3-Fluorophenyl
phenyl
3-Methoxyphenyl
3-Carboxyphenyl
380
96
17,600
840
760
n.d.
n.d.
n.d.
n.d.
>30,000
This also supported that inhibitory activity results against
D9
desaturase, a microsomal enzyme, were not affected to any signif-
icant extent by microsomal metabolism.
Table 3
Structure–activity relationships in series 6 (reverse amides, 6t–w)
Table 5
OMe
Structure–activity relationships in series 7
N
N
N
R3
O
R2
N
H
N
N
O
O
N
Cl
Cl
N
H
NHR4
R4
NHAc
Substituents
D
9 assay, IC50, nM
R2
Rat mic.
HEPG2
Substituents
R3
D
9 assay, IC50, nM
HEPG2
Rat mic.
6t
3,4-Dichlorophenyl
H
H
Me
OMe
29
27
360
930
16
6u
6v
6w
3-(Trifluoromethyl)phenyl
3-(Trifluoromethyl)phenyl
3-(Trifluoromethyl)phenyl
2.8
120
n.d.
7a
7b
7c
4-Methoxyphenyl
3-Pyridyl
4-Methylphenyl
190
157
343
34
21
40

2052
D. O. Koltun et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2048–2052
Table 6
Structure–activity relationships in series 8
N
N
R3
O
R2
N
H
NHAc
Substituents
D9 assay, IC50, nM
R2
R3
Rat mic.
HEPG2
8a
8b
8c
8d
8e
8f
3,4-Dichlorophenyl
4-Methoxyphenyl
4-Methoxyphenyl
3-Pyridyl
110
93
168
56
18
26
8.6
3.3
13
3.2
13
130
0.05
3.1
3-(Trifluoromethyl) phenyl
3-(Trifluoromethyl) phenyl
3-(Trifluoromethyl) phenyl
3-Methylphenyl
3,4-Dimethylphenyl
4-Chloro-3-(trifluoro methyl)phenyl
4-Fluoro-3-methylphenyl
4-Ethylphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
8g
8h
0.6
0.5
F3C
8i
4-Methoxyphenyl
25
6.5
N
Table 7
Desaturase selectivity and microsomal stability of selected analogues
Other stearolyl-CoA desaturase activity (
D
9 selectivity)
Liver microsomal stability, % after 30 min
Rat
Rat mic.
D
5 IC50
,
lM
Rat mic. 6 IC50
D
,
l
M
Human
5a
6a
6t
6u
6x
7a
8a
8g
>30 (>120)
>30 (>187)
>30 (>158)
>30 (>857)
>30 (>411)
>30 (>882)
>30 (>272)
>30 (>50,000)
>30 (>120)
>30 (>187)
>30 (>158)
>30 (>857)
>30 (>411)
>30 (>882)
>30 (>272)
>30 (>50,000)
51
85
94
69
69
97
83
81
47
72
106
61
49
92
54
83
6. Cohen, P.; Miyazaki, M.; Socci, N. D.; Hagge-Greenberg, A.; Liedtke, W.; Soukas, A.
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In conclusion, we conducted a SAR study of structurally novel
bicyclic SCD inhibitors based on pteridinone screening hits 5a
and 5b. Modifications of the ring A of the bicyclic core from
pyrimidine 5 to 5- and 7-isomers of pyridine (6 and 7) to ben-
zene 8 had the greatest impact on potency optimization. Pre-
ferred substituents were also identified in R1, R2, and R3
positions. Overall, our effort led to the discovery of highly potent
(against both human and rat enzymes), selective, metabolically
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P.; Ntambi, J. M.; Attie, A. D. Diabetes 2007, 56, 1228.
stable, and structurally novel
D9 desaturase (stearoyl-CoA desat-
urase, SCD) inhibitors. Work is underway to fully characterize
their in vivo pharmacokinetic and pharmacodynamic properties
in various animal models.
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Acknowledgments
We would like to thank Dr. Brent Blackburn of CV Therapeutics
for valuable discussions. We would like to thank Dr. Dmitry Genis,
Dr. Roman Kombarov, Ms. Olga Krasavina, and Ms. Irina Khrustal-
eva of ASINEX for their support in various aspects of the project.
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