4-Bicyclic heteroaryl-piperidine derivatives as potent, orally bioavailable stearoyl-CoA desaturase-1 (SCD1) inhibitors: Part 2. Pyridazine-based analogs

Article abstract of DOI:10.1016/j.bmcl.2013.12.075

Design, synthesis, and biological evaluation of pyridazine-based, 4-bicyclic heteroaryl-piperidine derivatives as potent stearoyl-CoA desaturase-1 (SCD1) inhibitors are described. In a chronic study of selected analog (3e) in Zucker fa/fa (ZF) rat, dose-dependent decrease of body weight gain and plasma fatty acid desaturation index (DI) in both C16 and C18 are also demonstrated. The results indicate that the plasma fatty acid DI may serve as an indicator for direct target engagement and biomarker for SCD1 inhibition.

Full text of DOI:10.1016/j.bmcl.2013.12.075

Accepted Manuscript
4-Bicyclic heteroaryl-piperidine derivatives as potent, orally bioavailable
stearoyl-CoA desaturase-1 (SCD1) inhibitors: Part 2. Pyridazine-based analogs
Shyh-Ming Yang, Yuting Tang, Thomas Rano, Huajun Lu, Gee-Hong Kuo,
Michael D. Gaul, Yaxin Li, George Ho, Wensheng Lang, James G. Conway,
Yin Liang, James M. Lenhard, Keith T. Demarest, William V. Murray
PII:
S0960-894X(13)01459-5
DOI:
http://dx.doi.org/10.1016/j.bmcl.2013.12.075
BMCL 21183
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Please cite this article as: Yang, S-M., Tang, Y., Rano, T., Lu, H., Kuo, G-H., Gaul, M.D., Li, Y., Ho, G., Lang, W.,
Conway, J.G., Liang, Y., Lenhard, J.M., Demarest, K.T., Murray, W.V., 4-Bicyclic heteroaryl-piperidine derivatives
as potent, orally bioavailable stearoyl-CoA desaturase-1 (SCD1) inhibitors: Part 2. Pyridazine-based analogs,
Bioorganic & Medicinal Chemistry Letters (2013), doi: http://dx.doi.org/10.1016/j.bmcl.2013.12.075
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4-Bicyclic heteroaryl-piperidine derivatives
as potent, orally bioavailable stearoyl-CoA
desaturase-1 (SCD1) inhibitors: Part 2.
Pyridazine-based analogs
Leave this area blank for abstract info.
Shyh-Ming Yang,* Yuting Tang, Thomas Rano, Huajun Lu, Gee-Hong Kuo, Michael D. Gaul, Yaxin Li,
George Ho, Wensheng Lang, James G. Conway, Yin Liang, James M. Lenhard, Keith T. Demarest and William
V. Murray

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
4-Bicyclic heteroaryl-piperidine derivatives as potent, orally bioavailable
stearoyl-CoA desaturase-1 (SCD1) inhibitors: Part 2. Pyridazine-based analogs
Shyh-Ming Yang, Yuting Tang, Thomas Rano, Huajun Lu, Gee-Hong Kuo, Michael D. Gaul, Yaxin Li,
George Ho, Wensheng Lang, James G. Conway, Yin Liang, James M. Lenhard, Keith T. Demarest and
William V. Murray
Cardiovascular and Metabolism Research, Janssen Research and Development, LLC
Welsh & McKean Roads, Spring House, PA 19477, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Design, synthesis, and biological evaluation of pyridazine-based, 4-bicyclic heteroaryl-
piperidine derivatives as potent Stearoyl-CoA desaturase-1 (SCD1) inhibitors are described. In a
chronic study of selected analog (3e) in Zucker fa/fa (ZF) rat, dose-dependent decrease of body
weight gain and plasma fatty acid desaturation index (DI) in both C16 and C18 are also
demonstrated. The results indicate that the plasma fatty acid DI may serve as an indicator for
direct target engagement and biomarker for SCD1 inhibition.
Keywords:
stearoyl-CoA desaturase
SCD1 inhibitors
desaturation index
obesity
2009 Elsevier Ltd. All rights reserved.
Stearoyl-CoA desaturase 1 (SCD1) is a major lipogenic
enzyme that converts saturated fatty acid (FA)-CoAs to mono-
unsaturated FA-CoAs.1 These mono-unsaturated FA-CoAs are
major components for the synthesis of lipids including
phospholipids, triglycerides, cholesterol esters and wax esters.2
SCD1 enzyme is abundantly expressed in liver and adipose tissue
and is regulated by several hormonal factors, such as insulin,
cholesterol, and poly-unsaturated fatty acids.3 Studies with SCD1
knockout (SCD1/) mice and antisense oligonucleotides against
SCD1 suggested a beneficial role of SCD1 inhibition in reducing
lipid synthesis, body weight and improving insulin sensitivity.4
Additionally, the SCD1/ mice also have lower levels of hepatic
cholesterol esters and triglycerides.5 Therefore, potential
inhibition of SCD1 activity may serve as a considerable
treatment for obesity, type-II diabetes, and other related
metabolic syndromes.
of compound 2 with particular focus on replacing the urea
functionality with an aryl-substituted pyridazine ring. Herein we
report the structure-activity relationships (SAR) and in vivo
efficacy studies of 4-bicyclic heteroaryl piperidine-based
pyridazine analogs (35) as potent and orally efficacious SCD1
inhibitors.
Among the structurally diverse SCD1 inhibitors disclosed
recently,6,7 linear 4-phenoxy-piperidine derivatives, such as 1a
(MF-438)6e and 1b6f (Figure 1), are quite interesting due to their
remarkable potency and in vivo efficacy. We recently reported a
series of 4-bicyclic heteroaryl-piperidine urea analogs as potent
SCD1 inhibitors as exemplified by compound 2, which
demonstrated a trend of dose-dependent decrease in body weight
gain in diet-induced obese (DIO) mice.8 Based on these
Figure 1. Representative 4-phenoxypiperidine-based and 4-bicyclic
heteroaryl piperidine-based SCD1 inhibitors.
e—nc—our—aging results, we were interested in further modifications
 Corresponding author. Tel.: +1-215-340-1635; e-mail: shyhyang99@yahoo.com

The general synthetic sequences for analogs 35 are outlined
in Scheme 1. The synthesis began with the mono-displacement of
2,6-dichloropyridazine with 4-bicyclic heteroaryl piperidine 6 to
afford intermediate 7.9 Subsequently, various aryl or heteroaryl
rings were introduced through facile Suzuki coupling or Stille
coupling with corresponding boronic acids, boronic esters, or
organo-tin reagents. An alternative method to afford imidazole
and 1-pyrazole analogs (4a4f) utilized a displacement of
intermediates 910, which were prepared from the corresponding
imidazole or pyrazole components and 2,6-dichloropyridazine
Table 1. SAR of bicyclic heteroaryl substitutions R1.
Compds
R1
rSCD1
A431
(nM)b
IC50 (nM)a
(8),
-
with 4-(6-fluoroindolin-1-yl)piperidine (11) under
microwave irradiation.
3a
394
422


3b
3c
678

3d
3e
3f
165
37
99
15
181
35
218
28
3g
3h
3i
286
317
173
23
241
407
42
25

Scheme 1. R1 represents bicyclic heteroaryl, such as indole, indoline,
indazole, benzoisoxazole etc. Reagents and conditions: (a) 3,6-
dichloropyridazine, Et3N, DMSO, 80-100 oC, 60-83%; (b) organo-boronic
acids or boronic esters (Suzuki coupling), Pd(PPh3)4, K2CO3, 1,4-dioxane,
H2O, 95-100 oC, 40-95%, or organo-Tin reagents (Stille coupling), Pd(PPh3)4,
1,4-dioxane, 120-140 oC, microwave, 38-76%; (c) Cs2CO3, MeCN, reflux; (d)
9 or 10, (i-Pr)2NEt, DMSO, 160-180 oC, microwave, 39-86%.
3j
The compounds 3a-m with N-methylpyrazole-4-yl
substitution were synthesized and tested against rat SCD1
enzyme (rSCD1) and human epithelial carcinoma A431 cells.7
The results in Table 1 focused on varying the substitution on the
bicyclic heteroaryl ring revealed the potency was dramatically
influenced by substituent type and the position substituted.
Unsubstituted indoline (3a) or indole (3b) gave only moderate
affinity. Consistent with previous findings,7 halogen substitution
on the 6-position of indole/indoline rings, such as F (3e, 3k) or Cl
(3g), significantly improved the potency to low nanomolar range
in both rSCD1 and the A431 assay. Halogen substitution at the 5-
and 4-position was less favorable, causing around 5- and 18-fold
drop in potency (3e vs. 3d and 3c). A similar trend was observed
in Cl-substitution (3g vs. 3f). Small electron donating groups
such as methyl and methoxy (3h, 3i) as well as electron
withdrawing groups such as –CF3 (3j) also resulted in a 5-9 fold
loss in potency. Modifying the bicyclic heteroaryl component
with 5-fluorobenzoisoxazole (3l) and 6-fluoroindazole (3m), also
provided comparable inhibitory activities as to the substituted
indoline.
3k
3l
125
38
3m
51
aSingle experiment or means of at least two runs.
bUsing 13C-palmitic acid and LC-MS method, see supplementary material.
By using the 6-fluoroindoline as a left-hand side piece, our
attention next focused on exploration of SAR by modifying the
pyrazole ring with various substituted 5-membered heteroarenes
(Table 2). An imidazole was first found to be a suitable
replacement for the pyrazole that produced analogs 4a4b with
excellent inhibitory activities. Unfortunately, these compounds
also showed significant hERG channel affinity (IC50 < 10 M)
(blockade activity) precluding them from further investigation.
Attaching a 3-substituted pyrazole through its N-1 nitrogen atom
(4c4f) also provided compounds with good potency against both
rSCD1 and A431 assays. Modifying the methyl group of 3e to
straight chain alkyl (4g4h), hydroxyalkyl (4i), and elongated

side chains (4j4k) resulted in no significant change in potency.
However, the linear side chains (such as 4f, 4h, and 4j) did show
a decrease in human and/or rat microsomal stabilities (< 50%
remained at 10 minutes). With other 5-membered heteroarenes
examined, thiophene (4l) showed a decrease of potency in rSCD1
enzymatic assay, while thiazole (4m4n) and thioisodiazole (4o)
demonstrated comparable affinity to those bearing pyrazole or
imidazole rings.
4n
4o
7
2
11

aSingle experiment or means of at least two runs.
bUsing 13C-palmitic acid and LC-MS method, see supplementary material.
Replacement of the pyrazole ring with para-substituted 6-
membered rings, such as phenyl or pyridine, was also examined
(Table 3). A direct comparison between 5ac and 5fh revealed
that the pyridine analogs exhibited better inhibitory activity than
phenyl analogs. In general, various substituents such as electron-
donating groups (Me, OMe, NMe2) or electron-withdrawing
groups (CF3, CONHMe) were well tolerated with exceptions of F
(5d) and carboxylic acid (5e). Consistent with the results
observed above for compounds 4b and 4di, the hydroxymethyl
substitution on both phenyl and pyridine rings provided
compounds with excellent in vitro potency in both the rSCD1 and
A431 assays (5b, 5g). Despite the important inhibitory activities,
most of these potent inhibitors either suffered with low
microsomal stabilities or displayed significant affinity towards
CYP450 inhibition and/or hERG channel binding (data not
shown) precluding them from further development.
Table 2. SAR of 5-membered heteroaryl substituent R2.
Compds
R2
rSCD1
A431
(nM)b
IC50 (nM)a
4a
16
11
21
9
3
4b
4c
23
4d
4e
4f
17
20
8
6
11
9
Table 3. SAR of substituent R3.
Compds
X
R3
rSCD1
A431
(nM)b
IC50 (nM)a
5a
5b
5c
5d
5e
5f
79
22
90
777
349
13
9
11
8
C
C
C
C
C
N
N
N
N
N
N
Me
CH2OH
CF3
3e
37
15
54

F

2
CO2H
Me
4g
4h
4i
17
22
22
12
30
72
21
41
5g
5h
5i
0.5
14
4
CH2OH
CF3
16
12
17
35
OMe
NMe2
CONHMe
5j
30
6
5k
aSingle experiment or means of at least two runs.
bUsing 13C-palmitic acid and LC-MS method, see supplementary material.
4j
To further select suitable compounds for chronic studies in
Zucker fa/fa rat (ZF), compounds with good in vitro potency and
desirable early ADME properties were selected and quickly
evaluated the effect on body weight (BW) change in DIO mice.
These compounds, such as 3m, 3e, 4d, 4i, and 5g, were tested in
DIO mice at 30 mg/kg once-daily (qd) administration for 10
days. The results complied in Table 4 demonstrated a significant
reduction of body weight (BW) gain when compared to vehicle-
treated group.
4k
15
12
4l
121
31
6
4m
12

Table 4. Body weight change in 10-day DIO mice studya.
Figure 2. Effect of 3e on reduction of body weight gain in 26 days Zucker
fa/fa rat (n= 8) study (*p< 0.05 vs. vehicle-treated group).
Compds
vehicle
3m
3e
4d
Body weight change (g)
2.8 ± 0.3
 3.3 ± 0.5*
 2.1 ± 0.3*
1.2 ± 0.3 *
4i
0.5 ± 0.1*
5g
 2.2 ± 0.5*
a30 mg/kg (n= 8); *p< 0.05 vs. vehicle-treated group.
Subsequently, compound 3e was chosen for further studies.
The pharmacokinetic (PK) profiles of 3e in Sprague Dawley
(SD) rats and Zucker fa/fa (ZF) rats were determined. These PK
results revealed that 3e has moderate volume of distribution (0.52
L/kg) and low clearance level (3.3 mL/min/kg; iv: 2 mg/kg). A
desirable plasma exposure for SD rats (po: 10 mg/kg; n= 4; Cmax
:
4.4 g/mL; AUC24h: 38.8 h*g/mL) and ZF rats (po: 10 mg/k; n=
4; Cmax: 1.6 g/mL; AUC24h: 10.8 h*g/mL) were also obtained
along with a 105% and 11% oral bioavailability, respectively. To
further measure chronic in vivo efficacy, a 26-day study in ZF
rats with compound 3e was carried out at 1, 3, and 10 mg/kg. The
results compiled in Table 5 and Figure 2 indicated that significant
reduction of BW gain was obtained at day 15 for 1 and 3 mg/kg
groups compared to vehicle-treated group, though no significant
separation was observed between 1 mg/kg and 3 mg/kg groups.
For 10 mg/kg treatment group, BW gain was significantly
decreased as early as day 8. Effects on reduction of BW gain
after 26 days treatment was 51%, 22% and 17% for 10 mg/kg, 3
mg/kg and 1 mg/kg groups, respectively. No significant change
in food intake was found for 1 and 3 mg/kg groups throughout
the study, while about a 10% decrease of food consumption was
observed in 10 mg/kg group after day 22. In addition, no
elevation of liver enzymes (ALT and AST) was observed at the
end of the study. More importantly, dose-dependent decrease of
plasma fatty acid desaturation index (DI) was observed for both
C16:1/C16:0 and C18:1/C18:0 (Figure 3). This line of evidence
strongly suggested that the plasma fatty acid DI may serve as an
indicator for direct target engagement and biomarker for SCD1
inhibition.
Figure 3. Effect of 3e on dose dependent decrease of plasma DI after a 26-
day study in ZF rats (n= 8) at 1, 3, and 10 mg/kg (*p< 0.05 vs. vehicle-treated
group).
In conclusion, a new series of 4-bicyclic heteroaryl piperidine-
based pyridazine analogs as potent SCD1 inhibitors is reported.
Selected analog 3e demonstrated in vivo efficacy by significantly
decreasing body weight gain in ZF rats. The ability of compound
3e to dose dependently decrease plasma fatty acid desaturation
index (DI) in ZF rats strongly indicate that plasma fatty acid DI
may potentially serve as a suitable target engagement biomarker
for SCD1 inhibition. The detailed pharmacological findings of 3e
in ZF rats and DIO mice will be disclosed in near future.10
Table 5. Effect of 3e on body weight gain (g) in 26 days Zucker fa/fa rat (n=
8) study.
treatment
day 8
day 15
day 22
day 26
vehicle
61 ± 7
42 ± 5
44 ± 4
29 ± 4*
103 ± 4
80 ± 4*
80 ± 5*
57 ± 4*
142 ± 4
116 ± 5*
112 ± 6*
72 ± 6*
161 ± 8
133 ± 5*
125 ± 4*
78 ± 6*
3e (1 mg/kg)
3e (3 mg/kg)
3e (10 mg/kg)
*p< 0.05 vs. vehicle-treated group.
Acknowledgment
The authors thank the ADME team for bioanalysis support.
Supplementary Material
Supplementary material associated with this article can be found,
in the online version, at doi:
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