Design, synthesis, and structure-activity relationships of novel spiro-piperidines as acetyl-CoA carboxylase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2012.04.047

Spiro-lactone (S)-1 is a potent acetyl-CoA carboxylase (ACC) inhibitor and was found to be metabolically liable in human hepatic microsomes. To remove one of the risk factors in human study by improving the metabolic stability, we focused on modifying the

Full text of DOI:10.1016/j.bmcl.2012.04.047

Bioorganic & Medicinal Chemistry Letters 22 (2012) 3643–3647
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis, and structure–activity relationships of novel
spiro-piperidines as acetyl-CoA carboxylase inhibitors
⇑
Makoto Kamata , Tohru Yamashita, Asato Kina, Masaaki Funata, Atsushi Mizukami, Masako Sasaki,
Akiyoshi Tani, Miyuki Funami, Nobuyuki Amano, Kohji Fukatsu
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 February 2012
Revised 2 April 2012
Accepted 9 April 2012
Available online 19 April 2012
Spiro-lactone (S)-1 is a potent acetyl-CoA carboxylase (ACC) inhibitor and was found to be metabolically
liable in human hepatic microsomes. To remove one of the risk factors in human study by improving the
metabolic stability, we focused on modifying the spiro-lactone ring and the benzothiophene portion of
the molecule. Spiro-imide derivative 8c containing a 6-methylthieno[2,3-b]pyridine core exhibited potent
ACC inhibitory activity and favorable pharmacokinetic profiles in rats.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Acetyl-CoA carboxylase
ACC
Spiro-piperidine
Metabolic stability
Lipophilicity
Obesity has become a serious health problem worldwide over
the past few decades, due in part to increased food intake and re-
duced physical activity.1 Moreover, obesity is associated with a
variety of serious human diseases, notably type 2 diabetes, cardio-
vascular diseases, depression, and cancer. Acetyl-CoA carboxylase
(ACC) catalyzes the biotin-dependent carboxylation of acetyl-CoA
to form malonyl-CoA,2 which is a known substrate for fatty acid
synthase in de novo lipogenesis and is also an allosteric inhibitor
of carnitine palmitoyltransferase 1.3 Therefore, ACC inhibition
may lower malonyl-CoA levels, resulting in reduced fatty acid syn-
thesis, accelerated fatty acid oxidation, and consequently improved
insulin sensitivity. In rodents and humans, two ACC isoforms,
ACC1, which is primarily expressed in lipogenic tissues, and
ACC2, which is expressed in oxidative tissues, have been reported.4
Genetic studies have demonstrated that knocking out ACC1 in mice
is embryonically lethal,5 whereas ACC2 homozygous knockout
mice are healthy, fertile, and have a higher fatty acid oxidation rate
and reduced fat accumulation compared to wild-type mice.6
We previously reported novel spiro-lactone (S)-1 containing a
ureidobenzothiophenyl group as a potent ACC inhibitor.7 The
X-ray co-crystal structure data of the human ACC2 carboxyl
transferase domain in complex with (S)-1 indicated that not only
the two carbonyl groups of amide and lactone are promptly bound
to the two backbones of Gly2162 and Glu2230 but also the ureido
moiety interacts with the side chain of Glu2230 (Fig. 1). However,
(S)-1 showed poor human metabolic stability, which may cause
unfavorable pharmokinetic (PK) profiles, including variations in
blood exposure level or high elimination clearance in clinical trials.
In order to remove one of these risk factors for human study, we
examined methods to improve the metabolic stability by lowering
the lipophilicity of the spiro-5-membered moiety and benzothi-
ophenyl group as shown in Figure 1. Herein, we describe the design,
synthesis, structure–activity relationship (SAR), and the relation-
ship between lipophilicity (logD) and metabolic stability.
Synthesis of spiro-lactams 6a–d and spiro-imides2a,b is outlined
in Scheme 1. Compound 10,7 derived from ester 9, was converted to
piperidinopiperidine derivative 11 by deprotection of the Boc group
and subsequent reductive alkylation with 1-Boc-4-piperidone (18).
Spiro-lactams 13a–c were obtained by reducing the cyano group
with Raney-Ni followed by alkylation of the resultant lactam using
NaH and alkyl halide. Finally, desired compounds 6a–d were
prepared by deprotection of the Boc group in 12 and 13a–c, conden-
sation with benzothiophenecarboxylic acid 19, and ureide forma-
tion using alkyl isocyanate or trichloroacetyl isocyante followed by
ammonolysis. Alkylation of ester 9 with benzyl bromoacetate
followed by deprotection of the Boc group in 14 and reductive
alkylation afforded piperidinopiperidine 15. After the benzyl group
of 15 was removed under reducing conditions, amides 16a,b were
obtained by condensation with primary amines. Cyclization by
treatment with NaH proceeded to give imide derivatives 17a,b.
Compound 17a was converted to the desired compounds 2a,b using
a procedure similar to that used for spiro-lactams 6a–d. Compounds
13c and 17b were asymmetrically separated by chiral HPLC to give
⇑
Corresponding author. Tel.: +81 466 32 1130; fax: +81 466 29 4451.
E-mail address: Kamata_Makoto@takeda.co.jp (M. Kamata).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.04.047

3644
M. Kamata et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3643–3647
R
N
N
X
N
Me
Me
R3
N
O
X
N
Y
S
O
O
O
O
N
O
H
R4
R4
R4
S
O
N
(S)-1
O
H
Gly2162
X = NR2, O, CH2 R2-4 = alkyl
N
N
Et
H
O
X, Y = CH or N
R = H, Me
Glu2230
H N
O
O
O
Figure 1. Synthetic strategy for spiro-piperidine derivatives.
a
b
c
e
N
N
N
BocN
BocN
CN
CO2Et
CO2Et
CN
CO2Et
S
N
N
O
N
BocN
BocN
d
O
R4
R4
O
NH
O
12 (R4 = H)
9
10
11
6a-d
R1
NH
13a (R4 = Me)
13b (R4 = Et)
13c (R4 = i-Pr)
f
h
e
NHR4
b
g
N
N
N
N
O
BocN
CO2Bn
CO2Et
O
S
CO2Bn
CO2Et
O
N
N
O
N
BocN
BocN
BocN
O
CO2Et
R4
O
O
Et
NH
14
15
16a (R4 = Et)
16b (R4 = iPr)
R1
17a (R4 = Et)
17b (R4 = iPr)
NH
2a, b
Scheme 1. (a) BrCH2CN, LHMDS, THF, À78 °C, 26%; (b) (i) 4 M HCl–AcOEt; (ii) 1-Boc-4-piperidone (18), Et3N, NaBH(OAc)3, THF, 67% (11), 70% (15); (c) Raney Ni, H2 (0.5 MPa),
NH3, EtOH, 88%; (d) R4-I, NaH, DMF, 75% (13a), 68% (13b), 60% (13c); (e) (i) 4 M HCl, dioxane; (ii) 2-amino-3-benzothiophenecarboxylic acid (19), WSC, HOBt, Et3N, DMF, 46%
(for 6a), 89% (for 6b), 91% (for 6c), 50% (for 6d), 67% (for 2a,b); (iii) Cl3CCONCO, THF then 7 M NH3–MeOH, 82% (2a) or R1NCO, pyridine, 80 °C, 30% (6a), 52% (6b), 40% (6c), 54%
(6d), 76% (2b); (f) BrCH2CO2Bn, LHMDS, THF, À78 °C, 78%; (g) (i) H2, Pd/C, EtOH, 100%; (ii) R4NH2, WSC, HOBt, DMF, 80% (16a), 100% (16b); (h) NaH, DMF, 75% (17a), 69%
(17b).
a
b
O
N
c
O
N
OH
N
N
OH
N
O
O
Ph
N
S
CO2Me
N
O
BocN
CO2Me
O
BocN
R4
O
Et
NH
O
20
21
22a (R4 = Et)
R1
NH
3a, b
22b (R4 = i-Pr)
Scheme 2. (a) (i) H2, Pd(OH)2/C, EtOH; (ii) 18, NaBH(OAc)3, THF, 52% (two steps); b) R4NCO, NaH, THF, 91% (22a), 75% (22b); (c) 4 M HCl–dioxane, 100%; (ii) 19, WSC, HOBt,
Et3N, DMF, 87%; iii) Cl3CCONCO, THF then 7 M NH3–MeOH, 78% (3a) or EtNCO, pyridine, 80 °C, 83% (3b).
H
H
N
R3
N
R3
N
b
c
N
N
a
d
e
BocN
N
N
R3
N
N
R3
N
R3
S
BocN
O
O
N
O
O
N
H
N
BocN
BocN
BocN
O
O
Et
N
N
O
R4
NH
O
24a (R3 = Me)
24b (R3 = Et)
24c (R3 = i-Pr)
25a (R3 = Me)
25b (R3 = Et)
26a (R3 = Me)
26b (R3 = Et)
26c (R3 = i-Pr)
27a (R3 = Me, R4 = Et)
27b (R3 = Et, R4 = Et)
27c (R3 = i-Pr, R4 = Et)
27d (R3 = Me, R4 = i-Pr)
5a (R3 = Me)
5b (R3 = Et)
5c (R3 = i-Pr)
23
2N
H
25c (R3 = i-Pr)
Scheme 3. (a) (i) NH4Cl, KCN, i-PrOH, aq NH3; (ii) R3-COCl, Et3N, THF, 78% (24a), 100% (24b), 84% (24c); (b) (i) 4 M HCl–AcOEt; (ii) 18, NaBH(OAc)3, THF, 43% (25a), 80% (25b),
64% (25c); (c) aq NaOH, H2O2, EtOH, 60 °C, 72% (26a), 50% (26b), 55% (26c); d) R2-I, NaH, DMF, 85% (27a), 71% (27b), 30% (27c), 33% (27d); (e) 4 M HCl–dioxane; (ii) 19, WSC,
HOBt, Et3N, DMF, 87% (for 5a), 43% (for 5b), 80% (for 5c); (iii) Cl3CCONCO, THF then 7 M NH3–MeOH, 100% (5a), 77% (5b), 14% (5c).
R2
N
R2
H
H
N
d
a
b
N
N
N
BocN
N
O
BocN
O
O
O
S
N
Et
N
N
N
O
BocN
N
H
O
O
O
R4
R4
NH
O
O
29a (R4 = Et)
29b (R4 = i-Pr)
30a (R2 = H, R4 = Et)
31 (R2 = Me, R4 = Et)
30b (R2 = H, R4 = i-Pr)
NH
28
4a, b
Et
c
Scheme 4. (a) R4-I, K2CO3, DMF, 32% (29a), 41% (29b); (b) (i) 4 M HCl–AcOEt; (ii) 18, NaBH(OAc)3, Et3N, CH2Cl2, 74% (30a), 50% (30b); (c) NaH, MeI, DMF, 100%; (d) (i) 4 M
HCl–AcOEt, 100% (for 4a), 94% (for 4b); (ii) 19, WSC, HOBt, Et3N, DMF, 100% (for 4a), 88% (for 4b); (iii) EtNCO, pyridine, 80 °C, 60% (4a), 70% (4b).
(S)-13c and (S)-17b in 49% and 44% yield, respectively. As shown in
Scheme 5, these chiral intermediates were used to prepare 8b and
8c, stereochemistry of which was determined using single X-ray
crystallographic analysis.8
Spiro-oxazolidinediones 3a,b were prepared using the method
shown in Scheme 2. Hydroxy ester 20, which was prepared from
commercially available 1-benzyl-3-piperidone via a known proce-
dure,9 was converted to piperidinopiperidine derivative 21 by

M. Kamata et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3643–3647
3645
X
X
d
e
X
N
X
Me
Me
X
N
a
b
c
N
N
N
Me
Me
N
N
N
X
S
O
S
O
S
N
O
BocN
O
S
S
Br
Br
CN
NH2
CO2H
O
Cl
NH
O
BocNH
EtO2C
37
EtO2C
BocNH
R1
NH
33a (X = CH)
33b (X = N)
34a (X = CH)
34b (X = N)
35a (X = CH)
35b (X = N)
36a (X = CH)
36b (X = N)
32a (X = CH)
32b (X = N)
7c, d
R
R
N
R
N
R
N
R
N
R
N
N
d
e or f
a
b
c
N
S
S
Br
S
Br
N
O
O
S
NH2
S
CO2H
BocNH
CN
Cl
O
NH
NH
BocNH
EtO2C
EtO2C
R1
39a (R = H)
39b (R = Me)
40a (R = H)
40b (R = Me)
41a (R = H)
41b (R = Me)
42a (R = H)
42b (R = Me)
7a, b, 8a-f
38b (R = Me)
Scheme 5. (a) HSCH2CO2Et, NaOEt, DMF, 70 °C, 86% (33a), 72% (33b), 97% (39b); (b) t-BuONO, CuBr2, MeCN, 55% (34a), 42% (34b), 66% (40a); (c) (i) aq NaOH, THF–MeOH; (ii)
DPPA, Et3N, t-BuOH, 41% (35a), 25% (35b), 74% (41a), 82% (41b, two steps); (d) n-BuLi, THF, À78 °C; CO2, 60% (36a), 79% (42a), 80% (42b); (e) (i) 37, WSC, HOBt, Et3N, DMF, 99%
(for 7a), 60% (for 7b, two steps), 70% (for 7c), 46% (for 7d); (ii) TFA then R1NCO, pyridine, 80 °C, 54% (7a), 76% (7b), 80% (7c), 67% (7d); (f) (i) (S)-13c, (S)-17b, (S/R)-22b,
(S/R)-27d, (S)-37, or 30b treated with 4 M HCl–AcOEt then WSC, HOBt, Et3N, DMF, 80% (for 8a), 86% (for 8b), 58% (for 8c), 52% (for 8d), 70% (for 8e), 67% (for 8f); (ii) TFA then
R1NCO, pyridine, 80 °C, 53% (8a), 67% (8b), 76% (8c), 81% (8d), 23% (8e), 51% (8f).
deprotection of the benzyl group and condensation with 18. Con-
struction of the oxazolidinedione ring was performed by treatment
with alkyl isocyanates and NaH to give 22a,b. Finally, compounds
3a,b were obtained from 22a in a similar manner to that shown
in Scheme 1. Compound 22b was asymmetrically separated by chi-
ral HPLC to give chiral (S/R)-22b in 42% yield. As shown in Scheme
5, this chiral intermediate was used to prepare 8d, stereochemistry
of which was not determined.
The synthetic route for spiro-imidazolones 5a–c is summarized
in Scheme 3. The Strecker reaction of 23 followed by acylation
afforded 3-acylamino-3-cyanopoperidines 24a–c. Successive
deprotection of the Boc group and reductive alkylation with 18
provided compounds 25a–c. Cyclization of 25a–c proceeded
smoothly under basic conditions to give imidazolone derivatives
26a–c. After introduction of an alkyl group to 26a–c using NaH
and alkyl halide, 5a–c was obtained from 27a–c using the same
method shown in Scheme 1. Optically active (S/R)-27d, which
was obtained by chiral resolution of 25a and subsequent cycliza-
tion and N-alkylation, was used to synthesize 8e as shown in
Scheme 5. The stereochemistry of 8e was also not determined.
Preparation of spiro-imidazolidinediones 4a,b was carried out
using the method described in Scheme 4. Starting with spiro-imi-
dazolidinedione 28, selective N-alkylation of the ring in 29a,b and
introduction of a 1-Boc-piperidine moiety afforded 30a,b. Com-
pound 30a was methylated on the remaining nitrogen atom of the
ring to give 31. Compounds 30a and 31 were converted to com-
pounds 4a,b using the similar method to that shown in Scheme 1.
Compounds 7c,d were prepared according to the synthetic
route shown in Scheme 5. Commercially available pyridine or pyr-
azine derivatives 32a,b were converted into thienopyridine or thi-
enopyrazine 33a,b, which were subjected to the Sandmeyer
reaction to afford 34a,b.10 Successive hydrolysis and the Curtius
rearrangement reaction gave 35a,b, followed by introduction of
carboxylic acid at the 3-position to obtain 36a,b. Condensation
with deprotected spiro-lactone 377 and conversion of the Boc
group to a ureide moiety afforded desired compounds 7c,d. Com-
pounds 7a,b and 8a–f were also prepared using the same method
as was used for the synthesis of 7c,d.
The spiro compounds prepared in this study were evaluated for
their ability to inhibit human ACC1 and ACC2 using the malachite
Table 1
ACC inhibitory activity, human metabolic stability, and logD of spiro-piperidines 2–6a
Me
Me
X
N
N
N
N
N
N
R3
O
S
S
S
S
O
N
N
O
N
Et
N
O
N
O
N
O
R4
Et
O
NH
O
O
NH
O
O
NH
O
NH
O
O
Me
NH
NH
NH
R1
NH2
R1
2 (X = CH2), 3 (X = O)
4 (X = NR2)
5
6
(S)-1
Substituents
IC50 (nM)
hMSb
logDc
X
R1
—
R2
R3
—
R4
—
ACC1
ACC2
(S)-1
1
—
—
32
63
5.4
13
23
32
49
40
22
51
75
43
17
79
64
33
18
230
180
64
130
41
3.01
3.01
2.20
2.82
1.85
2.47
2.44
2.79
1.77
2.09
2.43
2.06
2.23
2.62
2.61
2a
2b
3a
3b
4a
4b
5a
5b
5c
6a
6b
6c
6d
CH2
CH2
O
O
N
N
—
—
—
—
—
—
—
H
Et
H
Et
Et
Et
—
—
—
Et
Et
Et
Me
—
—
—
—
H
Me
—
—
—
—
—
—
–
—
—
—
—
—
—
Me
Et
i-Pr
—
—
—
—
—
—
—
—
—
—
H
350
230
290
190
280
360
300
410
80
650
510
350
120
98
110
190
60
150
230
35
45
71
66
—
—
——
Me
Et
i-Pr
a
b
c
Racemate.
In vitro metabolic clearance in human hepatic microsomes (
logD was measured using HPLC (pH 7.4).
lL/min/mg protein).

3646
M. Kamata et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3643–3647
backbone of Gly2162, all compounds (imide 2, oxazolidinedione 3,
Table 2
ACC inhibitory activity, human metabolic stabilities, and logD of spiro-Lactones 7a
imidazolidinedione 4, imidazolone 5, and lactam 6) predictably
displayed 10À8 M order potency. As a result of modification of
the spiro ring, installation of an oxo group (2b) to the spiro-lactam
ring (6c), and replacement of hetero atoms (3b, 4a) to the spiro-
imide ring (2b), activity was retained. Methylation (R2 groups) of
the imidazolidinedione core resulted in a threefold decrease in po-
tency (4a vs 4b). We next examined the substitution effect of R3
and R4 groups in the spiro ring. Incorporation of a dimethyl group
at the 3-position of the spiro-lactone ring significantly enhanced
activity;7 introduction of additional bulky substituent at the R3 po-
sition of the imidazolone ring led to more potent inhibitory activity
(5a vs 5b vs 5c). Furthermore, the X-ray co-crystal structure data of
ACC2 and (S)-1 indicates that a wide lipophilic cavity exists around
the substituent R4 and that alkyl substitution on the nitrogen of the
lactam ring potentiates ACC2 inhibitory activity. The inhibitory
activities were predictably increased in the order of an unsubsti-
tuted (6a), methyl (6b), ethyl (6c), and isopropyl group (6d) in
the lactam set. Converting the substituent on the ureide group
(R1) did not affect ACC2 inhibition (2a vs 2b, 3a vs 3b), as we pre-
viously reported.7 Regarding human metabolic stability, all spiro
derivatives exhibit an inverse correlation with their logD values
as shown in Figure 2. Among these, the imidazolone ring (red dia-
monds: 5a–c) was characterized as a metabolically liable core, par-
ticularly in the case of 5b,c. A methyl group (5a) introduced as the
R3 in the imidazolone core showed acceptable inhibitory activity
and metabolic stability. These results suggest that lipophilic substi-
tution (isopropyl) of the R4 group of 2–6 and no additional substi-
tution as R2 (hydrogen) for 4 or R3 (methyl) group for 5 are
preferable for ACC2 inhibitory activity and metabolic stability.
We next assessed the effect of introducing hetero atoms into
the benzothiophene ring to lower the lipophilicity of the com-
pounds. The results with prototype spiro-lactone are shown in
Table 2. Introduction of a nitrogen atom at the 7-position of the
benzothiophene ring (thieno[2,3-b]pyridine 7a) retained activity
compared with racemate 1 (ACC2: IC50 = 13 nM). Thieno[3,2-b]pyr-
idine 7c and thieno[2,3-b]pyrazine 7d showed slightly less potent
activity compared with 7a. Methyl substitution at the 6-position
of 7a had a minimal effect with regard to ACC2 inhibitory activity,
but rendered higher metabolic stability to 7b despite elevation of
the logD value (7b vs 7a). This result suggests that blocking the
6-position of thieno[2,3-b]pyridine core as a metabolic site may
be successful. We then evaluated various spiro-piperidines with
the 6-methylthieno[2,3-b]pyridine to confirm the potential of
improvement in metabolic stability.
6
b
7
c
4
a
Me
Me
N
S
O
N
O
O
NH
O
NH
Et
Substituents
b
IC50 (nM)
ACC1 ACC2
hMSb
logDc
a
c
7a
7b
7c
7d
C–H
C–H
N
C–H
C–Me
C–H
C–H
N
N
C–H
N
110
78
150
150
16
14
27
37
110
79
120
110
2.08
2.49
2.45
2.32
N
a
Racemate.
b
In vitro metabolic clearance in human hepatic microsomes
(
l
L/min/mg
protein).
c
logD was measured using HPLC (pH 7.4).
green method.11 The results of ACC1/2 inhibition studies, human
metabolic stability,12 and lipophilicity (logD) are summarized in
Tables 1–3. Because the IC50 ratios of the ACC2 and ACC1 inhibitory
activities were nearly the same, we primarily discuss only the SAR
for ACC2 inhibition in the present report.
First, we converted the spiro-lactone ring into various spiro-
5-membered rings to conduct a detailed investigation of SAR and
human metabolic stability (Table 1). Since designed spiro struc-
tures contain a key carbonyl group that can interact with the
Table 3
ACC inhibitory activity, human metabolic stabilities, and logD of spiro-piperidines 8
Me
N
N
S
N
O
O
NH
O
NH
R1
R1
Spiro ring
Configuration
IC50 (nM)
ACC1 ACC2
hMSa logDb
Me
N
8a
Me
S
S
48
93
4.4
9.0
90
45
2.18
2.43
Me
O
N
O
O
N
N
N
N
N
8b Et
Me
Me
O
8c
Me
S
160
160
76
8.5
33
38
47
26
2.51
2.39
2.27
N
O
Me
Me
O
N
*
O
O
8d Et
NDc
15
Me
Me
N
N
*
O
Me
Me
8e
8f
Et
Et
NDc
15
17
Me
H
N
O
Racemate
150
2.39
N
O
Me
Me
a
In vitro metabolic clearance in human hepatic microsomes
protein).
(
l
L/min/mg
Figure 2. Relationship between logD and metabolic stability of various spiro-
piperidines. Red diamonds indicate spiro-imidazolone and black diamonds indicate
other spiro derivatives.
b
logD was measured using HPLC (pH 7.4).
Absolute configuration has not been determined.
c

M. Kamata et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3643–3647
3647
Table 4
at the 6-position improved metabolic stability. We identified a
novel, highly potent, and bioavailable spiro-imide derivative 8c
possessing a thieno[2,3-b]pyridine core, which displayed high
human metabolic stability and favorable rat pharmacokinetic
profiles.
Pharmacokinetic profile of 8ca
Compound
iv (1 mg/kg)
po (3 mg/kg)
b
c
e
f
CLtotal
Vss
(L/kg) (h)
MRTd
Cmax
Tmax
AUCg
(ng h/
mL)
Fh
(%)
(L/h/kg)
(ng/mL) (h)
8c
0.95
1.3
1.3
440
0.5
1400
45
Acknowledgments
a
b
c
n = 3; Crl: CD(SD)(IGS) rats (male, 8W).
Total clearance.
Volume of distribution at steady state.
Mean residence time.
Maximal plasma concentration.
Time of maximal concentration.
Area under the plasma concentration versus time curve.
Bioavailability.
The authors appreciate the helpful discussion with Dr. Yu
Momose, and also thank Mr. Katsuhiko Miwa and Dr. Tooru
Yamano for chiral HPLC separation of compounds.
d
e
f
g
h
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.04.
047.
The results of the spiro-compounds possessing the 6-methylthi-
eno[2,3-b]pyridine are summarized in Table 3. Lactone 8a, lactam
8b, and imides 8c exhibited 10À9 M order potency and oxazolidin-
edione 8d, imidazolone 8e, and imidazolidinedione 8f also showed
10À8 M order potency; in particular, lactone 8a exhibited the most
potent activity. In addition, all enantiomers of 8a–e predictably
gave less potency as we previously reported.7 The metabolic stabil-
ity of all compounds, except for lactone 8a, significantly improved
relative to the corresponding benzothiophene derivatives 2–6.
Among these compounds, spiro-imide 8c, which showed potent
ACC inhibitory activity exhibited favorable pharmacokinetic pro-
files in rats as shown in Table 4.
References and notes
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In conclusion, to improve the metabolic stability of (S)-1, we
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lidinedione, imidazolone, or lactam scaffold displayed highly-
potent ACCs inhibitory activities. The SAR study revealed that
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ment of a nitrogen or oxygen atom on the spiro-imide ring
preserved the activity of the molecule. Moreover, bulky lipophilic
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5 was preferable for maintaining metabolic stability in humans.
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