The synthesis and structure-activity relationship studies of selective acetyl-CoA carboxylase inhibitors containing 4-(thiazol-5-yl)but-3-yn-2-amino motif: Polar region modifications

Article abstract of DOI:10.1016/j.bmcl.2006.12.047

The structure-activity relationship study focused on the polar region of the HTS hit A-80040 (1) producing several series of potent and selective ACC2 inhibitors. The SAR suggests a compact lipophilic pocket that does not tolerate polar and ionic groups.

Full text of DOI:10.1016/j.bmcl.2006.12.047

Bioorganic & Medicinal Chemistry Letters 17 (2007) 1803–1807
The synthesis and structure–activity relationship studies of selective
acetyl-CoA carboxylase inhibitors containing 4-(thiazol-5-yl)
but-3-yn-2-amino motif: Polar region modifications
Xiangdong Xu,* Moshe Weitzberg, Robert F. Keyes, Qun Li, Rongqi Wang,
Xiaojun Wang, Xiaolin Zhang, Ernst U. Frevert, Heidi S. Camp,
Bruce A. Beutel, Hing L. Sham and Yu Gui Gu
Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA
Received 14 September 2006; revised 13 December 2006; accepted 13 December 2006
Available online 21 December 2006
Abstract—The structure–activity relationship study focused on the polar region of the HTS hit A-80040 (1) producing several series
of potent and selective ACC2 inhibitors. The SAR suggests a compact lipophilic pocket that does not tolerate polar and ionic
groups. Replacement of the hydroxyurea group with isoxazoles improves ACC2 selectivity while maintaining potency. Variations
at the propargylic site of 11a reduce ACC2 potency.
Ó 2006 Elsevier Ltd. All rights reserved.
Metabolic syndrome and its associated insulin resistance
have been linked to the emerging plague of type II dia-
betes and coronary heart disease. One potential thera-
peutic approach to address insulin resistance is to
prevent the accumulation of fat in non-lipogenic tis-
sues,1 and inhibition of acetyl-CoA carboxylase (ACC)
has been suggested as an attractive mechanism for this
purpose.2,3 ACC, which catalyzes the biotin-dependent
carboxylation of acetyl-CoA to form malonyl-CoA
(mCoA), has two isoforms with distinct cellular localiza-
tions and tissue distributions.4,5 ACC1, a cytosolic en-
zyme highly expressed in liver and lipogenic tissues, is
a rate-limiting enzyme for fatty acid synthesis, whereas
ACC2, highly expressed in oxidative tissues such as
muscle, is located in the outer membrane of mitochon-
dria. It has been suggested that the mCoA produced
by ACC2 regulates carnitine palmitoyl-transferase
(CPT1),6 which transfers long chain fatty acyl-CoAs
into the mitochondria for oxidation.7–9 Thus, inhibition
of both ACC isoforms is expected to lower mCoA levels,
reduce fatty acid synthesis, and increase fatty acid
oxidation leading to improved insulin sensitivity.
Genetic studies have shown that ACC1 knockout mice
are lethal at the embryonic stage, whereas ACC2 knock-
out mice are healthy and maintain normal development
and life expectancy. Furthermore, despite consuming
more food, ACC2 knockout mice had lower body fat
mass than their wild-type counterparts and were pro-
tected from high fat induced obesity and insulin resis-
tance.6,10–12 It is conceivable that selective ACC2
inhibition may provide a superior safety profile. As a re-
sult, our research efforts have been focused on identify-
ing a selective ACC2 inhibitor as a potential therapeutic
agent for type II diabetes and obesity. Recently, we
reported the discovery of 113 (A-80040, Fig. 1) and
detailed structure–activity relationship studies on the
lipophilic region.14 In this communication, we describe
the effect of modification of the polar region of 1 on
ACC2 inhibitory activity and selectivity.
Keywords: ACC2 inhibitor; Polar region.
*
Corresponding author. Tel.: +1 847 936 3660; fax: +1 847 938
3403; e-mail: xiangdong.xu@abbott.com
Figure 1. Structure of ACC HTS hit from Abbott compound
collection.
Present address: Exploratory Clinical Development, Novartis Phar-
maceuticals, East Hanover, NJ 07936, USA.
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.12.047

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X. Xu et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1803–1807
Scheme 1. Reagents and conditions: (a) 2-bromothiazole (1 equiv), K2CO3 (1.2 equiv), DMSO, 160 °C, 4 h, 63–74%; (b) BuLi (1.2 equiv), THF
ꢀ78 °C, then I2, 84–95%; (c) 8 (1 equiv), Pd(Ph3P)2Cl2 (5%), CuI (2%), Et3N (5 equiv), CH3CN, 80 °C, 90%; (d) TBAF (1.5 equiv), THF, rt, 0.5 h, 76%;
(e) NH2NH2 (10 equiv), CH2Cl2/EtOH (10:1), reflux, 3 h; (f) i—p-nitrophenyl chloroformate (1.1 equiv), pyridine (10 equiv), CH2Cl2, rt, 90%; ii—
amines (2 equiv), Et3N (excess), CH3CN, rt or reflux; (g) acylation using anhydrides, acid chlorides, carbamoyl chlorides, and acids (or urea formation
using isocyanates) followed by deprotection or hydrolysis; (h) 9a–h (1.0 equiv), Ph3P (1.5 equiv), DEAD (1.5 equiv), THF, rt, 12 h 26–63%; (i) PhSH
(1.2 equiv), K2CO3 (4.0 equiv), DMF, rt, 2 h, 69–96%.
The general synthesis of 7a–h and 11a–o is outlined in
Scheme 1. Displacement of 2-bromothiazole with
4-phenoxyphenol in the presence of potassium carbon-
ate at 160 °C afforded the desired ether 3a. Lithiation
of 3a followed by iodination provided 4a as a single reg-
ioisomer. Sonogashira coupling15 with TBDMS-protect-
ed 3-butyn-2-ol followed by deprotection gave product
5a in 68% yield. Mitsunobu16 reaction of 5a with Boc-
protected aminoazoles did not produce the desired het-
erocyclic products in satisfactory yield. For example,
the reaction with 3-aminoisoxazole provided only 10%
of isolated product after 2 days. Therefore, we utilized
the Fukuyama methodology as a more practical synthe-
sis of compounds 7a–h.17 The reaction between the
various commercially available aminoazoles and
4-nitrophenylsulfonyl chloride afforded sulfonamide
intermediates 9a–h, which were successfully converted
to 6a–h via Mitsunobu reaction with 5a. Deprotection
of 6 with one equivalent of thiophenol in the presence
of potassium carbonate afforded the desired products
7a–h in very good yields (69–96%). Conditions employ-
ing excess thiophenol were found to exclusively produce
acetylene addition product such as 10. Compounds
11a–o were prepared from 5b as reported previously.13

X. Xu et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1803–1807
1805
Scheme 2. Reagents and conditions: (a) Ac2O (1.1 equiv), Et3N (1.5 equiv), CH2Cl2, 0 °C to rt, 70%; (b) Na2SO4 (1 equiv), H2SO4 (5 equiv), CH2CN,
ꢀ20 °C to rt, 50–74%; (c) 4b (1 equiv), Pd(Ph3P)2Cl2 (5%), CuI (2%), Et3N (5 equiv), CH3CN or THF, rt or reflux, 23–97%; (d) i—NH2NH2
(10 equiv), CH2Cl2/EtOH (10:1), reflux, 3 h; ii—Ac2O (excess), Et3N (excess), CH2Cl2; (e) BuLi (1.2 equiv), THF, ꢀ78 °C, 47%; (f) phthalimide
(1.2 equiv), Ph3P (1.5 equiv), DEAD (1.5 equiv), THF, rt, (37–94%); (g) AcOH/THF/water (3:1:1), rt, 92%.
Compounds with modifications at the a-position of the
alkyne (18a–f) were synthesized from 14a–e and 17 as
depicted in Scheme 2. Compound 14a was made by di-
rect acylation of the amine, while 14b and 14c were pre-
pared by the Ritter reaction18 with the corresponding
alcohols. Compound 18d was synthesized by conversion
of pentyn-3-ol to the corresponding phthalimidoyl-pro-
tected amine 14d and subsequent coupling with 4b fol-
lowed by deprotection and acylation. Compounds 18e
and 18f were synthesized in a similar way starting from
14e19 and 17, respectively. The latter was prepared from
TBDMS-protected hydroxyacetaldehyde 16 and alkyne
15.
Yet, polarity and size do not entirely explain the SAR
as demonstrated by the lipophilic and small thiazole
7a (IC50 of 0.69 lM), which is 16-fold less potent
than 7c. It appears that the ring oxygen or the
oxygen–nitrogen bond of the isoxazoles favorably
interacts with the ACC2 binding pocket. Overall,
aminoisoxazoles 7c and 7e–g provide potent and
selective ACC2 inhibition and therefore serve as effective
hydroxyurea replacements.
Further SAR investigations of the polar region proceed-
ed with the isopropoxy group in the lipophilic region of
the molecule since it has been shown to provide superior
selectivity and potency for ACC2 compared to other
phenyl ether replacements.14 Small amides (11a) and
carbamates (11b) are potent and selective ACC2 inhibi-
tors as discussed before (IC50s of 0.019 and 0.096 lM,
respectively).13 Similar potency and selectivity profiles
are achieved when small urea groups are introduced
(11c–e). The ACC2 potencies of methyl and dimethyl
urea derivatives 11d and 11e, respectively, are similar
to that of the parent unsubstituted analog (11c). Howev-
er, as the substituents on the terminal urea nitrogen
grow larger the potency decreases. Bulky urea analogs
11g and 11j are roughly 20-fold less potent than 11c,
while 11i, with an IC50 of 20 lM, is relatively inactive.
Similar to the urea series, increasing the amide size leads
to diminished ACC2 potency as demonstrated by the
The SAR results on the polar region of 1 are summa-
rized in Table 1. The cyclic aminoazoles 7a–h in Table
1 were initially investigated as hydroxyurea replace-
ments of HTS hit 1. These compounds are comprised
of varying polarities, hydrogen bond properties, and ste-
ric features. It is interesting that all of the aminoazoles
exhibit significantly less potency for the ACC1 isoform.
The ACC2 data for 7a–h portrays a compact pocket that
tolerates neither large groups, as exemplified by benzo-
thiazole 7b (IC50 >30 lM), nor polar aminoazoles such
as imidazole 7d (IC50 of 3.98 lM). Only the relatively
small and lipophilic isoxazole analogs (7c and 7e–g,
IC50s of 0.042, 0.083, 0.057, and 0.038 lM, respectively)
retain the ACC2 potency of the parent hydroxyurea 1.

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X. Xu et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1803–1807
Table 1. Human ACC enzymatic activity for compounds 1, 7a–h, 11a–o, and 18a–fa
Compound
R
R0
R00
ACC1 IC50 (lM)
ACC2 IC50 (lM)
1
7a
1.00
10.68
>30
5.02
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
0.075
0.69
>30
2-Thiazolyl
7b
7c
2-Benzothiazolyl
3-Isoxazolyl
2-Imidazolyl
5-Methyl-3-isoxazolyl
3-Methyl-5-isoxazolyl
3,4-Dimethyl-5-isoxazolyl
1-Ethyl-3-pyrazolyl
Me
0.042
3.98
0.083
0.057
0.038
0.44
0.019
0.096
0.037
0.032
0.071
0.33
0.67
0.68
20.49
0.92
0.85
>30
7d
7e
7f
7g
7h
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j
11k
11l
11m
11n
11o
18a
18b
18c
18d
18e
18f
OMe
NH2
NHMe
N(Me)2
NHOH
4-Morpholinyl
ONH2
NHOiBu
NHCH2CONH2
CO2Me
CO2H
Cyclopentyl
3-Tetrahydrofuranyl
(S)-2-Pyrrolidinyl
0.57
0.22
>30
H
H
Me
1.86
0.50
>30
Me
H
Ph
Et
H
0.53
0.88
0.91
H
Cyclopropyl
CH2OH
H
a Enzymatic inhibition values of recombinant human ACC1 and ACC2, which were determined by measuring the incorporation of ACC-mediated
14C] CO2 into malonyl-CoA.
[
methyloxalate (11k), cyclopentyl (11m), and 3-tetrahy-
drofuranyl (11n) analogs (ACC2 IC50s of 0.85, 0.57,
and 0.22 lM, respectively) which are significantly less
potent than 11a. The polar and small hydroxylamine
11h and hydroxyurea 11f (ACC2 IC50s of 0.68 and
0.33 lM, respectively) are weaker than 11b and 11c,
respectively, suggesting that added polarity is not favor-
able. Moreover, introducing acidic (11l) or basic (11o)
groups sharply decreases ACC2 activity (IC50s of
>30 lM). Consistent with the aminoazoles, the SAR in
this region suggests a compact binding pocket that nei-
ther tolerates ionic groups nor interacts significantly
with polar functionalities.
Modifications of HTS hit 1 have focused on the polar re-
gion. Aminoisoxazoles effectively replace the hydroxy-
urea group of 1, maintain its ACC2 potency, and
achieve a very good level of selectivity against ACC1
(>1000). SAR findings for aminoazoles and other
amide-like hydroxyurea replacements demonstrate a
lipophilic and compact binding pocket that does not tol-
erate polar or ionic interactions. Compared to the
monomethyl group, all variations at the propargylic po-
sition decreased ACC2 potency.
Acknowledgments
The tolerance for substitution at the propargylic posi-
tion of lead compound 11a was also explored. Com-
pared with 11a (IC50 of 0.019 lM), both removal (18a)
and addition (18b) of a methyl group at the a position
of the alkyne cause significant drop in ACC2 potency
(IC50s of 1.86 and 0.5 lM, respectively). Furthermore,
when the size is increased from methyl to ethyl (18d),
cyclopropyl (18e), and phenyl (18c), the ACC2 potency
correspondingly diminishes (IC50s of 0.53, 0.88, and
>30 lM, respectively). Introducing polar functionality
such as a hydroxymethyl group (18f) produces only
modest ACC2 potency (IC50 of 0.91 lM) which is in line
with the activity for the similar-sized ethyl analog 18d.
Generally, changes at the propargylic position of 11a
have no effect on ACC1 inhibition.
We thank Richard F. Clark and Dr. Teresa McNally for
their helpful suggestions in the preparation of this
manuscript.
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