Structure-activity relationships for a novel series of thiazolyl phenyl ether derivatives exhibiting potent and selective acetyl-CoA carboxylase 2 inhibitory activity

Article abstract of DOI:10.1016/j.bmcl.2006.08.100

Structure-activity relationships for a recently discovered thiazolyl phenyl ether series of acetyl-CoA carboxylase (ACC) inhibitors were investigated. Preliminary efforts to optimize the series through modification of the distal aryl ether moiety of the l

Full text of DOI:10.1016/j.bmcl.2006.08.100

Bioorganic & Medicinal Chemistry Letters 16 (2006) 6078–6081
Structure–activity relationships for a novel series of thiazolyl phenyl
ether derivatives exhibiting potent and selective acetyl-CoA
carboxylase 2 inhibitory activity
Richard F. Clark,* Tianyuan Zhang, Zhili Xin, Gang Liu, Ying Wang,
T. Matthew Hansen, Xiaojun Wang, Rongqi 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 27 July 2006; revised 24 August 2006; accepted 28 August 2006
Available online 14 September 2006
Abstract—Structure–activity relationships for a recently discovered thiazolyl phenyl ether series of acetyl-CoA carboxylase (ACC)
inhibitors were investigated. Preliminary efforts to optimize the series through modification of the distal aryl ether moiety of the lead
scaffold resulted in the identification of compounds exhibiting low-nanomolar potency and isozyme-selective ACC2 activity.
Ó 2006 Elsevier Ltd. All rights reserved.
The obesity epidemic in developed countries is linked to
an alarming rise in the prevalence of type 2 diabetes.
Although the precise mechanisms underlying this associ-
ation are unclear, the accumulation of fat in non-lipo-
genic tissues is increasingly recognized as a key causal
factor in the development of insulin resistance, an ante-
cedent of type 2 diabetes and other obesity-related disor-
ders.1–5 As critical regulators of fatty acid metabolism,
acetyl-CoA carboxylases (ACCs) present attractive tar-
gets for the reduction of whole body lipid content and
normalization of insulin sensitivity.6–9 In humans and
other mammals ACC exists in two tissue-specific iso-
forms. ACC1 catalyzes fatty acid synthesis in liver and
adipose tissue while ACC2 regulates fatty acid oxidation
in oxidative tissues such as heart and skeletal mus-
cle.10,11 Recent findings reported by Pfizer researchers
for isozyme-nonselective ACC inhibitor 1 (CP-640186,
Fig. 1)12,13 as well as studies conducted by Wakil and
co-workers on ACC2-deficient mice14–16 have validated
the therapeutic potential of ACC inhibition. Significant-
ly, the latter studies demonstrated that while ACC2À/À
mice were healthy and displayed a favorable metabolic
profile, ACC1 knockout resulted in embryonic lethali-
N
O
O
N
N
O
1
O
S
NH
N
O
O
2
Figure 1.
ty,17 suggesting that selective ACC2 inhibition may pro-
vide a safer therapeutic approach for chronic treatment
of obesity, diabetes, and other symptoms of the meta-
bolic syndrome.
Although several classes of isozyme-nonselective inhibi-
tors, exemplified by 1, have been described,6,7 reports of
isozyme-selective ACC2 inhibitors are lacking. Recently
our laboratories reported the identification of com-
pound 2 as a potent and selective inhibitor of ACC2.18
Based on the promise of these preliminary findings we
investigated the potential for further ACC2 potency
improvements within the series through modification
of the synthetically attractive isopropyl ether region of
the lead scaffold.
Keywords: Acetyl-CoA carboxylase; Insulin resistance; Obesity; Type 2
diabetes.
*
Corresponding author. Tel.: +1 847 938 2509; fax: +1 847 938
3403; e-mail: rick.clark@abbott.com
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.08.100

R. F. Clark et al. / Bioorg. Med. Chem. Lett. 16 (2006) 6078–6081
6079
O
N
Br
S
Br
H
O
O
S
S
OH
N
5
Br
X
X
X
NH
N
N
O
a
b
3
4
6a–6k
X = H, 2-OR, 3-OCF3,
3- or 4-OH, 3- or 4-OPh,
4-S(i-Pr), 4-CH2(i-Pr), 3- or 4-CO2Et
c (X = 4-OH)
d (X = 3- or 4-CO2Et)
e or f (X = 3- or 4-OH)
g (X = 4-S(i-Pr))
MeO
R4
O
S
NH
O
S
N
O
5
S
O
Y
Br
Y
NH
R3
N
N
b
O
9a : R3 = H, R4 = OMe
9b : R3 = OMe, R4 = H
7a–7z
8
Y = 4-O(Pyridin-2-yl),
4-O(Thiazol-2-yl), 3- or 4-CO2NHR
Y = 4-OCH2CO2Me
Y = 4-OCH2CO2H
Y = 4-OCH2CONHMe
h
i
Scheme 1. Reagents and conditions: (a) K2CO3, DMF, 125–180 °C, conventional or microwave heating, 51–84%; (b) Pd(PPh3)2Cl2 (cat.), CuI (cat.),
Et3N, THF, 80 °C in sealed pressure tube, 53–89%; (c) 2-fluoropyridine or 2-bromothiazole, K2CO3, DMF, 170 °C, microwave heating, 28–43%; (d)
i—LiOH, EtOH, rt, 79–87%; ii—oxalyl chloride, DMF (cat.), CH2Cl2, rt; iii—RNH2, Et3N, CH2Cl2, rt, 85–96%, 2 steps; (e) ROH, diethyl
azodicarboxylate, PPh3, THF, rt, 24–67%; (f) i-PrNCO, Et3N, THF, rt, 33%; (g) m-CPBA, CHCl3, 0 °C, 2 h, 69%; (h) LiOH, MeOH, rt, 98%; (i)
methylamine hydrochloride, TBTU, Hunig’s Base, DMF, rt, 85%.
As depicted in Scheme 1, a convergent and general route
for the rapid synthesis of target analogs was devel-
oped.19 Selective displacement of 2,5-dibromothiazole
by readily available phenols (3) at elevated temperatures
provided intermediates 4 which were elaborated in good
yields to the corresponding alkynyl products 6 and 7 un-
der Sonogashira coupling conditions either directly or
after subsequent functionalization as outlined. Requisite
alkyne 5 was prepared from 3-hydroxy-3-methyl-1-bu-
tyne by the Ritter reaction using a published proce-
dure.20 With the exception of compound 6f, all 4- and
3-substituted alkyl ethers represented in Table 1 (7a–
7k, 7n–7p, and 7v–7z) were synthesized from advanced
intermediates 6 (X = 3- or 4-OH), using the Mitsunobu
reaction and an appropriate alcohol. Carbamate 7r
was also prepared from 6 (X = 4-OH) employing isopro-
pyl isocyanate in the presence of triethylamine. Con-
versely, the synthesis of 2-alkoxy derivatives 6g–6i,
phenyl ethers 6d and 6e, and trifluoromethoxy analog
6f utilized fully functionalized phenol precursors. Acid
7l and amide 7m were derived from ester 7k by sequen-
tial saponification and coupling to methylamine in the
presence of TBTU. Heteroaryl ethers 7i and 7j were ac-
cessed through the displacement of 2-fluoropyridine and
O
O
a
O
OH
b, c
OH
10
Scheme 2. Reagents and conditions: (a) i-PrMgBr, THF, 0 °C, 57%;
(b) Et3SiH, CF3COOH, CH2Cl2, rt, 97%; (c) BBr3, CH2Cl2, 0 °C to rt,
94%.
isole which upon deprotection in the presence of boron
tribromide gave the desired phenol (10) in good overall
yield. Sulfur- and nitrogen-linked derivatives 6b and 6c
were prepared as previously described.18 In turn, oxida-
tion of thioether 6b under standard conditions with 3-
chloroperbenzoic acid yielded sulfone 7q.
Our initial structure–activity relationship (SAR) efforts
sought to define preferred steric and physicochemical
parameters for substitution at the C-4 isopropyl ether
position in parent compound 2. As shown in Table 1,
the size and nature of distal ether adducts were key
determinants of both potency and selectivity within the
series. In general, a hydrophobic binding element was
required to achieve optimal activity against ACC2.
Incorporation of polar functionality into position 4
ether extensions led to uniform reductions in potency.
Although acid, ester, amide, and amine side chains were
particularly detrimental (7k–7n), the introduction of less
hydrophilic ether and heteroaromatic groups was better
tolerated (7o, 7p vs 7e, 7g, and 7i vs 6d). As exemplified
by compounds 6d and 7a–7h a variety of lipophilic ether
groups exhibited excellent ACC2 activity. Compared to
2-bromothiazole, respectively, with intermediate
4
(X = 4-OH) prior to palladium-catalyzed coupling with
alkyne 5. Similarly, ethyl esters 4 (X = 3- or 4-CO2Et)
were transformed to corresponding isopropyl and isobu-
tyl amides before conversion to final products 7s–7u.
Synthesis of 6a, the carbon-linked homolog of parent
isopropyl ether 2, required the preparation of 4-isobu-
tylphenol 10, which was synthesized according to the
reaction sequence shown in Scheme 2. Treatment of 4-
formylanisole with isopropylmagnesium bromide at
0 °C followed by reduction of the resulting alcohol with
triethylsilane–trifluoroacetic acid provided 4-isobutylan-

6080
R. F. Clark et al. / Bioorg. Med. Chem. Lett. 16 (2006) 6078–6081
Table 1. ACC inhibitory activitya for derivatives 6, 7, and 9
Compound
X or Y
ACC1 IC50 (lM)
ACC2 IC50 (lM)
ACC1/ACC2b
1c
CP-640186
4-O(i-Pr)
0.41
>30
1.12
0.37
>30
0.26
0.65
>30
>30
>30
>30
>30
>30
>30
>30
0.14
0.23
0.47
0.12
0.028
0.086
2.12
6.79
>30
>30
>30
>30
>30
0.76
3.70
2.42
>30
1.28
3.78
>30
0.066
0.056
0.072
1.15
>30
>30
0.038
0.019
0.081
0.055
0.150
0.011
0.076
0.13
11
>1579
14
2
6a
6b
6c
6d
6e
6f
4-CH2(i-Pr)
4-S(i-Pr)
4-NH(i-Pr)
7
>200
24
4-OPh
3-OPh
9
3-OCF3
2-OMe
>227
>23
>23
>5
>15
>18
>64
>811
35
6g
6h
6i
1.32
1.31
2-OEt
2-O(i-Pr)
6.16
1.96
6j
4-H
4-OH
6k
7a
7b
7c
7d
7e
7f
1.70
0.47
4-OMe
4-OEt
0.037
0.004
0.010
0.013
0.016
0.005
0.027
0.057
0.29
4-OPr
4-O(i-Bu)
23
36
4-O(Cyclopentyl)
4-O(Cyclohexyl)
4-OCH2(Cyclopentyl)
4-OCH2(Cyclohexyl)
4-O(Pyridin-2-yl)
4-O(Thiazol-2-yl)
4-OCH2CO2Me
4-OCH2CO2H
4-OCH2CONHMe
4-O(CH2)3NMe2
4-O(THFd-3-yl)
4-OCH2(THFd-3-yl)
4-SO2(i-Pr)
4-OCONH(i-Pr)
4-CONH(i-Pr)
4-CONH(i-Bu)
3-CONH(i-Bu)
3-OMe
7
7g
7h
7i
6
3
37
7j
23
7k
7l
1.62
>19
1
>30
7m
7n
7o
7p
7q
7r
7s
7t
26.50
>30
0.37
>1
1
>82
11
0.067
4.05
0.34
1
7
19.48
0.35
0.38
>1
4
7u
7v
7w
7x
7y
7z
9a
9b
10
0.85
>35
5
3-O(i-Pr)
3-O(Cyclohexyl)
3-O(i-Bu)
3-O(THFd-3-yl)
3,4-dimethoxy
3,5-dimethoxy
0.014
0.026
0.013
0.21
2
6
6
>30
>30
1
1
a Inhibitory activity was determined using recombinant human ACC1 and ACC2 in an assay measuring ACC-mediated [14C]CO2 incorporation into
malonyl-CoA. Detailed protocols are described in Ref. 18.
b ACC2 selectivity expressed as rounded ratio of ACC1 IC50/ACC2 IC50
.
c Published IC50 values for compound 1 (Ref. 13) utilizing rat ACC1 (IC50 = 53 nM) and ACC2 (IC50 = 61 nM) enzyme sources were less ACC2
selective than corresponding values generated under our assay conditions.
d Tetrahydrofuran (THF).
2, position 4 side chains smaller than ethoxy were signif-
icantly less potent (6j, 6k, and 7a) while larger, chain-ex-
tended ether groups with enhanced flexibility resulted in
4- to 5-fold improvements in ACC2 activity (7c and 7g).
In fact, compounds 7c (IC50 = 4 nM) and 7g
(IC50 = 5 nM) were among the most potent ACC2 inhib-
itors identified in our study. However, since productive
binding to the ACC1 isozyme is also dependent on rela-
tively large C-4 alkoxy substituents (7c–7h vs 7a, 7b, 2),
the excellent potency associated with these analogs was
realized at the expense of ACC2 selectivity. Therefore,
relative to other potent derivatives, only the ethyl and
isopropyl ether adducts (7b and 2) appear to provide de-
grees of hydrophobicity and steric compactness suffi-
cient for both good potency (19–34 nM) and robust
ACC2 selectivity (>800-fold).
Having defined general SAR patterns for C-4 aryloxy
substitution we then investigated alternative linking
groups (6a–6c and 7q–7t). While replacement of the oxy-
gen linker in 2 with carbon (6a), sulfur (6b), or nitrogen
(6c) atoms produced good ACC2 activity as anticipated,
only the nitrogen-linked variant exhibited ACC2 selec-
tivity approximating that of the parent compound. In
line with SAR findings discussed above, the slightly larg-
er atomic size of sulfur relative to oxygen may explain
the improved ACC1 activity and corresponding loss of
selectivity observed for thioether 6b. However, the rela-
tively good ACC1 potency displayed by carbon-linked
analog 6a is more difficult to rationalize within this sub-
series. The introduction of sulfone (7q), carbamate (7r),
and amide (7s) groups in place of oxygen resulted in
more dramatic potency losses, although these effects

R. F. Clark et al. / Bioorg. Med. Chem. Lett. 16 (2006) 6078–6081
6081
appear to be mitigated by incorporation of more flexi-
ble, hydrophobic side chains that compensate for the rel-
ative rigidity and polarity of these linkers (7s vs 7t).
References and notes
1. Unger, R. H. Endochrinology 2005, 144, 5159.
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Regioisomeric preferences were also studied. In terms of
overall activity, positions 3 and 4 on the phenyl ring
were found to be preferred points of attachment for dis-
tal binding substituents. C-2 alkoxy ethers were uni-
formly less favored (6g–6i), particularly when larger,
sterically demanding groups were introduced (6i vs 2
and 7w). Generally, C-3 adducts displayed similar
ACC2 potency, enhanced ACC1 activity, and conse-
quently, reduced ACC2 selectivity in comparison to cor-
responding C-4 derivatives (2 vs 7w, 7d vs 7y, 7f vs 7x,
and 7o vs 7z). Despite the inherent lack of selectivity
for position 3 analogs, it is interesting that replacement
of the C-3 methoxy group in 7v with the similarly com-
pact yet more hydrophobic trifluoromethoxy variant
(6f) resulted in reasonably potent and selective ACC2
inhibition. These findings are consistent with trends ob-
served for C-4 substitution and reveal a general require-
ment for sterically compact hydrophobic substituents,
regardless of regiochemistry.
4. Friedman, J. Nature 2002, 415, 268.
5. Arner, P. Diabetes Metab. Res. Rev. 2002, 18, S5.
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7. Harwood, H. J., Jr. Expert Opin. Ther. Targets 2005, 9,
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8. Tong, L. Cell. Mol. Life Sci. 2005, 62, 1784.
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L. M.; Perry, D. A.; Makowski, M. R.; Hargrove, D. M.;
Martin, K. A.; Tracey, W. R.; Chapman, J. G.; Magee, W.
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15. Abu-Elheiga, L.; Oh, W.; Kordari, P.; Wakil, S. J. Proc.
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Finally, given the favorable ACC2 activity exhibited by
monoalkoxy groups tethered to either the C-3 or C-4
position of the phenyl ring, we also preliminarily inves-
tigated whether further potency improvements might be
gained by installing additional alkyl ether groups at
these positions. Compared to methoxy derivatives 7a
and 7v, 3,4- and 3,5-dimethoxy ethers 9a and 9b21 dis-
played greatly reduced activity indicating that multiple
distal alkoxy ring substituents have detrimental rather
than additive effects.
16. Oh, W.; Abu-Elheiga, L.; Kordari, P.; Gu, Z.; Shaikenov,
T.; Chirala, S. S.; Wakil, S. J. Proc. Natl. Acad. Sci.
U.S.A. 2005, 102, 1384.
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18. Gu, Y. G.; Weitzberg, M.; Clark, R. F.; Xu, X.; Li, Q.;
Zhang, T.; Hansen, T. M.; Liu, G.; Xin, Z.; Wang, X.;
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In summary, we have investigated the tolerance for varia-
tion of the isopropyl ether moiety in recently discovered
lead compound 2. SAR requirements for potent, selective
ACC2 inhibition were established. By tuning the size, nat-
ure, and regiochemistry of distal binding elements, excep-
tional levels of potency and selectivity were realized
within the structural series. Sterically compact alkoxy
substituents tethered to the C-4 position of the phenyl ring
provided the most selective ACC2 activity (>800-fold)
while larger, more flexible hydrophobic ethers produced
superior, though non-selective ACC2 potency
(IC50s ꢀ 4–5 nM). Although no modification in our study
resulted in a better overall profile than parent compound
2, the insights gained from this work will facilitate future
optimization efforts in other domains ofthe lead template.
19. Final compounds were isolated using either flash chroma-
tography on silica gel or reverse-phase HPLC on a Waters
Sunfire C18 column with a gradient of 5–95% acetonitrile:
0.1% aqueous trifluoroacetic acid. All analogs were in full
1
agreement with proposed structures by H NMR, HPLC,
and MS (>95% purity).
20. Gardner, J. N. Can. J. Chem. 1973, 51, 1416.
21. Compounds 9a and 9b were synthesized from commer-
cially available 3,4- and 3,5-dimethoxy phenols according
to reaction sequences described in Scheme 1.