2-Arylbenzoxazoles as CETP inhibitors: Substitution of the benzoxazole moiety

Article abstract of DOI:10.1016/j.bmcl.2009.10.099

A series of 2-arylbenzoxazole inhibitors of the cholesterol ester transfer protein (CETP) is described. Structure-activity studies focused on variation of the substitution of the benzoxazole moiety. Substitution at the 5- and 7-positions of the benzoxazol

Full text of DOI:10.1016/j.bmcl.2009.10.099

Bioorganic & Medicinal Chemistry Letters 20 (2010) 346–349
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
2-Arylbenzoxazoles as CETP inhibitors: Substitution of the benzoxazole moiety
a
a
a
b
b
Cameron J. Smith a, , Amjad Ali , Liya Chen , Milton L. Hammond , Matt S. Anderson , Ying Chen ,
Suzanne S. Eveland b, Qiu Guo b, Sheryl A. Hyland b, Denise P. Milot b, Carl P. Sparrow b,
Samuel D. Wright b, Peter J. Sinclair a
*
a Department of Medicinal Chemistry, Merck Research Laboratories, Rahway NJ 07065, United States
b Department of Cardiovascular Diseases, Merck Research Laboratories, Rahway NJ 07065, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 2-arylbenzoxazole inhibitors of the cholesterol ester transfer protein (CETP) is described.
Structure–activity studies focused on variation of the substitution of the benzoxazole moiety. Substitu-
tion at the 5- and 7-positions of the benzoxazole moiety was found to be beneficial for CETP inhibition.
Compound 47 was found to be the most potent inhibitor in this series and inhibited CETP with an IC50 of
28 nM.
Received 26 June 2009
Revised 23 October 2009
Accepted 26 October 2009
Available online 29 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Cholesteryl ester transfer protein
CETP
High density lipoprotein
HDL
Benzoxazole
O
O
O
Coronary heart disease (CHD) is now the leading cause of death
of people in developed countries. Elevated levels of low-density
lipoprotein-cholesterol (LDL-C) has been identified as a major risk
factor for CHD. The development of the statins has significantly
helped to reduce LDL-C levels in patients at risk for CHD.1,2 There
is now a growing body of epidemiological evidence linking in-
creased levels of high density lipoprotein-cholesterol (HDL-C) with
decreased risk of development of CHD.3–6 Some cholesterol lower-
ing drugs, including niacin, fibrates and statins, have a modest ef-
fect on increasing HDL-C levels.7–10 Regardless, niacin remains the
front line therapy for raising HDL-C levels despite its modest effi-
cacy (ꢀ20% increase). Consequently there is a need for better ther-
apies to address this problem.
O
O
F3C
NH
S
O
N
F3C
torcetrapib
CF3
dalcetrapib (JTT-705)
O
F
The beneficial effects of high density lipoprotein (HDL) are
thought to arise from its participation in reverse cholesterol trans-
port (RCT) as well as its anti-inflammatory and anti-oxidant prop-
erties.11,12 Cholesteryl ester transfer protein (CETP) mediates the
exchange of cholesteryl ester (CE) from HDL with triglycerides pri-
marily from very low-density lipoprotein (VLDL).11,12 Inhibition of
CETP would therefore be expected to increase serum HDL-C levels.
Clinical studies in humans with the CETP inhibitors, dalcetrapib
(JTT-705),13,14 torcetrapib,15–19 and anacetrapib20–22 established
that pharmacological inhibition of CETP leads to significant in-
creases in HDL-C concentrations. Despite this observation, imaging
F3C
N
O
O
CF3
F3C
anacetrapib
studies with torcetrapib showed the compound had no effect on
the progression of atherosclerosis.23–25 Additionally, the torcetra-
pib phase III trial was prematurely halted after the observation of
* Corresponding author. Tel.: +1 732 594 2529; fax: +1 732 594 9545.
E-mail address: cameron_smith@merck.com (C.J. Smith).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.10.099

C. J. Smith et al. / Bioorg. Med. Chem. Lett. 20 (2010) 346–349
347
increased mortality in patients receiving torcetrapib and atorva-
statin relative to the atorvastatin-only group.19 This adverse effect
may have been related to the observation of an increase in mean
systolic blood pressure in the torcetrapib treated arm. There is cur-
rently significant debate over whether the adverse effects observed
with torcetrapib were caused by mechanism based factors or off-
target activities.26–28 Despite the uncertainty regarding the viabil-
ity of CETP inhibitors, there is continued interest in the develop-
carboxylic acid 2 was synthesized from phenoxyacetic acid 3 by
first treating with oxalyl chloride to form the corresponding acid
chloride 4. Coupling with 4-aminobenzoic acid afforded carboxylic
acid 2. Benzoxazoles were then synthesized by one of three meth-
ods.31 Activation of 2 as the corresponding acid chloride using oxa-
lyl chloride followed by coupling with a range of substituted 2-
aminophenols afforded amides of the general structure 6. A solu-
tion of amides 6 in xylene was heated at reflux in a Dean–Stark
apparatus with either p-tolenesulfonic acid or pyridinium p-tolu-
enesulfonic acid, to afford 2-arylbenzoxazoles of general structure
7. Alternatively, a solution of carboxylic acid 2, a 2-aminophenol
and boric acid in xylene could be heated at reflux or subjected to
microwave irradiation at 270 °C to afford the corresponding 2-aryl-
benzoxazole. 2-Aminophenols were either commercially available
or obtained by reduction of the corresponding 2-nitrophenol using
either heterogeneous palladium or platinum oxide catalyzed
hydrogenation or treatment with tin (II) chloride (Scheme 2). Some
2-nitrophenols were obtained by nitration of the corresponding
phenols.
ment of
a
cardiovascular drug against this target. This
communication details the identification and optimization of a ser-
ies of 2-arylbenzoxazole based CETP inhibitors.
Inhibition of CETP mediated CE transfer was characterized
in vitro using a fluorescence transfer assay.29 The assay uses syn-
thetic HDL donor particles that contain self-quenching BODIPY la-
beled CE along with an additional fluorescence quencher. As the
BODIPY labeled CE is transferred from the donor particle to an
acceptor lipoprotein by CETP, fluorescence is observed and quanti-
fied. Inhibition of CETP mediated CE transfer was characterized by
a decrease in levels of fluorescence observed relative to control.
A high throughput screen of compounds in the Merck collection
The CETP inhibition data for a series of compounds of different
benzoxazole phenyl ring substitution is shown in Table 1 and it can
be seen that substitution of this ring appreciably alters CETP inhib-
itory activity. The unsubstituted benzoxazole (8) was 10-fold less
active than lead compound 1. A survey of a series of benzoxazole
substituents (compounds 9–22) showed a clear preference for sub-
stitution at the 5-position. In particular the 5-nitro and 5-cyano
at 2 lM using the above assay was conducted and hits were con-
firmed by titration. 2-Arylbenzoxazole 1 was identified as a screen-
ing hit. This lead class was also independently identified by
researchers at Bristol–Myers Squibb and published subsequent to
our studies.30 Their work showed the importance of substitution
at the benzoxazole 5-position on potency of CETP inhibition. The
work described in this publication is consistent with that described
by BMS, but also shows that further substitution of the benzoxaz-
ole moiety at the 7-position leads to compounds with additional
enhancement of CETP inhibition.
OH
OH
OH
a
b, c, d or e
R
R
R
NO2
NH2
O
O
Scheme 2. Reagents and conditions: (a) 90% HNO3, AcOH, 40 °C to room temper-
ature, 1 h, 16–70%; (b) H2, 10% Pd/C, EtOH, room temperature, 5–15 h, 97–99%; (c)
HCO2NH4, 10% Pd/C, MeOH, room temperature, 15 h, quant.; (d) H2, PtO2, EtOH,
room temperature, 2–15 h, 99%; (e) SnCl2Á2H2O, concd HCl, MeOH, room temper-
ature, 15 h, 38–97%.
O
N
NH
Cl
1
The development of lead compound 1 began with the investiga-
tion of the effect of variation of the substitution of the benzoxazole
moiety. The synthetic approach used is shown in Scheme 1. Key
Table 1
SAR of 2-arylbenzoxazoles
R4
O
O
O
O
a
7
R3
R2
6
5
O
N
HO
Cl
NH
O
3
4
4
R1
O
O
O
Compd
R1
R2
R3
R4
CEa
M)
O
b
a
NH
IC50
(l
% Max
HO
8
1
9
H
H
H
H
Me
H
H
NO2
H
H
H
H
H
H
Cl
H
H
H
Me
H
H
NO2
H
F
H
H
CN
H
H
H
H
Cl
H
H
H
Me
H
H
NO2
H
F
H
H
CN
H
H
H
H
Cl
H
H
H
H
H
H
H
H
F
13
1.1
79
94
32
71
62
89
34
42
79
71
91
50
36
90
97
89
2
n.d.b
21
O
O
O
c
10
11
12
13
14
15
16
17
18
19
20
21
22
NH
R
23
2.0
NH
n.d.b
n.d.b
0.94
3.2
6
OH
O
O
d
R
O
N
1.9
7.5
NH
e
or 2
n.d.b
0.13
0.41
5.2
7
H
H
H
H
H
CN
Scheme 1. Reagents and conditions: (a) (COCl)2, cat. DMF, CH2Cl2, room
temperature, 1 h, quant.; (b) 4-aminobenzoic acid, i-Pr3NEt, CH2Cl2, room temper-
ature, 30 min, 87%; (c) (i) (COCl)2, cat. DMF, CH2Cl2, room temperature, 2 h; (ii) 2-
aminophenol derivative, 1,4-dioxane, reflux, 2 h; (d) cat. TsOH or PPTS, xylene,
reflux under Dean–Stark, 16 h, 10–53%; (e) 2-aminophenol derivative, boric acid,
xylene, reflux, 24 h, 7–37%, or microwave irradiation, 270 °C, 1 h, 7–33%.
a
Data reported is derived from duplicate wells and three independent experi-
ments. Mean IC50 values were determined from 10-point, one-third log concen-
tration response curves and standard errors were 610%.
b
IC50 not determined if % max inhibition was <50%.

348
C. J. Smith et al. / Bioorg. Med. Chem. Lett. 20 (2010) 346–349
Table 3
derivatives 15 and 20 were found to be the most potent CETP
inhibitors with IC50s of 0.94 and 0.13 M, respectively. Compounds
SAR of disubstituted-2-arylbenzoxazoles
l
23–29 (Table 2) represent a series of substitutions that are toler-
ated at the 5-position with only methoxy (compound 24) showing
better potency than the original lead 1. Other 5-substituents such
as larger alkyl, trifluoromethyl, methyl ester, carboxylic acid,
amides, carbamates, sulfonamides, sulfones, hydroxyl, anilino,
amidine, tetrazole and substituted phenyl were found to have little
or no inhibitory activity (data not shown). The best 5-substituted
derivative found was therefore 5-cyano derivative 20 and this rep-
resented an early benchmark compound. This was consistent with
the work published by researchers at Bristol–Myers Squibb.30
Holding the cyano group constant, the SAR of additional benz-
oxazole substitution was then explored (Table 3). The three possi-
ble regioisomeric methyl derivatives 31, 33 and 35 were prepared
via palladium catalyzed cyanation of the corresponding aryl ha-
lides 30, 32 and 34, respectively. The CETP inhibition data clearly
shows that incorporation of a methyl group is preferred at the 7-
position and affords a twofold increase in potency (compare 35
to 20 and 34 to 23). Compound 35 has a CETP IC50 of 60 nM. Com-
pounds 36–41 show that a number of other substituents are toler-
ated at the 7-position in combination with either 5-cyano or 5-halo
the most potent being 5-cyano-7-fluoro derivative 39 with a CETP
IC50 of 62 nM.
R4
7
R3
R2
6
5
O
N
NH
O
4
R1
O
Compd
R1
R2
R3
R4
CEa
IC50 (lM)
30
31
32
33
34
35
36
37
38
39
40
41
Me
Me
H
H
H
H
H
H
H
Br
CN
Cl
CN
Br
CN
CN
Cl
H
H
Me
Me
H
H
H
H
H
H
H
H
H
Me
Me
CN
NO2
F
>100
38
>100
1.9
0.51
0.060
0.27
0.57
0.91
0.062
0.38
0.086
Br
CN
Br
H
H
H
H
H
H
F
COMe
COMe
CN
a
Data reported is derived from duplicate wells and three independent experi-
ments. Mean IC50 values were determined from 10-point, one-third log concen-
tration response curves and standard errors were 610%.
The substitution of the 7-position was further investigated by
the synthesis of a series of alcohols (compounds 44–57, Table 4).
These compounds were synthesized from acetophenone 40 as
shown in Scheme 3. Treatment of ketone 40 with sodium borohy-
dride or a Grignard reagent afforded secondary or tertiary alcohols
respectively of general structure 42. These compounds were then
transformed into nitriles of general structure 43 via palladium cat-
alyzed cyanation. By and large, potency of CETP inhibition is inver-
sely proportional to the size of the alkyl group added to
acetophenone 40, the best compound being methyl derivative 47
with a CETP IC50 of 28 nM. Replacement of the 5-cyano group of
47 with a hydrogen to give compound 57 results in a 10-fold loss
in potency of CETP inhibition confirming the importance of substi-
tution at both the 5- and 7-positions.
Table 4
SAR of 5,7-disubstituted-2-arylbenzoxazoles
R3
R2
OH
7
6
O
NH
O
R1
N
5
4
O
Compd
R1
R2
R3
CEa
IC50 (lM)
44b
45
46
47
48
49
50
51
52
53
54
55
56
57c
Br
CN
Br
CN
Br
CN
Br
CN
Br
CN
Br
Br
CN
H
H
H
Me
Me
Me
Me
Et
0.059
0.046
0.044
0.028
0.11
0.031
0.20
0.058
0.21
0.080
0.094
0.21
0.16
0.44
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Compounds 20, 35 and 47 were evaluated in a pharmacody-
namic model in mice expressing cynomolgus monkey CETP and
Et
n-Pr
n-Pr
i-Pr
i-Pr
Ethynyl
1-Propynyl
1-Propynyl
Me
Table 2
SAR of 5-substituted-2-arylbenzoxazoles
7
6
O
NH
R1
N
5
4
O
O
a
Compd
R1
CEa
IC50 (lM)
Data reported is derived from duplicate wells and three independent experi-
a
ments. Mean IC50 values were determined from 10-point, one-third log concen-
tration response curves and standard errors were 610%.
b
8
H
CN
Br
13
0.13
1.3
Synthesized by reduction of 40; NaBH4, MeOH, room temperature, 1 h, quant.
Synthesized from 46; LiAlH4, THF, room temperature, 1.5 h, 14%.
c
20
23
24
25
26
27b
28c
29d
OMe
SMe
COMe
CH(OH)Me
Vinyl
Ethynyl
0.84
2.9
1.3
3.4
2.8
did not show an increase in HDL-C levels. This may be attributed
to the lack of oral bioavailability observed with these compounds
in mouse PK studies.
2.0
a
In summary, after high throughput screening of the Merck com-
pound collection identified 2-arylbenzoxazole 1 as a lead, it was
developed into compounds 35 and 47 using a modular synthetic
approach that showed the importance of substitution at the 7-po-
sition for potency enhancement over the 5-position alone. These
compounds represent important leads for further development of
this structure class as CETP inhibitors. Further modifications of
the amide and aryloxy moieties will be reported.
Data reported is derived from duplicate wells and three independent experi-
ments. Mean IC50 values were determined from 10-point, one-third log concen-
tration response curves and standard errors were 610%.
b
Synthesized by reduction of 26; NaBH4, MeOH, room temperature, 1 h, quant.
Synthesized from 23 by Stille coupling; vinyltributyl tin. (Ph3P)4Pd, DMF, 80 °C,
c
12 h, 13%.
d
Synthesized from 23 by Sonagashira coupling; (i) TMS acetylene, Pd(PPh3)2Cl2,
CuI, Ph3P, Et2NH, DMF, microwave irradiation, 120 °C, 75 min, (ii) aq NaOH, THF,
room temperature, 1 h, 32%.

C. J. Smith et al. / Bioorg. Med. Chem. Lett. 20 (2010) 346–349
349
19. Barter, P. J.; Caulfield, M.; Eriksson, M.; Grundy, S. M.; Kastelein, J. J. P.;
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23. Kastelein, J. J. P.; van, L. S. I.; Burgess, L.; Evans, G. W.; Kuivenhoven, J. A.;
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356, 1304.
O
O
O
O
O
N
a or b
NH
Br
40
42
43
R
OH
O
O
c
NH
N
Br
R
OH
O
O
O
N
NH
25. Bots, M. L.; Visseren, F. L.; Evans, G. W.; Riley, W. A.; Revkin, J. H.; Tegeler, C. H.;
Shear, C. L.; Duggan, W. T.; Vicari, R. M.; Grobbee, D. E.; Kastelein, J. J. Lancet
2007, 370, 153.
NC
26. Rader, D. J. N. Eng. J. Med. 2007, 357, 2180.
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29. Eveland, S. S.; Milot, D. P.; Guo, Q.; Chen, Y.; Hyland, S. A.; Peterson, L. B.;
Jezequel-Sur, S.; O’Donnell, G. T.; Zuck, P. D.; Ferrer, M.; Strulovici, B.; Wagner,
J. A.; Tanaka, W. K.; Hilliard, D. A.; Laterza, O.; Wright, S. D.; Sparrow, C. P.;
Anderson, M. S. Anal. Biochem. 2007, 368, 239.
Scheme 3. Reagents and conditions: (a) R = alkyl, RMgX, THF, À20 °C to room
temperature, 4 h, 40–75%; (b) R = H, NaBH4, MeOH, room temperature, 1 h, quant.;
(c) Zn(CN)2, Pd2dba2, dppf, dimethylacetamide, microwave irradiation, 60 W,
200 °C, 1 h, 37–73%.
30. Harikrishnan, L. S.; Kamau, M. G.; Herpin, T. F.; Morton, G. C.; Liu, Y.; Cooper, C.
B.; Salvati, M. E.; Qiao, J. X.; Wang, T. C.; Adam, L. P.; Taylor, D. S.; Chen, A. Y. A.;
Yin, X.; Seethala, R.; Peterson, T. L.; Nirschl, D. S.; Miller, A. V.; Weigelt, C. A.;
Appiah, K. K.; O’Connell, J. C.; Michael Lawrence, R. Bioorg. Med. Chem. Lett.
2008, 18, 2640.
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31. Benzoxazole synthesis—General method 1:
A mixture of 2 (1.05 mmol), 2-
aminophenol derivative (1.05 mmol) and boric acid (1.37 mmol) in o-xylene
(60 mL) was heated at reflux under a Dean–Stark apparatus overnight. After
this time the reaction mixture was diluted with EtOAc (50 mL), washed
successively with saturated NaHCO3 (50 mL), H2O (50 mL), and brine (50 mL),
dried (Na2SO4) and concentrated in vacuo to afford the crude product. This was
purified by flash chromatography and/or reversed phase HPLC to afford the
desired benzoxazole.
Qizilbash, N.; Peto, R.; Collins, R. Lancet 2008, 370, 1829.
JAMA 1984, 251, 365.
General method 2: A mixture of 2 (0.307 mmol), 2-aminophenol derivative
(0.430 mmol) and boric acid (0.430 mmol) in o-xylene (2.5 mL) was subjected
to microwave irradiation (300 W, 270 °C, 60 min). The reaction mixture was
diluted with EtOAc (25 mL), washed successively with saturated NaHCO3
(25 mL), H2O (25 mL), and brine (25 mL), dried (MgSO4) and concentrated in
vacuo to afford the crude product. This was purified by flash chromatography
and/or reversed phase HPLC to afford the desired benzoxazole.
General method 3: A solution of oxalyl chloride (2 M in CH2Cl2, 1.40 mmol) was
added to a stirred suspension of 2 (0.702 mmol) in CH2Cl2 (11 mL) followed by
a few drops of DMF at room temperature under N2. The reaction was stirred at
room temperature for 4 h after which time the suspension dissolved. The
reaction mixture was concentrated in vacuo and azeotroped with toluene
(10 mL). The crude acid chloride and 2-aminophenol (1.05 mmol) were
dissolved in 1,4-dioxane (20 mL) and heated at reflux for 4 h under N2. The
reaction was diluted with EtOAc (50 mL) and water (50 mL) and the aqueous
layer was extracted with EtOAc (2 Â 50 mL). The combined organic extracts
were washed with brine (50 mL), dried (Na2SO4) and concentrated in vacuo to
afford the crude amide product. A mixture of the crude amide and pyridinium
p-toluenesulfonate (0.0702 mmol) in o-xylene (30 mL) was heated at reflux
under a Dean–Stark apparatus overnight under N2. The reaction was diluted
with EtOAc (100 mL) and washed successively with saturated NaHCO3 (50 mL),
water (50 mL) and brine (50 mL), dried (Na2SO4) and concentrated in vacuo to
afford the crude product. This was purified by flash chromatography and/or
reversed phase HPLC to afford the desired benzoxazole.
**
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