SAR studies on the central phenyl ring of substituted biphenyl oxazolidinone-potent CETP inhibitors

Article abstract of DOI:10.1016/j.bmcl.2011.11.039

SAR studies of the substitution effect on the central phenyl ring of the biphenyl scaffold were carried out using anacetrapib (9a) as the benchmark. The results revealed that the new analogs with substitutions to replace trifluoromethyl (9a) had a significant impact on CETP inhibition in vitro. In fact, analogs with some small groups were as potent or more potent than the CF₃ derivative for CETP inhibition. Five of these new analogs raised HDL-C significantly (>20 mg/dL). None of them however was better than anacetrapib in vivo. The synthesis and biological evaluation of these CETP inhibitors are described.

Full text of DOI:10.1016/j.bmcl.2011.11.039

Bioorganic & Medicinal Chemistry Letters 22 (2012) 199–203
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
SAR studies on the central phenyl ring of substituted biphenyl
oxazolidinone-potent CETP inhibitors
Zhijian Lu a, , Yi-heng Chen a, Joann B. Napolitano a, Gayle Taylor a, Amjad Ali a, Milton L. Hammond a,
⇑
Qiaolin Deng a, Eugene Tan a, Xinchun Tong a, Suoyu S. Xu a, Melanie J. Latham b, Laurence B. Peterson b,
Matt S. Anderson c, Suzanne S. Eveland c, Qiu Guo c, Sheryl A. Hyland c, Denise P. Milot c, Ying Chen c,
Carl P. Sparrow c, Samuel D. Wright c, Peter J. Sinclair a
a Department of Medicinal Chemistry, Merck Sharp & Dohme Corp., PO Box 2000, Rahway, NJ 07065, USA
b Department of Pharmacology, Merck Sharp & Dohme Corp., PO Box 2000, Rahway, NJ 07065, USA
c Department of Atherosclerosis and Endocrinology, Merck Sharp & Dohme Corp., PO Box 2000, Rahway, NJ 07065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
SAR studies of the substitution effect on the central phenyl ring of the biphenyl scaffold were carried out
using anacetrapib (9a) as the benchmark. The results revealed that the new analogs with substitutions to
replace trifluoromethyl (9a) had a significant impact on CETP inhibition in vitro. In fact, analogs with
some small groups were as potent or more potent than the CF3 derivative for CETP inhibition. Five of
these new analogs raised HDL-C significantly (>20 mg/dL). None of them however was better than
anacetrapib in vivo. The synthesis and biological evaluation of these CETP inhibitors are described.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 14 September 2011
Accepted 9 November 2011
Available online 16 November 2011
Keywords:
CTEP inhibitors
HDL-C
It has long been recognized that in mammals, variations in
circulating lipoprotein profiles correlate with the risk of athero-
sclerosis and coronary heart disease (CHD). The clinical success
of HMG-CoA reductase inhibitors,1–4 especially the statins, in
reducing coronary events is based on the reduction of circulating
Low Density Lipoprotein cholesterol (LDL-C), levels of which corre-
late directly with increased risk for atherosclerosis. More recently,
epidemiologic studies have demonstrated an inverse relationship
between High Density Lipoprotein cholesterol (HDL-C) levels and
atherosclerosis, leading to the conclusion that low serum HDL-C
levels are associated with an increased risk for CHD. In fact, a sub-
stantial number of people who develop atherosclerosis have total
plasma cholesterol levels in the ‘desirable’ range while having
abnormally low HDL (<35 mg/dL). Therefore, low HDL levels are
not only recognized as a risk factor for the disease, but are also
the single best predictor for the eventual development of CHD.5–8
Metabolic control of lipoprotein levels is a complex and dy-
namic process involving many factors. One important metabolic
control in man is the cholesteryl ester transfer protein (CETP), a
plasma glycoprotein that catalyzes the movement of cholesteryl
esters from HDL to the apoB containing lipoproteins, especially
VLDL. Under physiological conditions, the net reaction is a het-
ero-exchange in which CETP carries triglyceride to HDL from the
apoB lipoproteins and transports cholesterol ester from HDL to
the apoB lipoprotein. It has been established clinically that phar-
macological inhibition of CETP will lead to increased HDL-C con-
centrations. However, there remains uncertainty as to whether a
CETP inhibitor can provide clinical benefit to high risk CHD pa-
tients. More studies are needed to determine if increasing HDL-C
via CETP inhibition will reduce atherosclerosis in patients.9–11 Sev-
eral CETP inhibitor scaffolds have been reported from this labora-
tory and other research organizations, most notably the
tetrahydroquinoline core of Pfizer’s torcetrapib 1 and the acylami-
nobenzenethiol core of the Roche/Japan Tobacco inhibitor dalcetra-
pib 2, compounds from Pharmacia 3 and Lilly’s evacetrapib 4
(Fig. 1).12–24 Tocetrapib was the first CETP inhibitor that underwent
large PhIII trials involving more than 15,000 patients.25–27 All
ongoing clinical trials with torcetrapib were discontinued abruptly
in December 2006 when the investigators from one of the trials
(ILLUMINATE) reported an increase in all-cause mortality associ-
ated with torcetrapib though positive lipid targets were met.25–27
Discussion surrounding the withdrawal of torcetrapib from devel-
opment is still ongoing, centered around the question of whether
the increased rate of deaths associated with torcetrapib resulted
from inhibition of CETP, off-target effects, or a combination of
these two factors.16,28–30
A chemistry program was initiated at Merck in order to identify
a suitable CETP inhibitor for development as a treatment for ath-
erosclerosis, and the program has led to the discovery of anacetra-
pib.43 The ability of anacetrapib to inhibit CETP-mediated transfer
of both cholesteryl ester and triglycerides and its mechanism of
⇑
Corresponding author. Tel.: +1 732 594 4392.
E-mail address: zhijian_lu@merck.com (Z. Lu).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.11.039

200
Z. Lu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 199–203
CO2H
Cl
O
O
N
N
N
N
O
F3C
O
NH
O
N
CF2CF2H
N
S
N
O
N
N
O
F3C
CF3
CF3
F3C
F3C
OH
3
1
2
4
Figure 1. Representative published CETP inhibitors.
action has been characterized.31 Anacetrapib itself was extensively
profiled in phase I and II clinical trials and was shown to cause a
dose-dependent increase in HDL-C levels and decrease in LDL-C
levels.32–37 It was also found that HDL isolated from humans trea-
ted with anacetrapib had potentially promoted cholesterol efflux
and retained anti-inflammatory effects.38 Preclinical and clinical
studies with anacetrapib, including recent results from the phase
III safety study DEFINE, have thus far given no evidence of blood
pressure or aldosterone increases which were observed with tocet-
rapib. As such, the development of anacetrapib continues.39–41 The
design of the biphenyl scaffold and the subsequent work that led to
the discovery of anacetrapib were published recently from this lab-
oratory.42,43 We intended to explore the structure–activity rela-
tionship (SAR) of the substitution effect on the central phenyl
ring of the biphenyl scaffold using anacetrapib (9a) as the bench-
mark. The results revealed that the new analogs with substitutions
to replace trifluoromethyl (9a) could significantly impact the
in vitro CETP inhibition. In fact, analogs with some small groups
were as potent as or better than CF3 group for CETP inhibition. Five
of these new analogs raised HDL-C significantly (>20 mg/dL). None
of them however was better than anacetrapib in vivo.
The general approach to prepare these compounds is exempli-
fied by the synthesis of analog 9 as shown in Scheme 1. Thus, pre-
vious disclosed compound 643 was treated with NaH at 0 °C in THF
followed by addition of the commercially available 4-substituted
benzyl bromide 5 afforded compound 7 in good to excellent yields.
Suzuki coupling of compound 7 with previously described boronic
acid 843 and Pd(PPh3)4 gave compound 9 in good yield (Scheme 1).
Several compounds were prepared from 9h by functional group
manipulations. Hydrogenation of 9h with Pd/C in methanol at
40 psi gave the aniline 9i in excellent yield. Treatment of 9i with
n-amyl nitrite and iodine in chloroform under reflux afforded io-
dide 9f (Scheme 2). 9g was obtained by treatment of 9f with cop-
per cyanide in DMF at 100 °C. Suzuki coupling reaction resulted in
compounds 9j, 9k, 9q, and 9t in respectable yields (Scheme 3). All
other analogs were prepared in a similar fashion.
F
O
Br
R
Br
N
R
a
b
O
N
R
O
O
Br
O
CF3
5
CF3
F3C
H
7
F3C
N
O
9
F
O
O
HO
B
CF3
OH
F3C
6
8
R = H, F, Cl, NO2 , t-Bu, MeS, PrS, i-PrS, CF3 S
Scheme 1. Synthesis of the biphenyl analogs. Reagents and conditions: (a) (1) NaH, 6, 0 °C, THF; (2) 5, 0 °C to rt, 70–95% (b) Pd(PPh3)4, K2CO3, toluene/EtOH/H2O (4:2:1),
reflux, 80–90%.

Z. Lu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 199–203
201
F
O
F
O
F
O
O2N
H2N
I
a
N
b
N
O
O
N
O
O
O
O
CF3
CF3
CF3
F3C
F3C
F3C
9h
9i
9f
Scheme 2. Synthesis of the substituted biphenyl analogs. Reagents and conditions: (a) H2, Pd/C, 40 psi, MeOH, 95% (b) n-amyl nitrite, I2, CHCl3, reflux, 76%.
The final compounds were evaluated in a fluorescence-based
assay measuring the compound’s ability to inhibit CETP-mediated
neutral lipid transfer.45 The results are reported as IC50s. As can be
Table 1
SAR of the substituted top phenyl analogs
seen in Table 1, the binding activity was significantly affected by
the choice of phenyl substitution. Compared with 9a, the unsub-
F
O
stutited analog 9b was two fold less active. Halogen substitutions
generally gave potent CETP inhibition and Cl was the most potent
substituent (9d) with activity slightly better than CF3 (9a). Electron
withdrawing groups, including CN and NO2, were tolerated and
NO2 group was more potent than CF3 (9h vs 9a). A hydrogen donor
R
N
O
O
F
O
F
O
CF3
F3C
I
NC
9
a
N
N
O
O
Entry
R
IC50 (nM)
Entry
R
IC50 (nM)
O
O
9a
9b
9c
9d
CF3
H
F
17.2
31.21
25
9m
9n
9o
9p
MeS
PrS
iPrS
CF3S
16.2
1229
689.1
19.6
CF3
CF3
Cl
16.5
9e
9f
Br
I
19.8
23.5
9q
9p
254.2
18
F3C
F3C
F
9f
9g
OH
9g
9h
9i
CN
23.3
13.3
296.4
9s
9t
71.8
24.8
33.5
F
O
F
O
NO2
NH2
O
O
9u
S
O
O
I
R
9j
Me
16.7
54.1
9v
6935
2599
S
b
N
N
O
O
O
O
O
S
9k
iPr
9w
O
O
O
CF3
CF3
S
9l
t-Bu
24.9
9x
27.1
F3C
F3C
F3C
9f
R = Me 9j,
9
led to the loss of potency (9i and 9s). For the alkyl substitutions,
smaller group like Me was more potent than CF3 (9j vs 9a). More-
over, as the size grew, the potency decreased. Cyclopetene analog
was the least active among 9j, 9k, 9l, 9t and 9q. Alkyl sulfides pre-
sented a similar trend. MeS was the most active group and more
9k,
9q,
9t,
Scheme 3. Synthesis of the substituted biphenyl analogs. (a) CuCN, DMF, 100 °C,
84%. (b) RB(OH)2, Pd(PPh3)4, K2CO3, toluene/EtOH/H2O (4:2:1), reflux, 60 to 80%.

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9r
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9o and 9p, respectively). The sulfones were less potent compared
to the corresponding sulfides. The fluorinated isopropyl 9r was
more active than isopropyl 9k, indicating a general trend that the
target CETP favored the fluorine substitution at this position. To
summarize, small and neutral groups were well tolerated at this
position to give potent CETP inhibitors as shown in Table 1.
In light of these in vitro SAR studies, 11 compounds were tested
in the transgenic mouse pharmacodynamic assay,44 using ana-
cetrpib 9a as benchmark. These compounds were evaluated for
their ability to raise HDL utilizing a BID dosing regimen. Thus,
the animals were given a first dose of these compounds individu-
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than any other analogs in the series in vivo (Table 2).
In summary, we have described a class of CETP inhibitors that
are potent in both in vitro and in vivo assays. SAR studies of the
substitution effect on the central phenyl ring of the biphenyl scaf-
fold were carried out using anacetrapib (9a) as the benchmark.
The results revealed that the new analogs with substitutions to
replace trifluoromethyl (9a) had a significant impact on the CETP
inhibition in vitro. In fact, analogs with some small groups were
as potent as or better than CF3 group for CETP inhibition. Five
of these new analogs raised HDL-C significantly (>20 mg/dL).
None of them however was better than anacetrapib in raising
HDL-C in vivo.
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