Design of a novel class of biphenyl CETP inhibitors

Article abstract of DOI:10.1016/j.bmcl.2010.10.019

A new class of CETP inhibitors was designed and prepared. These compounds are potent both in vitro and in vivo. The most active compound (12d) has shown an ability to raise HDL significantly in transgenic mouse PD model.

Full text of DOI:10.1016/j.bmcl.2010.10.019

Bioorganic & Medicinal Chemistry Letters 20 (2010) 7469–7472
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design of a novel class of biphenyl CETP inhibitors
Zhijian Lu a, , Joann B. Napolitano a, Ashleigh Theberge a, Amjad Ali a, Milton L. Hammond 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, United States
b Department of Pharmacology, Merck Sharp & Dohme Corp., PO Box 2000, Rahway, NJ 07065, United States
c Department of Atherosclerosis and Endocrinology, Merck Sharp & Dohme Corp., PO Box 2000, 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 new class of CETP inhibitors was designed and prepared. These compounds are potent both in vitro and
in vivo. The most active compound (12d) has shown an ability to raise HDL significantly in transgenic
mouse PD model.
Received 16 August 2010
Revised 1 October 2010
Accepted 5 October 2010
Available online 15 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
CETP inhibitors
HDL-C
Biphenyl
Atherosclerosis and its clinical consequences, coronary heart
disease (CHD), stroke and peripheral vascular disease, are the lead-
ing causes of death and represent a heavy burden to the health care
systems around the world. For example, based on Centers for
Disease Control and Prevention (CDC), in the United States alone,
approximately 13 million patients have been diagnosed with
CHD, and greater than one half million deaths are attributed to
CHD each year.1 Furthermore, this toll is expected to grow over
the next 10–25 years as an epidemic in obesity and diabetes con-
tinues to grow.1
It has long been recognized that in mammals, variations in circu-
lating lipoprotein profiles correlate with the risk of atherosclerosis
and CHD. The clinical success of HMG-CoA reductase inhibitors,2–5
especially the statins, in reducing coronary events is based on the
reduction of circulating Low Density Lipoprotein cholesterol
(LDL-C), levels of which correlate directly with increased risk for
atherosclerosis. More recently, epidemiologic studies have demon-
strated 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 substantial number of people
who develop atherosclerosis have plasma cholesterol levels in the
‘desirable’ range while having abnormal low HDL (<35 mg/dl).
Therefore, low HDL levels are not only recognized as a risk factor
for the disease, but are considered the single best predictor of an
individual’s likelihood of developing CHD.6–9
Metabolic control of lipoprotein levels is a complex and dynamic
process involving many factors. One important metabolic control in
man is the cholesteryl ester transfer protein (CETP), a plasma glyco-
protein that catalyzes the movement of cholesteryl esters from HDL
to the apoB containing lipoproteins, especially VLDL. Under physio-
logical conditions, the net reaction is a hetero-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 pharmacological inhibition of
CETP will lead to increased HDL-C concentrations. However, there
remains uncertainty as to whether a CETP inhibitor can provide
clinical benefit to high risk CHD patients. More studies are needed
to determine if increasing HDL-C via CETP inhibition will reduce
atherosclerosis in patients.10–12 A number of CETP inhibitor scaf-
folds have been reported from this laboratory and other research
organizations in the world, most notably the tetrahydroquinoline
core of Pfizer’s torcetrapib and the acylaminobenzenethiol core of
the Roche/Japan Tobacco inhibitor dalcetrapib.13–24 Tocetrapib
was the first CETP inhibitor that underwent large PhIII trials involv-
ing 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 associated with torcetrapib though
positive lipid targets were met.25–27 Discussion surrounding the
withdrawal of torcetrapib from development is still ongoing,
⇑
Corresponding author. Tel.: +1 732 594 4392; fax: +1 732 594 9473.
E-mail address: zhijian_lu@merck.com (Z. Lu).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.10.019

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Z. Lu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7469–7472
centered around the question of whether the increased rate of
deaths associated with torcetrapib resulted from inhibition of CETP,
off-target effects, or some combination of these two factors.17,28–30
This letter will discuss the design of a new class of biphenyl CETP
inhibitors which ultimately led to the discovery of anacetrapib. We
initiated an effort to design a proprietary CETP inhibitor scaffold
utilizing Pfizer’s torcetrapib as a model. In examining torcetrapib,
we reasoned that breaking the nitrogen containing ring of the tetra-
hydroquinoline core would afford compounds that were syntheti-
cally accessible and without the added complexity of stereogenic
centers. As shown in Figure 1, the initial acyclic variants were
promising, as they were low micromolar inhibitors of CETP (as in
compound 1, IC50 = 3.89 lM), but efforts to increase the potency
via alternate substitutions on either the carbamate or the pendant
benzylic group were largely unsuccessful. We investigated the
incorporation of a conformational constraint in an attempt to
increase intrinsic potency of the series. The heterocyclic
Br
Br
R
a
N
O
R
O
Br
13
CF3
F3C
14
O
O
O
O
O
N
N
N
N
b
F3C
F3C
R
O
O
R = H, F, Cl, NO2,
OMe, tBu
N
O
O
O
O
CF3
Torcetrapib
F3C
CF3
F3C
CF3
F3C
1
15
R =
H
H
N
R
O
N
O
NH2
O
O
c
N
N
O
F3C
N
O
2
3
CF3
F3C
CF3
F3C
O
16
O
17
O
CF3
F3C
Scheme 2. Synthesis of the substituted biphenyl analogs. Reagents and conditions:
(a) NaH, 17, THF, 0 °C, 70–90%; (b) 2-methoxy-5-isopropyl phenyl boronic acid,
Pd(OAC)2, acetone/H2O (4:1), 80 °C, 40–70%; (c) methyl chloroformate, CH2Cl2,
25 °C, 95%.
4
5
Figure 1. Design of a novel biphenyl class of CETP inhibitors.
NH2
NH2
NH2
O
O
NH2
b
a
F3C
F3C
I
F3C
CN
a
8
b
6
O2N
H2N
7
N
N
O
O
NH2
NH2
O
O
F3C
F3C
c
d
NH
N
O
CF3
CF3
F3C
F3C
15c
15b
O
F3C
CF3
F3C
CF3
9
10
O
I
O
R
F3C
F3C
c
N
e
f
O
N
O
I
NC
N
O
O
O
N
O
O
O
CF3
F3C
CF3
F3C
CF3
12
11
CF3
F3C
F3C
15d
Scheme 1. Synthesis of the biphenyl analogs. Reagents and conditions: (a) CuCN,
DMF, 100 °C, 76%; (b) H2, Raney Ni, NH4OH, 40 psi, 60%; (c) 3,5-di-trifluoromethyl-
benzyl bromide, N-methylmorpholine, dimethoxyethane, rt, 55%; (d) MeOC(O)Cl,
N-methylmorpholine, DME, 0 °C, 80%; (e) iso-amyl nitrite, I2, CHCl3, reflux, 85%; (f) R-
B(OH)2, Pd(OAC)2, acetone/H2O (4:1), reflux. 20–80%.
15e
Scheme 3. Synthesis of the substituted biphenyl analogs. Reagents and conditions:
(a) H2, Pd/C, MeOH, 25 °C, 90%; (b) n-amyl nitrite, I2, CHCl3, reflux, 70%; (c) CuCN,
DMF, 100 °C, 85%.

Z. Lu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7469–7472
7471
Table 1
Table 2
SAR of the substituted top phenyl analogs
SAR of the middle substituted phenyl analogs
O
R
F3C
R
N
O
N
O
O
O
CF3
F3C
CF3
F3C
Compound R
R
IC50 (nM)
1601
Compound
R
IC50 (nM)
MeO
12d
15a
15b
15c
15d
15e
15f
15g
15h
15i
CF3
H
NO2
NH2
I
CN
OMe
F
108
3832
134
4664
365
224
694
1725
1430
9514
4
MeO
MeO
5
469
444
12a
OMe
Cl
tBU
EtO
12b
12c
4494
210
MeO
Table 3
The effects of dose related HDL increase for compound 12d on the transgenic mouse
MeO
O
12d
108
F
MeO
F3
C
12e
12f
12g
117
753
N
O
O
MeO
MeO
CF3
F3C
12d
PO dose
(mg/kg)
HDL start
(mg/dL)
HDL end
(mg/dL)
Increase of HDL
(%)
2590
1
3
10
30
32.5
26.0
27.2
22.5
44.5
37.1
41.8
41.8
37
43
54
86
Male cynoCETP mice, n = 5 for each dose.
compounds oxazolidinone 2 and imidazolidinone 3, however, were
found to be inactive. Replacement of the heterocycles with a substi-
tuted phenyl ring showed low micromolar activity and compound 4
was our first active compound in the biphenyl series. Incorporation
of a 2,5-disubstitution pattern to better approximate the way tor-
cetrapib displays its pendant groups led to compound 5 which
was 10-fold more potent than 1 in vitro. Further, compound 5 also
elicited a significant increase in HDL-C (40%@100 mpk) in a
pharmacodynamic assay31 utilizing transgenic mice expressing
cynomolgus monkey CETP, and was the first such compound to
do so. This letter will discuss the synthesis and SAR of this series
of biphenyl CETP inhibitors.
commercially available boronic acids and Pd(OAc)2 gave the final
compounds 12 (Scheme 1).
In a similar fashion, the other biphenyl analogs were prepared
as shown in Scheme 2. Alkylation of commercially available benzyl
bromides 13 with NaH and compound 17 provided 14 in good
yield. Suzuki coupling of 14 with commercially available 2-
methoxy-5-isopropyl phenyl boronic acid and Pd(OAc)2 gave the
final compound 15. Compound 16 was obtained in excellent yield
by treatment of 3,5-bis-trifluoromethyl benzylamine 17 with
methyl chloroformate (Scheme 2).
The general approach to the preparation of these compounds is
exemplified by the synthesis of analog 12 as shown in Scheme 1.
Thus, commercially available 2-iodo-4-trifluoromethylaniline 6
was mixed with copper cyanide in DMF at 100 °C for 24 h to afford
aminocyanide 7. Hydrogenation of 7 with Raney nickel at 40 psi
gave 2-amino-5-trifluoro benzylamine 8. Alkylation of 8 with
3,5-di-trifluoromethyl-benzyl bromide and N-methylmorpholine
at room temperature in dimethoxyethane produced compound 9.
Carbamate 10 was obtained in good yield by treatment of 9 with
methyl chloroformate. Treatment of compound 10 with iso-amyl
nitrite and iodine in chloroform under reflux conditions gave the
corresponding iodide 11. Suzuki coupling of iodide 11 with
Several compounds were prepared from 15b by functional
group manipulations. Hydrogenation of 15b with Pd/C in methanol
at 40 psi gave the aniline 15c in good yield. Treatment of 15c with
n-amyl nitrite and iodine in chloroform under reflux conditions
afforded iodide 15d. 15e was obtained by treatment of 15d with
copper cyanide in DMF at 100 °C (Scheme 3).
All final compounds were evaluated in a fluorescence-based as-
say measuring the compound’s ability to inhibit CETP-mediated
neutral lipid transfer.32 The results are reported as IC50s. As can
be seen in Table 1, the 2-methoxy-5-alkyl substituted pattern on
the phenyl ring is preferred and 5-methyl-2-methoxy phenyl ana-
log (5) is used as the starting point to discuss the SAR. 2-Ethoxy

7472
Z. Lu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7469–7472
13. Clark, R. W.; Sutfin, T. A.; Ruggeri, R. B.; Willauer, A. T.; Sugarman, E. D.;
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analog 12b is less active than the 2-methoxy analog 5 due to the
steric effect. Both 5-methyl and 5-methoxy groups are equally po-
tent (5 and 12a, respectively). 5-Ethyl analog 12c is twice as active
as methyl analog 5. The isopropyl analog 12d is the most active
CETP inhibitor in the series with IC50 108 nM. Adding a F atom at
the 4-position of phenyl ring did not have much effect on potency
(12d vs 12e). The analogs with 5-n-propyl and 5-t-butyl groups
(12f and 12g, respectively) are less active than the isopropyl analog
12d because of the steric hindrance.
In a separate SAR study (Table 2), we attempted to determine
the effect of the substitutions on the central phenyl ring, using
compound 12d as a comparator. The unsubstituted analog com-
pound 15a was approximately 30–40-fold less potent than 12d.
A clear SAR was observed when halogens were introduced and
the order was I > Cl > F (15d, 15h, and 15g, respectively). Substitu-
tions with NO2 (15b) and CN (15e) were less potent than the tri-
fluoromethyl group (12d) but better than any of the other groups
in this study.
In light of these in vitro SAR studies, we selected compound 12d
to benchmark in our transgenic mouse pharmacodynamic assay.31
Compound 12d was evaluated for its ability to raise HDL utilizing a
BID dosing regimen. Thus, the animals were given a first dose of
12d at the beginning of study, an equivalent dose 7 h later and
blood was collected 24 h post the first dose. The difference in
HDL-C levels between t = 24 and t = 0 h was then determined.
Compound 12d showed a good dose-dependent increase in HDL-
C levels. At 30 mpk, it raised HDL-C up to 86%. It was also active
as low as 1 mpk, raising HDL by 37% (Table 3).
23. Kuo, G.-H.; Rano, T.; Pelton, P.; Demarest, K. T.; Gibbs, A. C.; Murray, W. V.;
Damiano, B. P.; Connelly, M. A. J. Med. Chem. 2009, 52, 1768.
24. 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.; Lawrence, R. M. Bioorg. Med. Chem. Lett. 2008, 18,
2640.
25. Barter, P. J.; Caulfield, M.; Eriksson, M.; Grundy, S. M.; Kastelein, J. J. P.;
Komajda, M.; Lopez-Sendon, J.; Mosca, L.; Tardif, J.; Waters, D. D.; Shear, C. L.;
Revkin, J. H.; Buhr, K. A.; Fisher, M. R.; Tall, A. R.; Brewer, B.for the ILLUMINATE
investigators N. Eng. J. Med. 2007, 357, 2109.
26. Nissen, S. E.; Tardif, J. C.; Nicholls, S. J.; Revkin, J. H.; Shear, C. L.; Duggan, W. T.;
Ruzyllo, W.; Bachinsky, W. B.; Lasala, G. P.; Tuzcu, E. M.for the ILLUSTRATE
investigators N. Eng. J. Med. 2007, 356, 1304.
27. Kastelein, J. J. P.; van Leuven, S. I.; Burgess, L.; Evans, G. W.; Kuivenhoven, J. A.;
Barter, P. J.; Revkin, J. H.; Grobbee, D. E.; Riley, W. A.; Shear, C. L.; Duggan, W. T.;
Bots, M. L.for the RADIANCE 1 investigators N. Eng. J. Med. 2007, 356, 1620.
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In summary, we have discovered a new class of CETP inhibitors
that are potent in both in vitro and in vivo assays. The most active
compound of these inhibitors has shown an ability to raise HDL
significantly in a transgenic mouse PD model.
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