2-(4-Carbonylphenyl)benzoxazole inhibitors of CETP: Scaffold design and advancement in HDLc-raising efficacy

Article abstract of DOI:10.1016/j.bmcl.2010.11.090

The development of 2-phenylbenzoxazoles as inhibitors of cholesteryl ester transfer protein (CETP) is described. Initial efforts aimed at engineering replacements for the aniline substructures in the benchmark molecule. Reversing the connectivity of the central aniline lead to a new class of 2-(4-carbonylphenyl)benzoxazoles. Structure-activity studies at the C-7 and terminal pyridine ring allowed for the optimization of potency and HDLc-raising efficacy in this new class of inhibitors. These efforts lead to the discovery of benzoxazole 11v, which raised HDLc by 24 mg/dl in our transgenic mouse PD model.

Full text of DOI:10.1016/j.bmcl.2010.11.090

Bioorganic & Medicinal Chemistry Letters 21 (2011) 1890–1895
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
2-(4-Carbonylphenyl)benzoxazole inhibitors of CETP: Scaffold design
and advancement in HDLc-raising efficacy
Ramzi F. Sweis a, , Julianne A. Hunt a, Florida Kallashi a, Milton L. Hammond a, Ying Chen b,
⇑
Suzanne S. Eveland b, Qiu Guo b, Sheryl A. Hyland b, Denise P. Milot b, Anne-Marie Cumiskey c,
Melanie Latham c, Raymond Rosa c, Larry Peterson c, Carl P. Sparrow b, Samuel D. Wright b,
Matt S. Anderson b, Peter J. Sinclair a
a Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
b Department of Cardiovascular Diseases, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
c Department of Pharmacology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA (ES)
a r t i c l e i n f o
a b s t r a c t
Article history:
The development of 2-phenylbenzoxazoles as inhibitors of cholesteryl ester transfer protein (CETP) is
described. Initial efforts aimed at engineering replacements for the aniline substructures in the bench-
mark molecule. Reversing the connectivity of the central aniline lead to a new class of 2-(4-carbonylphe-
nyl)benzoxazoles. Structure–activity studies at the C-7 and terminal pyridine ring allowed for the
optimization of potency and HDLc-raising efficacy in this new class of inhibitors. These efforts lead to
the discovery of benzoxazole 11v, which raised HDLc by 24 mg/dl in our transgenic mouse PD model.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 25 October 2010
Revised 17 November 2010
Accepted 19 November 2010
Available online 25 November 2010
Keywords:
Cholesteryl ester transfer protein
Cholesterol
HDLc
LDLc
Atherosclerosis
Lipid
Cholesteryl ester transfer protein (CETP) inhibitors have gar-
nered intense interest as a possible treatment for atherosclerosis.1
The inverse correlation between CETP activity and high-density
lipoprotein cholesterol (HDLc) levels suggests that CETP inhibition
may be an effective way to elevate levels of anti-atherogenic HDLc
in humans. Noteworthy are epidemiological studies correlating a
1 mg/dl increase in plasma HDLc concentration to a 6% decrease
in the risk of death from cardiovascular disease.2 Accordingly,
small-molecule CETP inhibitors have recently been reported in
these3 and other laboratories.4
In continuation of our ongoing studies on the development of
2-phenylbenzoxazoles as inhibitors of CETP, we focused on further
refining this class of inhibitor to address its existing liabilities. The
benchmark compound in this class, 1a, is a potent inhibitor of CETP
(IC50: 16 nM) and elevates HDL cholesterol levels by 24 mg/dl in
our transgenic mouse PD model.5 However, the physicochemical
properties (such as aqueous solubility) of this compound and
others in its class are not ideal. In addition, aniline substructures
are embedded in the molecule, and one of these forms part of a
potentially labile amide bond. Since aniline is a toxic substance
that is classified by the EPA as a Group B2 probable human carcin-
ogen,6 we strove to find suitable replacements for the aniline moi-
eties in 1a and 1b while maintaining the in vitro potency and
in vivo efficacy of these compounds (Fig. 1).
This goal was achieved through reversal of the central amide
moiety to remove the aniline, installation of a C-7 isopropyl group
O
N
NH
N
1a: X = CH : IC50 : 16 nM
Δ HDL: +24 mg/dl
1b: X = N : IC50 : 15 nM
Δ HDL: +21 mg/dl
Me
NC
X
O
CF3
N
HN
N
OiPr
O
11v: IC50 : 13 nM
Δ HDL: +24 mg/dl
N
O
N
F
NC
⇑
Corresponding author. Tel.: +1 732 594 2742.
E-mail address: ramzi.sweis@merck.com (R.F. Sweis).
Figure 1. 2-Phenylbenzoxazole CETP inhibitors.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.11.090

R. F. Sweis et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1890–1895
1891
Me
N
O
N
N
BZO
ArP
=
=
NC
CF3
O
N
H
N
Cl
HN
Br
O
O
c
a, b
Br
S
ArP
BZO
BZO
NH2
BZO
N
O
d, e
ArP
CF3
2
4j
4l
f
N
p
O
N
OH
4k
H
N
g
CF3
ArP
BZO
O
h, i, j
k
q
BZO
ArP
4h
BZO
I
4b
BZO
ArP
4d
N
4a
r
l
3
N
OMe
4i
CF3
OH
BZO
ArP
HO
s
N
4c
BZO
N
O
O
ArP
m, n, o
4g
BZO
ArP
O
4f
Scheme 1. Synthesis of benzoxazoles 4a–l. Reagents and conditions: (a) 2-chloroethanesulfonyl chloride, pyridine, CH2Cl2 (99%); (b) 4-trifluoromethylphenylpiperidine,
EtOH, 70 °C (86%); (c) Na3PO4, CH3CN (97%); (d) K2CO3, MeOH 80 °C (96%); (e) MeOH, 140 °C, microwave (44%); (f) CeCl3 (0.3 equiv), NaI (0.3 equiv), EtOH, microwave 150 °C
(15%); (g) n-amylnitrite, I2, CHCl3 (76%); (h) allyltributyltin, Pd(PPh3)2Cl2 (10 mol %), dioxane (87%); (i) H2O2, CH3CN, CH2Cl2 (91%); (j) 4-trifluoromethylphenyl piperidine,
EtOH (91%); (k) Dess–Martin periodinane, CH2Cl2 (95%); (l) NaH, MeI, dioxane (40%); (m) NaH, Pd2dba3 (10 mol %), BINAP (10 mol %) toluene, 90 °C (79%); (n) HCl, dioxane
(98%); (o) 4-trifluoromethyl-iodobenzene, NaOtBu (1.5 equiv), Pd2dba3 (10 mol %), BINAP (20 mol %), toluene, 90 °C (75%); (p) triethylamine, Pd(PPh3)2Cl2 (5 mol %), CuI,
dioxane 50 °C (90%); (q) H2, 10% Pd/C (79%); (r) HgSO4, HCO2H, 60 °C (16%); (s) NaBH4, methanol (45%).
I
O
Me
OH
a, b
NC
OH
Cl
+
OMe
NC
NO2
NH2
O
c, d
Me
O
O
N
OH
HN
NC
H2N
5
N
e
N
H2N
CF3
g
N
f
N
CF3
h
O
BZO
ArP
O
CF3
4n
BZO
H
BZO
HN
4e
N
ArP
O
N
4m
4o
CF3
Scheme 2. Synthesis of 2-(4-carbonylphenyl)benzoxazoles 4e, 4m–o. Reagents and conditions: (a) MeB(OH)2 (5 equiv), Cs2CO3, Pd2dba3 (10 mol %), DMF, 130 °C (53%); (b)
FeCl3–6H2O (5 mol %), hydrazine (5 equiv) charcoal, MeOH, 70 °C (89%); (c) TsOH, dioxane, toluene 110 °C (59%); (d) LiOH, THF/MeOH/H2O (97%); (e) HOBT–H2O, EDC,
(i-Pr)2EtN, dioxane, 50 °C (36%); (f) (COCl)2, DMF, (i-Pr)2EtN, CH2Cl2 (44%); (g) (COCl)2, DMF, (i-Pr)2EtN, CH2Cl2 (73%); (h) NaH (10 equiv), MeI (2 equiv), THF (73%).
on the benzoxazole to restore in vitro potency, and evaluation of
various aryl piperidines at the terminus of the molecule to achieve
effective HDLc elevation. These efforts culminated in three potent
CETP inhibitors (11k, 11p, and 11v), which produced robust eleva-
tions of HDLc levels (>20 mg/dl).
ification of the central ‘linker’ region of the molecule, the second
evaluated the C-7 position of the benzoxazole, and the third tar-
geted changing the substitution pattern at the terminal pyridine
ring.
As shown in Scheme 1, the common intermediate 2-(4-amino-
phenyl)benzoxazole 2 was used as a divergent starting point for a
wide variety of linker modifications, including sulfonamide 4j, cyclic
The synthesis of the various 2-phenylbenzoxazoles reported
herein followed three main approaches. The first focused on mod-

1892
R. F. Sweis et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1890–1895
O
Br
Br
Br
OH
OH
Br
c
O
O
N
Cl
a, b
d
+
OMe
NC
NH2
OMe
Me
NC
NC
6
O
+
(HO)2B
O
N
H
O
O
O
e, f
O
N
O
N
Ar1
g
N
OMe
NC
OH
NC
N
7
8
+
NC
H2N
N
Ar
Scheme 3. Synthesis of ‘reversed amide’ benzoxazoles 9e, 10, 11a–i. Reagents and conditions: (a) NaNO2, AcOH (82%); (b) FeCl3–6H2O, hydrazine (78%); (c) TsOH, toluene,
110 °C (69%); (d) 2 M Na2CO3 (3 equiv), Pd(PPh3)4 (5 mol %), toluene/H2O/EtOH (81%); (e) H2, Pd/C (10%) THF/MeOH 2:1 (85%); (f) LiOH, THF/MeOH/H2O (80%); (g) (COCl)2,
DMF, (i-Pr)2EtN, CH2Cl2 (31–85%).
amide 4l, b-hydroxyamine 4k,7 and 2-(4-iodophenyl)benzoxazole 3.
The latter served as the starting point for further analog generation
via Stille cross-coupling, palladium-catalyzed C–O cross-coupling,
and Sonogashira coupling. Further, synthetic manipulations of the
products of the cross-coupling reactions provided compounds
4a–d and 4f–i.
Our most successful series of linker modifications derived from
a reversal of the amide connectivity in compound 1. 2-(4-Carboxy-
phenyl)benzoxazoles such as 5 were the key intermediates in the
synthesis of the reverse amides, as shown in Scheme 2. Beginning
with commercially available 4-hydroxy-3-iodo-5-nitrobenzonitri-
le, a Suzuki cross-coupling with methylboronic acid followed by
iron(III) chloride-mediated reduction of the nitro-group with
hydrazine furnished the desired aminophenol, which was con-
densed with methyl 4-chlorocarbonylbenzoate to provide the
required benzoxazole. Basic hydrolysis of the ester gave rise to
the key 2-(4-carboxyphenyl)benzoxazole intermediate, 5, which
could be then be coupled with a variety of amines under standard
conditions.
Work in these laboratories showed that the terminal aniline in
1a could be replaced by an aminopyridine (as in 1b) without a sig-
nificant effect on potency (IC50: 15 nM vs 16 nM; see Fig. 1). How-
ever, employing this strategy to address the central aniline was
unsuccessful, as replacement with an aminopyridyl ring led to a
significant reduction in potency.9 Therefore, we turned to modify-
ing the ‘linker’ region of the molecule in order to address the re-
moval of the central aniline, and the results of this approach are
highlighted in Table 1.
The importance of the central amide unit in the benchmark
phenylbenzoxazole structures 1a and 1b became apparent by the
significant attenuation in potency observed with seemingly simple
substitutions. For example, potency was reduced by approximately
two orders of magnitude when the amide was replaced with either
a propyl or propynyl group (entries 1 and 2), a keto- or alkoxy-
group (entries 3–5 and 7–8), or an ether linkage (entry 6). Other
modifications such as 2-methoxypropyl linkages (entry 9), sulfon-
amides (entry 10), and b-hydroxyamines (entry 11) were also not
well-tolerated. Even the relatively conservative substitution of a
cyclic amide (entry 12) was deleterious to in vitro potency. These
results may point to the participation of the amide in a hydrogen
donor/acceptor interaction with the transfer protein. Ultimately,
our only successful modification of the linker region was the
reversed amide series, in which the necessary amide bond is main-
tained, but the aniline substructure is eliminated.
Our first foray into this series necessitated extending the ‘linker’
region by one carbon unit to avoid introduction of a potentially
labile hemiaminal (entry 13), resulting in a severe attenuation of
in vitro potency. In order to determine whether this reduced
potency was due to the reversed amide, or simply to the greater
degree of rotational freedom introduced by the extra carbon, the
piperidine reversed amide analog of 1a (without the extra methy-
lene unit) was synthesized next (entry 14). Although the IC50 of
this compound, 4n, was still greatly reduced (300 nM) compared
to that of 1a, the potency showed nearly an order of magnitude
improvement over all the other compounds in Table 1. Methylation
of this amide had a strong deleterious effect on potency (entry 15),
Our second approach to improving the 2-phenylbenzoxazole
class of CETP inhibitors involved an evaluation of analogs at the
C-7 position of the benzoxazole ring. Bromobenzoxazole
6
provided a handle for the introduction of functionality at the C-7
position of the benzoxazole in the reverse amide scaffold. As
shown in Scheme 3, this intermediate resulted from selective
nitration of 3,5-dibromo-4-hydroxybenzonitrile,8 followed by iro-
n(III) chloride-mediated hydrazine reduction to the amino alcohol,
which was then coupled with methyl 4-chlorocarbonylbenzoate
and cyclized to the corresponding benzoxazole.
A Suzuki coupling reaction installed the desired isopropenyl
group at C-7, and Pd-catalyzed reduction provided the isopropyl-
substituted benzoxazole 8, which was condensed with a variety
of amines to furnish aminopiperidine-substituted analogs.
Finally, our third approach utilized 3-bromopyridine as the aryl
functionality attached to the piperidine (Scheme 4). Further
manipulation of the bromide, via palladium-catalyzed N-arylation
reactions, was utilized to evaluate SAR at C3 of the pyridine ring.
O
O
N
H
(HO)2B
R
N
H
O
N
Ar2
O
N
Ar1
N
N
NC
Ar1:
Ar2:
NC
N
N
Br
R
Scheme 4. Synthesis of various aryl pyridines at the terminus of benzoxazoles 11j–v. Reagents and conditions: 2 M Na2CO3 (3 equiv), Pd(PPh3)4 (5 mol %), toluene/H2O/EtOH
(25–59%).

R. F. Sweis et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1890–1895
1893
Table 1
Table 2
Effect of various linker groups on inhibition of CETP
Effect of benzoxazole C-7 substitution on CETP inhibition
R1
R2
O
Me
N
H
N
O
R
O
N
N
CF3
N
N
CF3
NC
NC
Entry
R1
R2
N
IC50
Entry
R
IC50 (nM)
1
2
975
4a
4b
1
2
3
243
3186
198
9a
9b
9c
N
2172
2053
CF3
O
3
4
N
N
4c
5741
4d
O
4
5
131
40
9d
9e
O
O
5
6
7
N
N
N
4029
4554
2249
4e
4f
OH
O
4g
N
H
O
N
8
9
N
N
874
4h
4i
Ar
OH
N
8940
OMe
NC
9e:
H
N
CF3
S
10
11
12
N
N
N
—
4j
IC50 : 40 nM
Δ HDL: + 16 mg/dl
O
O
OH
N
N
H
N
18,760
2742
4k
4l
N
IC50 : 22 nM
Δ HDL: + 7 mg/dl
10:
O
CF3
N
Figure 2. Isopropyl-substituted ‘reversed amide’ CETP inhibitors and their effect on
HDLc elevation.
O
O
O
13
14
CH
CH
11,600
300
4m
4n
N
H
Benzoxazole 9e was subsequently evaluated in our mouse PD
assay along with a similar compound, pyrimidine 10 (Fig. 2). Both
of these compounds showed only modest effects in raising HDLc.
There also was substantial variability in this assay, presumably
owing to the poor solubility of these compounds in many solvents,
including DMSO and water.
N
H
15
CH
2612
4o
N
Me
Our strategy then shifted to evaluating substitution at the
terminal pyridine of the molecule, since initial studies revealed
that a variety of groups could be incorporated at this site without
severely impeding in vitro potency. A series of pyridine analogs
were studied, as shown in Table 3.
The potency of the unsubstituted pyridine (entry 1) dropped
almost threefold compared to 9e, demonstrating the importance
of the CF3 moiety on the pyridine ring; the 2-CF3- and 4-CF3-
substituted pyridines (entries 2 and 4) were comparable in potency
to 9e. However, the reduced potency of the 2-methoxy- (entry 3),
2-methylcarboxy- (entry 6), and 3-methylcarboxy- (entry 5) vari-
ants revealed the superiority of nonpolar substituents, and variants
with highly polar substituents such as 2-carboxy- (entry 7) and
3-nitro- (entry 8) showed no inhibition of CETP activity.
The 3-bromopyridine 11i (entry 9) was synthesized in order to
pursue more nonpolar substituents on the pyridine ring. While
small groups such as isopropenyl (entry 10) led to insufficient
potency, larger groups such as phenyl (entry 11) 4-methylphenyl
(entry 12), and 3-methylphenyl (entry 13) drove the IC50 values
to below 50 nM. When we discovered that ortho-substitution on
the phenyl ring was well-tolerated (entry 14), we became intrigued
by the possibility of incorporating a 2-methoxy-4-fluoro-5-isopro-
once again highlighting the sensitivity of the SAR in the linker
region.
Having identified the reversed amide as our most promising lin-
ker modification, we shifted the direction of our efforts towards
improving the potency of 4n. Prior SAR at the C-7 position of
benzoxazole 1a suggested that surveying substituents at this posi-
tion could help us regain some of the potency that was lost by
removing the aniline substructures.3b The C-7 methyl was known
to be a potency-enhancing group in the previous amide class. Con-
sequently, a series of alkyl substitutions at this position was eval-
uated in the reversed amide series (Table 2).
Replacing the C-7 methyl with a cyclopropyl group did not re-
sult in any improvement in IC50 value (entry 1). Similarly, substitu-
tion with a trifluoromethyl (entry 2) and tert-butyl group (entry 3)
were either deleterious or lacked any significant enhancement in
potency. Substitution with a C-7 isopropenyl group did, however,
show some promise as the IC50 was reduced to 131 nM. Subse-
quent reduction of the alkene in compound 9d to form the C-7 iso-
propyl group of compound 9e (entry 5) brought the potency of this
benzoxazole back to the range of compounds 1a and 1b (40 nM).

1894
R. F. Sweis et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1890–1895
Table 3
Table 3 (continued)
Effect of pyridine substitution on inhibition of CETP
Entry
Ar
IC50 (nM)
413
O
BnO
N
H
N
O
CF3
18
11r
11s
Ar
N
N
i-PrO
NC
19
20
29
31
Entry
1
Ar
IC50 (nM)
114
N
O
11a
11b
11c
N
N
11t
2
3
37
CF3
O
N
110
N
CF3
21
22
19
13
11u
11v
4
5
61
11d
11e
N
N
i-PrO
CO2Me
CO2Me
F
114
N
N
N
N
6
7
306
11f
pylphenyl group onto the pyridine ring (entry 15), based on the use
of this substitution pattern in our clinical CETP inhibitor, anacetra-
pib.10 Similar compounds with an ortho-alkoxy, meta-alkyl substi-
tution pattern were then prepared: 2-isopropoxy analogs (entries
16 and 17) showed comparable potency, but a further increase in
the size of the alkoxy group proved deleterious (entry 18).
The complexity of the substitution pattern was then scaled back
to simple 2-substituted aryl groups without the meta-alkyl substit-
uents (entries 19, 20, and 21). Finally, replacement of the meta-al-
kyl group with a fluoro led to the most potent compound in the
series (entry 22).
Three compounds in the arylpiperidine series were evaluated in
our mouse PD assay. Compounds 11k, 11p, and 11v (Table 3) raised
HDLc levels by 22, 28, and 24 mg/dl at 10 mpk. These compounds,
in addition to producing robust elevations of HDLc levels, were not
plagued by the irreproducibility previously observed with com-
pounds 9e and 10.
In summary, our efforts to develop a 2-phenyl benzoxazole CETP
inhibitor devoid of aniline substructures began with an initial eval-
uation of the central amide portion of our lead compound 1a. This
work revealed that reversal of the amide connectivity was the most
viable path forward towards this objective. The lost potency of 4n
was recovered via installation of an isopropyl group at the C-7 posi-
tion of the benzoxazole (9e). The resultant IC50 of 40 nM was compa-
rable to our benchmark compound 1a, although the HDLc elevation
inourmousePDmodelremainedinadequate. Furtherrefinementvia
substitution on the terminal pyridine ring led to a class of arylpyri-
dine inhibitors. From this class, three compounds (11k, 11p, and
11v) were evaluated and found to strongly elevate HDLc levels
(>20 mg/dl). Continuing work on this class of compounds to address
off-target activities will be reported in due course.
>10,000
11g
CO2
NO2
H
8
9
>10,000
223
11h
11i
N
N
Br
10
11
229
43
11j
N
N
Ph
11k
Me
Me
12
13
14
48
39
47
11l
N
11m
11n
N
MeO
Cl
N
MeO
F
15
16
17
24
22
28
11o
11p
11q
N
i-PrO
References and notes
Me
1. (a) Sikorski, J. A. J. Med. Chem. 2006, 49, 1; (b) Tall, A. R. N. Eng. J. Med. 2007, 356,
1362; (c) Hunt, J. A.; Lu, Z. Curr. Top. Med. Chem. 2009, 9, 419.
2. Gordon, D. J.; Rifkind, B. M. N. Eng. J. Med. 1989, 321, 1311.
3. (a) Smith, C. J.; Ali, A.; Chen, L.; Hammond, M. L.; Anderson, M.; Chen, Y.;
Eveland, S. S.; Guo, Q.; Hyland, S.; Milot, D. P.; Sparrow, C. P.; Wright, S. D.;
Sinclair, P. J. Bioorg. Med. Chem. Lett. 2010, 20, 346; (b) Hunt, J. A.; Gonzalez, S.;
Kallashi, F.; Hammond, M. L.; Pivnichny, J. V.; Tong, X.; Xu, S. S.; Anderson, M.
N
i-PrO
CF3
N

R. F. Sweis et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1890–1895
1895
S.; Chen, Y.; Eveland, S. S.; Guo, Q.; Hyland, S. A.; Milot, D.; Sparrow, C. P.;
Wright, S. D.; Sinclair, P. J. Bioorg. Med. Chem. Lett. 2010, 20, 1019.
were screened and found to have similar (within 2Â) IC50 values against CETP-
mediated triglyceride transfer (TG) as well.; (c) All mouse PD experiments were
dosed at 10 mpk of compound.
4. (a) Durley, R. C.; Grapperhaus, M. L.; Hickory, B. S.; Massa, M. A.; Wang, J. L.;
Spangler, D. P.; Mischke, D. A.; Parnas, B. L.; Fobian, Y. M.; Rath, N. P.; Honda, D.
D.; Zeng, M.; Connolly, D. T.; Heuvelman, D. M.; Witherbee, B. J.; Melton, M. A.;
Glenn, K. C.; Krul, E. S.; Smith, M. E.; Sikorski, J. A. J. Med. Chem. 2002, 45, 3891;
(b) Shinkai, H.; Maeda, K.; Yamasaki, T.; Okamoto, H.; Uchida, I. J. Med. Chem.
2000, 43, 3566; (c) Paulsen, H.; Schmeck, C.; Brandes, A.; Schmidt, G.;
Stoltefuss, J.; Wirtz, S. N.; Loegers, M.; Naab, P.; Bremm, K.-D.; Bischoff, H.;
Schmidt, D.; Zaiss, S.; Antons, S. Chimia 2004, 58, 123; (d) 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.
5. (a) Kallashi, F.; Ali, A.; Kim, D.; Kowalchick, J.; Park, Y. J.; Hunt, J.; Smith, C. J.;
Hammond, M. L.; Pivnichny, J. V.; Tong, X.; Xu, S. S.; Anderson, M. S.; Chen, Y.;
Eveland, S. S.; Guo, Q.; Hyland, S. A.; Milot, D. P.; Cumisky, A.; Latham, M.; Rosa,
R.; Peterson, L.; Sparrow, C. P.; Wright, S. D; Sinclair, P. Bioorg. Med. Chem. Lett.,
2010, doi:10.1016/j.bmcl.2010.10.062; (b) All IC50 values reported herein
reflect inhibition of cholesterol ester (CE) transfer by CETP. All compounds
6. http://www.epa.gov/NCEA/iris/subst/0350.htm.
7. (a) Colson, J.-P.; Babiak, K. A.; Korte, D. E.; Przybyla, C. A.; Seaney, L. M.; Wise, B.
E. Patent Application, 1999, WO 99/51573.; Reddy, L. R.; Reddy, M. A.;
Bhanumathi, N.; Rao, K. R. Synthesis 2001, 831; (b) Reddy, L. R.; Reddy, M. A.;
Bhanumathi, N.; Rao, K. R. Synthesis 2001, 831.
8. Raiford, L. C.; LeRosen, A. L. J. Am. Chem. Soc. 1944, 66, 1872.
9. Unpublished data.
10. (a) Bloomfield, D.; Carlson, G. L.; Sapre, A.; Tribble, D.; McKenney, J. M.;
Littlejohn, T. W.; Sisk, C. M.; Mitchel, Y.; Pasternak, R. C. Am. Heart J. 2009, 157,
352; (b) Krishna, R.; Anderson, M. S.; Bergman, A. J.; Jin, B.; Fallon, M.; Cote, J.;
Rosko, K.; Chavez-Eng, C.; Lutz, R.; Bloomfield, D. M.; Gutierrez, M.; Doherty, J.;
Bieberdorf, F.; Chodakewitz, J.; Gottesdiener, K. M.; Wagner, J. A. Lancet 2007,
370, 1907; (c) Krishna, R.; Bergman, A.; Jin, B.; Fallon, M.; Cote, J.; Van, H. P.;
Laethem, T.; Gendrano, I. I.; Van, D. K.; Hilliard, D.; Laterza, O.; Snyder, K.;
Chavez-Eng, C.; Lutz, R.; Chen, J.; Bloomfield, D.; De, S. M.; Van, B. L.; Gutierrez,
M.; Al-Huniti, N.; Dykstra, K.; Gottesdiener, K.; Wagner, J. A. J. Clin. Pharmacol.
Ther. 2008, 84, 679.