Design, synthesis, and biological evaluation of (2R,αS)-3,4-dihydro- 2-[3-(1,1,2,2-tetrafluoroet-hoxy)phenyl]-5-[3-(trifluoromethoxy)-phenyl] -a-(trifluoromethyl)-1(2H)-quinolineethanol as potent and orally active cholesteryl ester transfer protein inhibi

Article abstract of DOI:10.1021/jm801319d

With the goal of identifying a CETP inhibitor with high in vitro potency and optimal in vivo efficacy, a conformationally constrained molecule was designed based on the highly potent and flexible 13. The synthetic chemistry efforts led to the discovery of

Full text of DOI:10.1021/jm801319d

1768
J. Med. Chem. 2009, 52, 1768–1772
Brief Articles
Design, Synthesis, and Biological Evaluation of (2R,rS)-3,4-Dihydro-2-[3-(1,1,2,2-tetrafluoroet-
hoxy)phenyl]-5-[3-(trifluoromethoxy)-phenyl]-r-(trifluoromethyl)-1(2H)-quinolineethanol as
Potent and Orally Active Cholesteryl Ester Transfer Protein Inhibitor
Gee-Hong Kuo,* Thomas Rano, Patricia Pelton, Keith T. Demarest, Alan C. Gibbs, William V. Murray, Bruce P. Damiano, and
Margery A. Connelly*
Drug DiscoVery DiVision, Johnson and Johnson Pharmaceutical Research and DeVelopment, LLC 8 Clarke DriVe, Cranbury, New Jersey 08512
ReceiVed October 18, 2008
With the goal of identifying a CETP inhibitor with high in vitro potency and optimal in vivo efficacy, a
conformationally constrained molecule was designed based on the highly potent and flexible 13. The synthetic
chemistry efforts led to the discovery of the potent and selective 12. In high-fat fed hamsters, human CETP
transgenic mice, and cynomolgus monkeys, the in vivo efficacy of 12 for raising HDL-C was demonstrated
to be comparable to torcetrapib.
Introduction
Cardiovascular disease (CVDa) is the most common cause
of morbidity and mortality in developed nations.1 Atherogenic
dyslipidemia, characterized by an abnormal circulating lipid
profile including low levels of high density lipoprotein choles-
terol (HDL-C), elevated levels of small-dense low density
lipoprotein cholesterol (LDL-C), or elevated triglycerides (TG),
is often found in patients who are obese, have type 2 diabetes,
or metabolic syndrome.2 These individuals are at high risk for
premature CVD. Due to the fact that LDL-C is prone to
accumulate in the arterial wall leading to the formation of
atherosclerotic cholesterol-laden foam cells, studies suggest that
for every 1 mg/dL (0.026 mmol/L) decrease in plasma LDL-C,
CVD risk is reduced by 0.5%.3 Despite aggressive lowering of
LDL-C with HMG-CoA reductase inhibitors (statins),4 however,
two-thirds of statin-treated patients continued to develop CVD.
In addition, several epidemiological studies have established that
a low level of HDL-C (<40 mg/dL) is a critical determinant of
CVD, independent of LDL-C levels.5 Analysis of the epide-
miological data suggests that for every 1 mg/dL increase in
HDL-C, CVD risk is reduced by 2-3%.6
Cholesteryl ester transfer protein (CETP) is a plasma glyco-
protein that transfers cholesterol ester (CE) from HDL to LDL
and VLDL, thereby lowering antiatherogenic HDL and raising
Figure 1. Structures of 1, 2, and 3.
transfer on atherogenesis remains controversial,8 many animal
studies support the hypothesis that inhibition of CETP activity
is beneficial. For example, expression of CETP in animals
lacking CETP can exert marked atherogenesis. On the other
hand, inhibition of CETP can reduce the progression of
atherosclerosis.9 In addition, plasma CETP levels are typically
increased by 2- to 3-fold in those at risk for CVD when
compared to normal subjects (1-3 µg/mL).10 Therefore, there
has been great interest in identifying potent and selective CETP
inhibitors7 since the early reports connecting CETP deficiency
to HDL-C elevation in late 1980s. To date, with the discon-
tinuation of development of 1 (torcetrapib, Pfizer, Figure 1)11
that occurred in December 2006, 2 (dalcetrapib, JTT-705,
Roche/Japan Tobacco)12 and 3 (anacetrapib, MK-0859, Merck)13
became the two most advanced CETP inhibitors undergoing
clinical trials. This paper describes our identification and
pro-atherogenic LDL and VLDL, and in return, it transfers TG
from VLDL (or LDL) to HDL. The resulting TG-enriched HDL
are more readily hydrolyzed by hepatic lipase to generate smaller
HDL particles, which are more effective in promoting reverse
cholesterol transport.7 While the impact of CETP-mediated lipid
* To whom correspondence should be addressed. For G.-H.K.: phone,
609-655-6967; fax, 609-655-6930; E-mail, gkuo@its.jnj.com. For M.A.C.:
phone, 215-628-5202; fax, 215-628-5047; E-mail, mconnell@its.jnj.com.
a Abbreviations: CVD, cardiovascular disease; HDL-C, high density
lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; TG,
triglycerides; CETP, cholesteryl ester transfer protein; CE, cholesteryl ester;
VLDL, very low density lipoprotein cholesterol; PLTP, phospholipids
transfer protein; MTP, microsomal triglyceride transfer protein; LCAT,
lecithin-cholesterol acyltransferase; LPL, lipoprotein lipase; HL, hepatic
lipase; EL, endothelial lipase; AUC, area under the curve; CL, systemic
clearance; F%, oral bioavailability.
10.1021/jm801319d CCC: $40.75
2009 American Chemical Society
Published on Web 02/23/2009

Brief Articles
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6 1769
Scheme 1a
a (i) Sodium diethyl malonate, DMF, 20 °C, 75%; (ii) NaCl, DMSO,
H2O, 180 °C, 100%; (iii) 3 N NaOH, THF, 65 °C, 100%; (iv) oxalyl
chloride, CH2Cl2, 20 °C; (v) 6, N,N-diisopropylethylamine, Pd2(dba)3, THF,
50 °C, 66%; (vi) NaBH4, EtOH, 95%; (vii) CH3SO2Cl, Et3N, CH2Cl2, 0
°C; (viii) NaN3, DMF, 50 °C, 95%; (ix) Me2S-BHCl2, 1,2-dichloroethane,
20-50 °C, 98%; (x) NsCl, Et3N, CH2Cl2, 20 °C, 95%; (xi) CuI, CsOAc,
DMSO, 95 °C, 96%; (xii) thioacetic acid, LiOH, DMF, 20 °C, 88%; (xiii)
3-trifluoromethoxy-phenyl-boronic acid, Pd(PPh3)4, K2CO3, 1,4-dioxane, 108
°C, 91%; (xiv) chiral HPLC; (xv) (S)-1,1,1-trifluoro-2,3-epoxy-propane,
Yb(OTf)3, CH2Cl2, 50 °C, 69%.
Figure 2. Design of the lead molecules.
racemate 11, followed by N-alkylation with (S)-1,1,1-trifluoro-
2,3-epoxypropane,17 gave the target 12.18
Results and Discussion
characterization of (2R,RS)-3,4-dihydro-2-[3-(1,1,2,2-tetrafluo-
roethoxy)phenyl]-5-[3-(trifluoromethoxy)phenyl]-R-(trifluoro-
methyl)-1(2H)-quinolineethanol as a novel, potent, and orally
active CETP inhibitor.
Lead Generation. The primary goal of this project was the
identification of a potent and selective CETP inhibitor with
optimal in vivo efficacy and maximal safety margin. High-
throughput screening of internal compound libraries resulted
in the discovery of only a few hits with micromolar potencies.
However, subsequent studies of the structure-activity relation-
ship (SAR) of these hits did not yield compounds with
submicromolar inhibitory potencies. At that time, Pharmacia19
disclosed 13 (Figure 2) as a highly potent CETP inhibitor (IC50
) 3 nM in buffer, and IC50 ) 59 nM in human serum), although
it had relatively modest oral exposure and in vivo efficacy.
While examining the structure of 13, we felt the molecule was
quite flexible (with 12 rotatable bonds), and this high flexibility
might be the basis for poor absorption in vivo.20 Therefore, a
conformationally constrained analogue would reduce the flex-
ibility and may potentially increase absorption and improve oral
exposure and in vivo efficacy. While there were several ways
to design the conformationally constrained molecules, we found
that one of the cyclized molecules (13B, proposed first target,
Figure 2) superimposed nicely to 1. Therefore, we synthesized
this target compound first. Interestingly, it displayed good
Chemistry
Displacement of the benzylic bromide of the readily available
1,3-dibromo-2-bromomethyl-benzene 414 with sodium diethyl
malonate gave the malonic acid diethyl ester adduct (Scheme
1). Removal of one of the carboxylic acid ester with NaCl in
DMSO/H2O, followed by base hydrolysis, provided the car-
boxylic acid 5. Conversion of 5 to the corresponding acid
chloride, followed by the palladium-catalyzed acylation with
organo-stannane 6, afforded the ketone 7. The organo-stannane
6 was easily prepared from the bromo-precursor. The conversion
of 7 to the azide 8 was accomplished in three steps: reduction
of 7 with NaBH4 to give the alcohol, conversion of the alcohol
to the mesylate, and followed by the reaction of the mesylate
with NaN3 to give the azide 8. Reduction of 8 with Me2S-BHCl2
gave the primary amine that was subsequently converted to the
sulfonamide 9 by reaction with NsCl (Ns is o-nitrobenzene-
sulfonyl).15 A copper-mediated intramolecular amination16 of
sulfonamide 9, followed by deprotection with thioacetic acid,
gave 10 in good yield. A palladium-catalyzed Suzuki coupling
reaction of 10 with 3-trifluoromethoxy-phenylboronic acid
afforded 11. Using chiral HPLC to separate (2R)-11 from
potency (IC50 ) 400 nM) although not as potent as 13 (IC50
)
3 nM). Meanwhile, because bromo-tetrahydroquinoline 10
(Scheme 1) was the intermediate for the synthesis of the
biphenyl-ether molecule, we envisioned that the palladium-
catalyzed Suzuki coupling reaction of 10 with various phenyl-

1770 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6
Brief Articles
boronic acids might generate diverse biphenyl molecules (13D,
proposed second target, Figure 2). Indeed, many biphenyl
analogues were prepared in a short period of time. Most
excitingly, the trifluoromethoxy-substituted biphenyl analogue
gave ∼10-fold increase in potency (IC50 ) 45 nM, racemic 12,
Scheme 1). Later, the optically active 12 was synthesized and
proved to be the most potent CETP inhibitor in this series, with
IC50 ) 39 nM in a CETP SPA assay and IC50 ) 0.2 µM in a
human plasma 3H-CE HDL assay. The in vitro CETP inhibitory
potency of 12 in a plasma CETP Roar assay with samples from
different species were also measured. For example, 12 was more
potent in species with relatively low plasma CETP activity
(hamster plasma, IC50 ) 0.1 µM) and less potent in species
with relatively high plasma CETP activity (rabbit plasma, IC50
) 3.5 µM). Meanwhile, 12 displayed moderate potencies in
species that express moderate plasma CETP activity (human
plasma, IC50 ) 1.2 µM; monkey plasma, IC50 ) 1.4 µM). We
next explored the selectivity of 12 against other lipid transfer
proteins or proteins that modify lipoproteins,21 including phos-
pholipid transfer protein (PLTP), microsomal triglyceride
transfer protein (MTP), lecithin-cholesterol acyltransferase
(LCAT), lipoprotein lipase (LPL), hepatic lipase (HL), and
endothelial lipase (EL). In summary, 12 exhibited little or no
inhibition in any of these cellular assays, similar to that of 1.21
Compound 12 was also screened in a panel of 50 GPCR or ion
channel binding assays, and no significant inhibitions were
observed. Compound 12 was highly stable in human liver
microsomes with t1/2 >128 min. The pharmacokinetic studies
of 12 in rat, dog, and monkey were conducted. Compound 12
displayed acceptable oral bioavailability in rat (F% ) 31%),
with slow oral absorption (Tmax ) 6 h), significant plasma drug
exposure (AUC ) 31.3 µg·h/mL), and long plasma duration
(t1/2 ) 28 h). It also exhibited low systemic clearance (CL )
1.8 mL/min·kg) and low volume of distribution (Vdss ) 0.36
L/kg). Because the target (CETP) is present in plasma, the low
volume of distribution of 12 is optimal for its pharmacodynamic
actions and potential for reduced nonspecific actions in vivo.
Compound 12 displayed low oral bioavailability (F% ) 5%)
in dogs, but oral bioavailability in monkeys (F% ) 27%) was
comparable to that in rats (F% ) 31%).
Figure 3. Effects of 12 and 1 on HDL-C and HDL-C/LDL-C in the
high-fat-diet hamster model (5 days oral dosing). Bars represent means
( SD (n ) 8 per group; *p < 0.05, **p < 0.01 relative to HF vehicle).
Figure 4. Effects of 12 and 1 on HDL-C in the hCETP transgenic
mice model (5 days oral dosing). Bars represent means ( SD (n ) 8
per group; *p < 0.05, **p < 0.01 relative to vehicle group).
In Vivo Studies. Because mice, rats, and dogs do not express
CETP, hamsters, human CETP transgenic mice, and monkeys
were used to evaluate the in vivo efficacy of CETP inhibitor
12. High-fat fed hamsters were orally gavaged with vehicle
(10% solutol, 5% ethanol, 85% D5W), 12, or 1 for 5 days. The
lipid parameters measured from the plasma are shown in Figure
3. Compound 12 produced a dose related increase in HDL-C
levels. At the 10 and 30 mg/kg doses of 12, the HDL-C was
increased 36% and 40%, respectively. Meanwhile, a 30 mg/kg
dose of 1 increased HDL-C by 44%. There were no significant
changes in LDL-C and triglyceride levels with either compound.
Overall, increasing doses of 12 produced a less atherogenic lipid
profile as indicated by the increase in the HDL-C/LDL-C ratio
(from 2.9 to 4.6).
RH40/70% water), 12, or 1 for 5 days. Compound 12 produced
a dose-dependent inhibition of CETP and an increase in plasma
HDL-C levels (Figure 5). At the 3, 10, and 30 mg/kg doses of
12, CETP was inhibited by 11%, 51%, and 67%, respectively.
Concurrently, plasma HDL-C was increased 4%, 16%, and 32%
at the 3, 10, and 30 mg/kg doses, respectively. In comparison,
when dosed with 1 at the same three doses (3, 10, and 30 mg/
kg), CETP was inhibited by 35%, 66%, and 85%, respectively,
and the plasma HDL-C was increased 24%, 41%, and 44%,
respectively. Moreover, these changes were observed with fairly
equivalent plasma concentrations of compound (0.4, 2.7, and
5.9 µM of 12 and 0.3, 1.3, and 2.9 µM of 1 at the respective
dose levels of 3, 10, and 30 mg/kg). Overall, 12 displayed in
vivo efficacy comparable to 1 in monkeys.
Human CETP transgenic mice fed a normal chow diet were
orally treated with vehicle, 12, or 1 for 5 days. As shown in
Figure 4, there was a dose related increase in HDL-C with 12
treatment. At 3 mg/kg, 12 already produced a significant increase
in HDL-C compared to the vehicle group. At 10 and 30 mg/kg,
12 increased HDL-C by 36% and 25%, respectively. In
comparison, HDL-C was increased by 28% at 30 mg/kg dose
of 1.
Conclusions
With the goal of identifying a CETP inhibitor with high in
vitro potency and optimal in vivo efficacy, a conformationally
constrained molecule was designed based on the highly potent
and flexible 13 (IC50 ) 3 nM). The synthetic efforts led to the
discovery of 12 (IC50 ) 39 nM) that proved to be very selective
over other lipid transfer proteins and a large panel of GPCRs
and ion channels. Compound 12 had in vivo efficacy (HDL-C
raising) comparable to that of 1 in high-fat fed hamsters, human
Male cynomolgus monkeys fed a normal chow diet were
dosed orally with vehicle (10% Imwitor 742/20% cremophor

Brief Articles
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6 1771
5-Bromo-2-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-1,2,3,4-tet-
rahydro-quinoline (10). A mixture of 9 (3.54 g, 5.26 mmol), CuI
(2.00 g, 10.5 mmol), and CsOAc (5.04 g, 26.3 mmol) in DMSO
(52 mL) under N2 was heated at 95 °C for 24 h. After cooling to
20 °C, the reaction mixture was worked up with EtOAc/H2O and
purified by column chromatography (25% EtOAc/hex) to afford
2.99 g (96%) of 5-bromo-1-(2-nitro-benzenesulfonyl)-2-[3-(1,1,2,2-
tetrafluro-ethoxy)-phenyl]-1,2,3,4-tetrahydro-quinoline as an oil. 1H
NMR (400 MHz, CDCl3) δ 7.81 (d, J ) 8.1 Hz, 1 H), 7.69-7.73
(m, 1 H), 7.50-7.63 (m, 3 H), 7.43 (d, J ) 8.0 Hz, 1 H), 7.09-7.39
(m, 5 H), 5.88 (tt, J ) 53.1, 2.9 Hz, 1 H), 5.62 (t, J ) 6.9 Hz, 1
H), 2.66-2.74 (m, 1 H), 2.39-2.47 (m, 1 H), 2.27-2.35 (m, 1 H),
1.96-2.05 (m, 1 H). MS (ES) m/z: 589 (M). To a solution of
protected-quinoline (2.99 g, 5.06 mmol) in DMF (25 mL) was added
thioacetic acid (0.707 mL, 10.1 mmol) and powdered LiOH (485
mg, 20.2 mmol). The reaction mixture was stirred at 20 °C for 6 h
and then worked up with EtOAc/H2O and purified by column
chromatography (25% EtOAc/hex) to afford 1.80 g (88%) of 10
as an oil. 1H NMR (300 MHz, CDCl3) δ 7.37 (t, J ) 7.8 Hz, 1 H),
7.21-7.30 (m, 2 H), 7.15 (d, J ) 7.9 Hz, 1 H), 6.71-6.95 (m, 2
H), 6.51 (d, J ) 7.8 Hz, 1 H), 5.90 (tt, J ) 53.1, 2.8 Hz, 1 H), 4.40
(dd, J ) 9.3, 3.1 Hz, 1 H), 4.13 (brs, 1 H), 2.79-2.88 (m, 2 H),
2.11-2.21 (m, 1 H), 1.90-2.05 (m, 1 H). MS (ES) m/z: 406 (M +
2).
2-[3-(1,1,2,2-Tetrafluoro-ethoxy)-phenyl]-5-(3-trifluoromethoxy-
phenyl)-1,2,3,4-tetrahydro-quinoline (11). A mixture of bromide
10 (30 mg, 0.074 mmol), 3-trifluoromethoxy-phenyl-boronic acid
(30 mg, 0.148 mmol), Pd(PPh3)4 (9 mg, 0.0074 mmol), and 2 N
K2CO3 (0.11 mL, 0.22 mmol) in 1,4-dioxane (0.75 mL) was heated
at reflux for 2 h. After cooling to 20 °C, the mixture was worked
up with EtOAc/H2O and purified by column chromatography to
give 33 mg (91%) of 11 as a clear oil. 1H NMR (400 MHz, CDCl3)
δ 7.30-7.42 (m, 4 H), 7.25 (m, 1 H), 7.08-7.21 (m, 4 H), 6.62 (s,
1 H), 6.60 (s, 1 H), 5.90 (tt, J ) 53.1, 2.8 Hz, 1 H), 4.51 (dd, J )
8.9, 3.3 Hz, 1 H), 4.20 (brs, 1 H), 2.71-2.81 (m, 1 H), 2.53 (dt, J
) 16.6, 4.8 Hz, 1 H), 2.02-2.10 (m, 1 H), 1.82-1.92 (m, 1 H).
MS (ES) m/z: 486 (M + H+).
Figure 5. Effects of 12 and 1 on CETP inhibition and HDL-C in the
cynomolgus monkey (5 days oral dosing). Bars represent means ( SD
(n ) 6 per group; *p < 0.05 relative to prebleed control).
CETP transgenic mice, and monkeys. Taken together, the
potency, selectivity, stability, and in vivo HDL raising efficacy
in three animal modes support the utility of 12 for HDL raising
through CETP inhibition, with the potential for having a positive
impact on atherosclerosis without the off-target cardiovascular
liability.
(2R,rS)-3,4-Dihydro-2-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-
5-[3-(trifluoromethoxy)-phenyl]-r-(trifluoromethyl)-1(2H)-quin-
olineethanol (12). Using chiral HPLC (OJ column, using 95%
heptane, 5% ethanol as the eluent, 80 mL/min as the flow rate,
retention time 4.7 min, wavelength 220 nm) to separate (2R)-1,2,3,4-
tetrahydro-2-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-5-[3-(trifluo-
Experimental Section
1
Chemistry. H NMR spectra were measured on a Bruker AC-
300 (300 MHz) spectrometer using tetramethylsilane as an internal
standard. Elemental analyses were obtained by Quantitative Tech-
nologies Inc. (Whitehouse, NJ). Electrospray mass spectra (MS-
ES) were recorded on a Hewlett-Packard 59987A spectrometer.
Synthesis of 5-8 are included in Supporting Information.
20
romethoxy)-phenyl]quinoline (2R)-11 as a clear oil (45%): [R]D
) -12.9° (C ) 1, CHCl3). To a solution of (2R)-11 (33 mg, 0.068
mmol) and (S)-1,1,1-trifluoro-2,3-epoxy-propane (38 mg, 0.34
mmol) in CH2Cl2 (0.45 mL) under N2 was added Yb(OTf)3 (10.5
mg, 0.0169 mmol). The reaction mixture was heated at 50 °C for
48 h and then cooled to 20 °C, worked up with EtOAc/H2O, and
purified by column chromatography to get 28 mg (69%) of 12 as
N-{3-(2,6-Dibromo-phenyl)-1-[3-(1,1,2,2-tetrafluoro-ethoxy)-
phenyl]-propyl}-2-nitro-benzenesulfonamide (9). To a solution
of 8 (2.90 g, 5.67 mmol) in 1,2-dichloroethane (38 mL) under N2
was added Me2S·BHCl2 (1.64 mL, 14.2 mmol) dropwise. The
solution was stirred at 20 °C for 0.5 h and then heated at 50 °C for
1.5 h. The reaction was cooled to 0 °C, and then 6 N HCl (10 mL)
was added and heated at reflux for 1 h. Upon cooling to 0 °C, the
solution was basified with 3 N NaOH, worked up with H2O, and
purified by column chromatography (100% EtOAc) to provide
2.69 g (98%) of 3-(2,6-dibromo-phenyl)-1-[3-(1,1,2,2-tetrafluoro-
ethoxy)-phenyl]-propylamine as an oil; MS (ES) m/z: 486 (M +
H+). To a solution of the amine (2.67 g, 5.50 mmol) and Et3N
(1.53 mL, 11.0 mmol) in CH2Cl2 (27 mL) was added NsCl (1.34
g, 6.05 mmol) under N2. The reaction mixture was stirred at 20 °C
for 1 h and then poured into EtOAc/Et2O, worked up with H2O,
and purified by column chromatography (5%-10%-15%-20%
20
1
an oil: [R]D ) -117.3° (C ) 1, CHCl3). H NMR (400 MHz,
CDCl3) δ 7.20-7.40 (m, 2 H), 7.10-7.28 (m, 6 H), 7.04 (s, 1 H),
6.73 (d, J ) 8.3 Hz, 1 H), 6.67 (d, J ) 7.4 Hz, 1 H), 5.89 (tt, J )
53.1, 2.8 Hz, 1 H), 4.89 (t, J ) 4.4 Hz, 1 H), 4.42 (m, 1 H), 3.91
(d, J ) 15.5 Hz, 1 H), 3.30 (dd, J ) 15.6, 9.7 Hz, 1 H), 2.48 (dt,
J ) 16.3, 4.4 Hz, 1 H), 2.31-2.42 (m, 2 H), 2.09-2.19 (m, 1 H),
1.92-2.00 (m, 1 H). MS (ES) m/z: 598 (M + H+). Anal.
(C27H21F10NO3) C, H, N.
Acknowledgment. We thank the J&JPRD ADME team at
Spring House for the pharmacokinetic studies. We also thank
Dr. Troy C. Sarich for the thoughtful discussions during the
designing of the cynomolgus monkey study.
1
EtOAc/hex) to afford 3.54 g (95%) of 9 as an oil. H NMR (400
MHz, CDCl3) δ 7.72 (d, J ) 8.0 Hz, 1 H), 7.66 (d, J ) 7.9 Hz, 1
H), 7.33-7.56 (m, 4 H), 7.08-7.13 (m, 2 H), 7.01 (s, 1 H),
6.88-6.95 (m, 2 H), 5.96 (d, J ) 8.9 Hz, 1 H), 5.86 (tt, J ) 53.1,
2.8 Hz, 1 H), 4.69 (dd, J ) 16.0, 7.8 Hz, 1 H), 3.11-3.19 (m, 1
H), 2.80-2.88 (m, 1 H), 1.94-2.14 (m, 2 H). MS (ES) m/z: 693
(M + Na+).
Supporting Information Available: Elemental analysis data of
target molecule, experimental procedures for 5-8, biological assays,
and PK assays. This material is available free of charge via the
Internet at http://pubs.acs.org.

1772 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6
Brief Articles
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