Synthesis and evaluation of a series of benzopyran derivatives as PPAR α/γ agonists

Article abstract of DOI:10.1016/j.ejmech.2008.01.029

A series of benzopyran derivatives were synthesized and evaluated for PPAR α/γ agonist activities. Most of the compounds exhibit reasonable PPAR α and PPAR γ agonist activities. In particular, compounds 7b, 8b, 8e and 8h with remarkable PPARg EC₅₀ values of 0.001 μM are excellent full PPAR γ agonists with the functional potency about 130, 20 times stronger than that of leading compound 5 and rosiglitazone, respectively. Compounds 7a, 7c, 7d and 8a are dual PPAR α/γ agonists, and all of them gave comparable or stronger PPAR α/γ agonist efficacy than that of the corresponding positive control.

Full text of DOI:10.1016/j.ejmech.2008.01.029

Available online at www.sciencedirect.com
European Journal of Medicinal Chemistry 43 (2008) 2428e2435
http://www.elsevier.com/locate/ejmech
Original article
Synthesis and evaluation of a series of benzopyran derivatives as
PPAR a/g agonists
a
Juanhong Yu a, Lei Tang b, Yushe Yang a, , Ruyun Ji
*
a State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences,
Graduate School of the Chinese Academy of Sciences, CAS, Shanghai 201203, China
b School of Pharmacy, Guiyang Medical College, Guiyang 550004, China
Received 4 July 2007; received in revised form 7 January 2008; accepted 18 January 2008
Available online 2 February 2008
Abstract
A series of benzopyran derivatives were synthesized and evaluated for PPAR a/g agonist activities. Most of the compounds exhibit reason-
able PPAR a and PPAR g agonist activities. In particular, compounds 7b, 8b, 8e and 8h with remarkable PPARg EC50 values of 0.001 mM are
excellent full PPAR g agonists with the functional potency about 130, 20 times stronger than that of leading compound 5 and rosiglitazone,
respectively. Compounds 7a, 7c, 7d and 8a are dual PPAR a/g agonists, and all of them gave comparable or stronger PPAR a/g agonist efficacy
than that of the corresponding positive control.
Ó 2008 Elsevier Masson SAS. All rights reserved.
1. Introduction
suppress vessel wall inflammatory activity and reduce athero-
sclerosis in animal models through complementary mecha-
nisms [3]. Since most of type 2 diabetic patients suffer from
insulin resistance in addition to atherogenic lipid abnormali-
ties, an agent that simultaneously activates both PPAR a and
PPAR g has the potential advantage over the single selective
PPAR a or PPAR g agonist for the treatment of diabetic
patients with the additional risk factor of dyslipidemia. In
the recent decades, much attention has been paid to the devel-
opment of PPAR a/g dual agonists [4e14]. Compound 1 (far-
glitazar) [5], a potent PPAR g agonist with moderate PPAR
a relative activity, was developed as a clinical candidate but
was dropped due to the emergence of edema at phase III.
Two dual agonists 2 (ragaglitazar or DRF2725) [6] and 3
(MK-767 or KRP-297) [4] with more substantial PPAR a ac-
tivity also discontinued the development in the late clinical
stage due to carcinogenicity in rodent toxicity models. Com-
pound 4 (muraglitazar) [10], also a dual PPAR a/g agonist,
was abandoned after phase III because of the possibility of
increasing incidence of adverse cardiovascular events. Though
suffered so much frustration, the work to investigate PPAR a/g
dual agonists with novel biological profiles and structural
diversity still remains attractive [15,16].
The peroxisome proliferator-activated receptors (PPARs)
are a subfamily of ligand-activated nuclear hormone transcrip-
tion factors. By governing lipid and glucose homeostasis,
PPARs (PPAR a, PPAR g, and PPAR d) play a central role
in cardiovascular diseases, obesity and diabetes. PPAR g is
highly distributed in skeletal muscle, liver and adipose tissue
which is important for insulin action. Activation of PPAR g
improves glycemic control by improving insulin sensitivity,
via activation of genes involved in the control of glucose pro-
duction, transportation and utilization [1]. Alternatively, PPAR
a is localized in tissues of the heart, liver and muscle, where it
plays an important role in lipid metabolism by controlling
genes relating to cellular free fatty acid metabolism and cho-
lesterol trafficking. PPAR a activation decreases serum tri-
glycerides (TGs) and increases levels of serum high-density
lipoprotein (HDL)-cholesterol [2]. In addition, both PPAR g
and PPAR a selective activators have been demonstrated to
* Corresponding author. Tel.: þ86 21 50806600x3403; fax: þ86 21
50806786.
E-mail address: ysyang@mail.shcnc.ac.cn (Y. Yang).
0223-5234/$ - see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.01.029

J. Yu et al. / European Journal of Medicinal Chemistry 43 (2008) 2428e2435
2429
COOH
O
COOH
O
HN
N
N
O
O
O
1
2
H
N
O
COOH
O
N
O
F3C
O
H
N
N
O
O
O
S
O
3
4
OCH3
We previously reported the synthesis and insulin sensitizing
activity of a novel kind of benzopyran derivatives [17], the
representative compound 5, which is now under preclinical
research as a candidate for treatment of type 2 diabetes,
exhibited more potent insulin sensitizing activity than that of
positive control rosiglitazone. However, the molecular target
of the novel kind of benzopyran derivatives is not clear. As
part of our continuing research directed toward the structural
development of dual PPAR a/g agonists, we subsequently
found that compound 5 is a selective potent dual PPAR a/g
agonist. In this article, we report our efforts related to the
synthesis of a series novel benzopyran-based dual PPAR a/g
agonists, and evaluations of their in vitro PPAR a and PPAR
g transactivation activity. The putative pharmacophore 2-(5-
methyl-2-phenyloxazol-4-yl)ethanol, originally reported by
Sohda et al. [18] was the most effective block selected in
our previous investigation [17]. The oxobenzopyran-3-methyl
carboxylate was retained as a core skeleton to keep the func-
tional activity and various substitutions on the phenyl ring of
the 2-(5-methyl-2-aryloxazol-4-yl)ethanol block were de-
signed as modification to develop more potent PPAR agonists.
prepared similarly to the reported literature [19]. The sequence
involved acylation to incorporate variety of substituted aryl
ring, DarkineWest conversion to form methyl ketoamide,
cyclodehydration to the oxazole ring and reduction of the ester
side chain (Scheme 2). The compounds obtained are summa-
rized in Table 1.
3. Biological evaluation
All compounds prepared were evaluated for activity at each
of the human PPAR subtypes by using an established cell-
based transactivation assay in U2OS cells [20]. The results
obtained (Table 1) were compared with the corresponding
data for WY14643 and rosiglitazone, used as reference com-
pounds in the PPAR a and PPAR g transactivation assays, re-
spectively. The activating efficacy of the test compound was
judged by the maximal activation and given as the percentage
of the corresponding result obtained with the reference
compounds. The activating potency of the test compound
was expressed as EC50 (the concentration at which 50% of
the maximum activation was observed).
COOCH3
O
4. Results and discussion
N
O
O
O
As described in Table 1, modification on the phenyl ring of
phenyloxazol resulted in significant fluctuation in both PPAR
a and PPAR g transactivation activity. It is encouraging that
compounds listed in Table 1, except 7f and 7j, all showed
stronger PPAR a agonist potency than that of WY14643.
Compounds 7a, 7c, 7d and 8a, showing EC50 values for
both PPAR a and g in almost the same rank, were defined
as dual PPAR a/g agonists, and all of them gave comparable
or stronger PPAR a/g agonist efficacy than that of the corre-
sponding positive control. For the other compounds listed in
Table 1, all exhibited selective PPAR g agonist activity 100
to 1000-fold stronger than that of PPAR a agonist activity.
Compounds 7b, 8b, 8e and 8h are full PPAR g agonists, all
exhibited the functional potency about 130, 20 times stronger
5
2. Chemistry
Condensation of methyl 7-hydroxy-2-oxo-2H-chromene-3-
carboxylate with substituted 2-(5-methyl-2-aryloxazol-4-yl)e-
thanols 6(a-ej) via Mitsunobu reaction yield compounds
7(aej). Catalytic hydration of 7(aei) with palladium on
carbon gave compounds 8(aei) (Scheme 1). The desired
heterocyclic alcohols 6(aec), 6e and 6f were synthesized as
previously reported [11,19] and alcohols 6d, 6(gej) were

2430
J. Yu et al. / European Journal of Medicinal Chemistry 43 (2008) 2428e2435
COOCH3
O
R
R
O
O
COOCH3
a
+
N
N
HO
O
OH
O
O
O
7(a-j)
6(a-j)
R
O
COOCH3
b or c
7(a-i)
N
O
O
O
8(a-i)
Scheme 1. Reagents and conditions: (a) Ph3P, DEAD, THF; (b) H2, 10% Pd/C, MeOH/dioxane (1:3); (c) H2, 5% Pd/C, EtOAc/dioxane (1:1).
than that of leading compound 5 and rosiglitazone, respec-
tively. In addition, these compounds also displayed noticeable
agonist potency and efficacy on PPAR a. It is interesting that
the compounds showing good PPAR g agonist activity also
possess good PPAR a agonist activity judged by their maxi-
mum activity. It might imply that these two types of agonists
may exhibit similar structureeactivity relationship, thus many
group-replacement operations in the search of PPAR g ago-
nists, may be applicable in the design of selective PPAR
a or dual PPAR a/g agonists. With the comparison of 7b
and 7c, 8b and 8c, 7e and 7f, 8e and 8f, 7h and 7i, 8h and
8i, compounds with para substitutions on the phenyl ring
showed more potent PPAR a and g agonist efficacy than
that of the compounds with meta substitutions judged by
EC50. Introduction of strong electron-withdrawing trifluoro-
methyl group provided compounds 7g and 8g with relatively
low PPAR a and PPAR g efficacy (Emax). Similar result was
obtained in compound 7j, also, with the introduction of a nitro
group, with electron-withdrawing and poor lipophilicity char-
acteristics, and even no activation of PPAR a was produced. A
significant improvement in PPAR g efficacy was obtained with
the more bulky phenyl (7a) or tert-butyl (7d) groups as substit-
uent on the phenyl ring. There is no obvious trend of transac-
tivation activity for most of the double-bond and single-bond
congeners, though the unsaturated compounds 7(aed) have
more effective maximal activity (Emax) than their saturated
congeners 8(aed).
In conclusion, we prepared a new series of benzopyran
derivatives and primarily investigated their structure and activ-
ity relationships (SAR). All compounds, except 7f and 7j,
exhibited stronger PPAR a agonist potency than that of
WY14643. Compounds 7a, 7c, 7d and 8a are dual agonists
with comparable or stronger activating efficacy for both
PPAR a and PPAR g isomers than that of the positive control,
respectively. Compounds 7b, 8b, 8e and 8h are full PPAR g
agonists with about 130, 20 times stronger agonist potency
than that of leading compound 5 and rosiglitazone, respec-
tively. Further pharmacological studies on these compounds
are ongoing in our lab.
5. Experimental
5.1. General methods
Tetrahydrofuran was dried by distillation from sodium/ben-
zophenone. N,N-Dimethylformamide was dried by distillation
in vacuo from calcium hydride. Other commercially available
chemicals and solvents were used without further purification.
NMR spectra were recorded on a Varian Mercury-400 MHz
spectrometer. Low resolution mass spectra were obtained us-
ing a Finnigan MAT 95 mass spectrometer. Elemental analysis
for carbon, hydrogen, and nitrogen was determined on a Vario
EL elemental analyzer.
COOH
H3COOC
a
b
R
COOH
NH2
NH
H3COOC
+
COCl
.HCl
O
R
9(d, g-j)
COCH3
R
H3COOC
NH
O
O
O
d, e
c
O
R
R
N
N
OCH3
OH
10(d, g-j)
11(d, g-j)
6(d, g-j)
Scheme 2. Reagents and conditions: (a) Na2CO3, acetone, H2O, 0 ꢀC; (b) acetic anhydride, pyridine, 90 ꢀC; (c) POCl3, DMF, 90 ꢀC; (d) NaOH, MeOH; (e) BH3e
THF, MeOH, 50 ꢀC.

J. Yu et al. / European Journal of Medicinal Chemistry 43 (2008) 2428e2435
2431
Table 1
Structure and transactivation activity of the compounds
brine (30 ml), dried, and concentrated to obtain a brown oil.
The residue was purified by column chromatography
(EtOAc/hexane) to provide 0.75 g (72.1%) of the desired prod-
uct as a white solid.
R
O
COOCH3
N
O
O
O
5.2.3. Step 3: 2-(2-(4-tert-Butylphenyl)-5-methyloxazol-
4-yl)ethanol (6d)
Compound
R
Double PPAR a
bonda
PPAR g
Methyl 2-(2-(4-tert-butylphenyl)-5-methyloxazol-4-yl)ace-
tate (0.75 g, 2.61 mmol), methanol (8 ml), water (2 ml), and
NaOH (0.2 g) were stirred at 40 ꢀC for 1 h. The reaction mix-
ture was concentrated, diluted with water (10 ml), extracted
two times with ethyl ether. The combined organic phases
were discarded. The aqueous layer was acidified and extracted
with EtOAc (2 ꢁ 15 ml). The combined organic layers were
washed with water, brine and concentrated to obtain 0.71 g
of 2-(2-(4-tert-butylphenyl)-5-methyloxazol-4-yl)acetic acid.
BH3eTHF complex (6.5 ml, 6.5 mmol) was added drop-
wise to a solution of 2-(2-(4-tert-butylphenyl)-5-methyloxa-
zol-4-yl)acetic acid (0.71 g, 2.6 mmol) in THF. The reaction
mixture was stirred for 0.5 h, quenched by saturated sodium
bicarbonate aqueous and concentrated. The residue was dis-
solved in EtOAc (20 ml), washed by water (10 ml) and brine
(10 ml), dried over anhydrous sodium sulfate and concentrated
to obtain 0.66 g (98.5%) 2-(2-(4-tert-butylphenyl)-5-methylox-
EC50 (mM) % max EC50 (mM) % max
7a
8a
p-Ph
p-Ph
Yes
No
1.23
0.91
5.25
1.74
1.62
1.20
2.29
0.10
0.001
0.91
116
68
163
96
100
23
90
26
65
94
ia
1.26
1.12
0.001
0.001
0.35
0.1
263
164
122
101
109
75
7b
8b
p-OMe Yes
p-OMe No
m-OMe Yes
m-OMe No
p-tBu
p-tBu
p-Me
p-Me
m-Me
m-Me
7c
8c
7d
8d
Yes
No
Yes
No
Yes
No
1.74
0.25
0.001
0.001
0.001
0.001
0.42
0.16
1.62
0.001
0.96
0.17
3.55
0.13
0.02
e
239
84
7e
8e
89
101
76
7f
iab
8f
7g
1.55
1.20
0.17
0.07
0.1
83
21
23
44
98
38
30
ia
88
72
m-CF3 Yes
m-CF3 No
p-F
p-F
m-F
m-F
8g
7h
75
89
Yes
No
Yes
No
8h
7i
173
65
1.29
0.72
8i
78
62
1
azol-4-yl)ethanol as a white solid. Mp 124e125 ꢀC. H NMR
7j
m-NO2 Yes
No
ia
0.14
(CDCl3): d 1.34 (s, 9H), 2.32 (s, 3H), 2.71 (t, J ¼ 5.49 Hz, 2H),
3.92 (t, J ¼ 5.49 Hz, 2H), 7.44 (dd, J ¼ 6.77 Hz, J ¼ 2.01 Hz,
2H), 7.90(dd, J ¼ 6.77 Hz, J ¼ 2.01 Hz, 2H).
5
Rosiglitazone
WY14643
H
42
e
100
96
e
12
100
e
a
Yes: 3,4-double bond; No: 3,4-single bond.
ia: Inactive.
b
5.3. 2-(5-Methyl-2-(4-(trifluoromethyl)phenyl)oxazol-
4-yl)ethanol (6g)
5.2. 2-(2-(4-tert-Butylphenyl)-5-methyloxazol-
4-yl)ethanol (6d)
The title compound was prepared as a white solid from
4-methoxy-4-oxo-2-(4-(trifluoromethyl)benzamido)butanoic
acid according to the procedure described for 2-(2-(4-tert-
butylphenyl)-5-methyloxazol-4-yl)ethanol (6d). 1H NMR
(CDCl3): d 2.37 (s, 3H), 2.74 (t, J ¼ 5.50 Hz, 2H), 3.94
(t, J ¼ 5.50 Hz, 2H), 7.56 (m, 1H), 7.65 (d, J ¼ 7.51 Hz,
1H), 8.15 (d, J ¼ J ¼ 7.51 Hz, 1H), 8.23 (s, 1H).
5.2.1. Step 1: Methyl 3-(4-tert-butylbenzamido)-
4-oxopentanoate (10d)
A mixture of 2-(4-tert-butylbenzamido)-4-methoxy-4-oxo-
butanoic acid (9d) (6.3 g, 20.5 mmol), pyridine (20.8 ml),
and acetic anhydride (12.5 ml) was heated at 90 ꢀC for
1.5 h. Excess acetic anhydride and pyridine were evaporated
in vacuum and the residue was diluted with ether (200 ml).
The organic phase was washed with 1.0 M HCl (100 ml),
water (150 ml) and brine (150 ml), then dried over anhydrous
sodium sulfate and concentrated under reduced pressure to
yield the desired product 4.20 g (67.1%) as a pale yellow
oil. The residue was used in the next reaction without
purification.
5.4. 2-(2-(4-Fluorophenyl)-5-methyloxazol-
4-yl)ethanol (6h)
The title compound was prepared as a white solid from
2-(4-fluorobenzamido)-4-methoxy-4-oxobutanoic acid accord-
ing to the procedure described for 2-(2-(4-tert-butylphenyl)-5-
1
methyloxazol-4-yl)ethanol (6d). H NMR (CDCl3): d 2.35 (s,
3H), 2.74 (t, J ¼ 5.50 Hz, 2H), 3.86 (t, J ¼ 5.50 Hz, 2H), 7.44
5.2.2. Step 2: Methyl 2-(2-(4-tert-butylphenyl)-
(m, 2H), 8.29 (m, 2H).
5-methyloxazol-4-yl)acetate (11d)
Phosphorus oxychloride (1.0 ml) was added dropwise to
a solution of methyl 3-(4-tert-butylbenzamido)-4-oxopenta-
noate (1.11 g, 3.64 mmol) in DMF (8 ml). The mixture was
heated to 90 ꢀC for 0.5 h and then cooled to ambient temper-
ature before being poured into an ice-water bath. The mixture
was extracted with ethyl ether (3 ml) after the ice melted. The
combined organic phases were washed with water (30 ml) and
5.5. 2-(2-(3-Fluorophenyl)-5-methyloxazol-
4-yl)ethanol (6i)
The title compound was prepared as a white solid from
2-(3-fluorobenzamido)-4-methoxy-4-oxobutanoic acid accord-
ing to the procedure described for 2-(2-(4-tert-butylphenyl)-5-
1
methyloxazol-4-yl)ethanol (6d). H NMR (CDCl3): d 2.35 (s,

2432
J. Yu et al. / European Journal of Medicinal Chemistry 43 (2008) 2428e2435
1
3H), 2.74 (t, J ¼ 5.50 Hz, 2H), 3.86 (t, J ¼ 5.50 Hz, 2H), 6.93
Mp 161e162 ꢀC. H NMR (CDCl3): d 2.37 (s, 3H), 3.01 (t,
J ¼ 6.74 Hz, 2H), 3.85 (s, 3H), 3.93 (s, 3H), 4.34 (t,
J ¼ 6.74 Hz, 3H), 6.83 (d, J ¼ 2.25 Hz, 1H), 6.88 (dd,
J ¼ 8.60 Hz, J ¼ 2.34 Hz, 1H), 6.94 (m, 2H), 7.48 (d,
J ¼ 8.69 Hz, 1H), 7.91 (dd, J ¼ 6.84 Hz, J ¼ 2.15 Hz, 2H),
8.53 (s, 1H). MS (EI) m/z 435 [M]þ. Anal. Calcd for
C24H21NO7: C, 66.20; H, 4.86; N, 3.22. Found: C, 66.25; H,
4.77; N, 3.32.
(m, 1H), 7.19 (m, 1H), 7.25 (m, 1H), 7.30 (m, 1H).
5.6. 2-(5-Methyl-2-(3-nitrophenyl)oxazol-
4-yl)ethanol (6j)
The title compound was prepared as a white solid from
2-(4-fluorobenzamido)-4-methoxy-4-oxobutanoic acid accord-
ing to the procedure described for 2-(2-(4-tert-butylphenyl)-5-
1
methyloxazol-4-yl)ethanol (6d). H NMR (CDCl3): d 2.35 (s,
3H), 2.74 (t, J ¼ 5.50 Hz, 2H), 3.86 (t, J ¼ 5.50 Hz, 2H), 6.93
5.10. Methyl 7-(2-(2-(4-methoxyphenyl)-5-methyloxazol-
4-yl)ethoxy)-2-oxochroman-3-carboxylate (8b)
(m, 1H), 7.19 (m, 1H), 7.25 (m, 1H), 7.30 (m, 1H).
5.7. Methyl 7-(2-(2-(biphenyl-4-yl)-5-methyloxazol-
4-yl)ethoxy)-2-oxo-2H-chromene-3-carboxylate (7a)
The title compound was prepared according to the proce-
dure described for compound 8a from compound 7b as a white
solid. Yield 92.4%. Mp 132e133 ꢀC. 1H NMR (CDCl3):
d 2.35 (s, 3H), 2.95 (t, J ¼ 6.72 Hz, 2H), 3.09 (dd,
J ¼ 15.61 Hz, J ¼ 5.87 Hz, 1H), 3.36 (dd, J ¼ 15.61 Hz,
J ¼ 8.56 Hz, 1H), 3.74 (m, 4H), 3.85 (s, 3H), 4.21 (t,
J ¼ 6.72 Hz, 2H), 6.63 (d, J ¼ 2.52 Hz, 1H), 6.67 (dd,
J ¼ 8.39 Hz, J ¼ 2.52 Hz, 1H), 6.94 (m, 2H), 7.07 (d,
J ¼ 8.23 Hz, 1H), 7.91 (m, 2H). MS (EI) m/z 437 [M]þ.
Anal. Calcd for C24H23NO7: C, 65.90; H, 5.30; N, 3.20.
Found: C, 66.02; H, 5.25; N, 3.25.
Diethyl azodicarboxylate (0.50 ml, 3.20 mmol) was added
dropwise into a cold (0 ꢀC) solution of 2-(2-(biphenyl-4-yl)-
5-methyloxazol-4-yl)ethanol (6a) (0.90 g, 3.20 mmol), triphe-
nylphosphine(0.84 g, 3.20 mmol), and methyl 7-hydroxy-2-
oxo-2H-chromene-3-carboxylate (0.70 g, 3.20 mmol) in anhy-
drous THF (50 ml). The reaction temperature was allowed to
come to room temperature, and the mixture was stirred for
12 h. Solvent was evaporated in vacuo. The residue was crys-
tallized in methanol to give the title compound 7a 0.80 g
(51.6%) as a white solid. Mp 159e160 ꢀC. 1H NMR
(CDCl3): d 2.40 (s, 3H), 3.04 (t, J ¼ 6.30 Hz, 2H), 3.94 (s,
3H), 4.36 (t, J ¼ 6.30 Hz, 2H), 6.88 (m, 2H), 7.37 (m, 5H),
7.60 (m, 4H), 8.04 (dd, J ¼ 8.41 Hz, 1H), 8.54 (s, 1H). MS
(EI) m/z 481 [M]þ. Anal. Calcd for C29H23NO6: C, 72.34; H,
4.81; N, 2.91. Found: C, 72.23; H, 4.92; N, 2.88.
5.11. Methyl 7-(2-(2-(3-methoxyphenyl)-5-methyloxazol-
4-yl)ethoxy)-2-oxo-2H-chromene-3-carboxylate (7c)
The title compound was prepared in 70.0% yield from
2-(2-(3-methoxyphenyl)-5-methyloxazol-4-yl)ethanol
(6c)
and methyl 7-hydroxy-2-oxo-2H-chromene-3-carboxylate as
a white solid according to the procedure described for 7a.
5.8. Methyl 7-(2-(2-(biphenyl-4-yl)-5-methyloxazol-
4-yl)ethoxy)-2-oxochroman-3-carboxylate (8a)
1
Mp 142e143 ꢀC. H NMR (CDCl3): d 2.39 (s, 3H), 3.02 (t,
J ¼ 6.60 Hz, 2H), 3.89 (s, 3H), 3.93 (s, 3H), 4.34 (t,
J ¼ 6.60 Hz, 2H), 6.84 (d, J ¼ 2.33 Hz, 1H), 6.88 (dd,
J ¼ 8.65 Hz, J ¼ 2.47 Hz, 1H), 6.96 (m, 1H), 7.34 (t,
J ¼ 8.11 Hz, 1H), 7.48 (s, 1H), 7.50 (d, J ¼ 2.74 Hz, 1H),
7.56 (m, 1H), 8.53 (s, 1H). MS (EI) m/z 435 [M]þ. Anal.
Calcd for C24H21NO7: C, 66.20; H, 4.86; N, 3.22. Found: C,
65.97; H, 4.99; N, 3.19.
A solution of compound 7a (0.07 g, 0.14 mmol) in a mix-
ture of methanol (5 ml) and dioxane (15 ml) was stirred in
the presence of 10% PdeC (10 mg) under 5 atm of hydrogen
at room temperature until hydrogen uptake ceased. The solu-
tion was filtered and the filtrate was evaporated under vacuum.
The residue was crystallized in methanol to give the title com-
pound 8a 0.06 g (85.4%) as a white solid. Mp 122e123 ꢀC. 1H
NMR (CDCl3): d 2.40 (s, 3H), 3.03 (t, J ¼ 6.30 Hz, 2H), 3.29
(dd, J ¼ 15.80 Hz, J ¼ 6.05 Hz, 1H), 3.54 (dd, J ¼ 15.80 Hz,
J ¼ 8.66 Hz, 1H), 3.93 (m, 4H), 4.35 (t, J ¼ 6.30 Hz, 2H),
6.86 (m, 2H), 7.02 (d, J ¼ 8.65 Hz, 1H), 7.37 (m, 5H), 7.59
(m, 4H). MS (EI) m/z 483 [M]þ. Anal. Calcd for
C29H25NO6: C, 72.04; H, 5.21; N, 2.90. Found: C, 72.13; H,
5.12; N, 2.82.
5.12. Methyl 7-(2-(2-(3-methoxyphenyl)-5-methyloxazol-
4-yl)ethoxy)-2-oxochroman-3-carboxylate (8c)
The title compound was prepared in 92.4% yield from com-
pound 7c as a white solid according to the procedure described
1
for 8a. Mp 88e89 ꢀC. H NMR (CDCl3): d 2.37 (s, 3H), 2.97
(t, J ¼ 6.46 Hz, 2H), 3.09 (dd, J ¼ 15.79 Hz, J ¼ 6.04 Hz, 1H),
3.34 (dd, J ¼ 15.79 Hz, J ¼ 8.20 Hz, 1H), 3.74 (m, 4H), 3.87
(s, 3H), 4.22 (t, J ¼ 6.46 Hz, 2H), 6.63 (d, J ¼ 2.34 Hz, 1H),
6.67 (dd, J ¼ 8.37 Hz, J ¼ 2.47 Hz, 1H), 6.96 (dd,
J ¼ 7.96 Hz, J ¼ 2.06 Hz, 1H), 7.08 (d, J ¼ 8.53 Hz, 1H),
7.33 (m, 1H), 7.50 (s, 1H), 7.57 (d, J ¼ 7.70 Hz, 1H). MS
(EI) m/z 437 [M]þ. Anal. Calcd for C24H23NO7: C, 65.90;
H, 5.30; N, 3.20. Found: C, 65.63; H, 5.31; N, 3.14.
5.9. Methyl 7-(2-(2-(4-methoxyphenyl)-5-methyloxazol-
4-yl)ethoxy)-2-oxo-2H-chromene-3-carboxylate (7b)
The title compound was prepared according to the procedure
described for compound 7a from 2-(2-(4-methoxyphenyl)-5-
methyloxazol-4-yl)ethanol (6b) and methyl 7-hydroxy-2-oxo-
2H-chromene-3-carboxylate as a white solid. Yield 54.5%.

J. Yu et al. / European Journal of Medicinal Chemistry 43 (2008) 2428e2435
2433
5.13. Methyl 7-(2-(2-(4-tert-butylphenyl)-
5-methyloxazol-4-yl)ethoxy)-2-oxo-2H-chromene-
3-carboxylate (7d)
J ¼ 8.24 Hz, 2H). MS (EI) m/z 421 [M]þ. Anal. Calcd for
C24H23NO6: C, 68.40; H, 5.50; N, 3.32. Found: C, 68.33; H,
5.32; N, 3.17.
The title compound was prepared in 61.6% yield from
2-(2-(4-tert-butylphenyl)-5-methyloxazol-4-yl)ethanol
5.17. Methyl 7-(2-(5-methyl-2-m-tolyloxazol-4-
yl)ethoxy)-2-oxo-2H-chromene-3-carboxylate (7f)
(6d)
and methyl 7-hydroxy-2-oxo-2H-chromene-3-carboxylate as
a white solid according to the procedure described for 7a.
The title compound was prepared in 58.3% yield from
2-(5-methyl-2-m-tolyloxazol-4-yl)ethanol (6f) and methyl 7-
hydroxy-2-oxo-2H-chromene-3-carboxylate as a white solid
according to the procedure described for 7a. Mp 134e
1
Mp 168e169 ꢀC. H NMR (CDCl3): d 1.34 (s, 9H), 2.38 (s,
3H), 3.02 (t, J ¼ 6.88 Hz, 2H), 3.93 (s, 3H), 4.34 (t,
J ¼ 6.88 Hz, 2H), 6.83 (d, J ¼ 2.18 Hz, 2H), 6.88 (m, 3H),
7.90 (d, J ¼ 8.38 Hz, 2H), 8.53 (s, 1H). MS (EI) m/z 461
[M]þ. Anal. Calcd for C27H27NO6: C, 70.21; H, 5.90; N,
3.03. Found: C, 70.21; H, 5.80; N, 3.03.
1
134.5 ꢀC. H NMR (CDCl3): d 2.40 (s, 3H), 2.38 (s, 3H),
3.02 (t, J ¼ 6.59 Hz, 2H), 3.93 (s, 3H), 4.34 (t, J ¼ 6.59 Hz,
2H), 6.83 (d, J ¼ 2.33 Hz, 1H), 6.88 (dd, J ¼ 8.66 Hz,
J ¼ 2.34 Hz, 1H), 7.22 (d, J ¼ 7.70 Hz, 1H), 7.32 (t,
J ¼ 7.69 Hz, 1H), 7.48 (d, J ¼ 8.79 Hz, 1H), 7.76 (d,
J ¼ 7.69 Hz, 1H), 7.81 (s, 1H), 8.53 (s, 1H). MS (EI) m/z
419 [M]þ. Anal. Calcd for C24H21NO6: C, 68.73; H, 5.05;
N, 3.34. Found: C, 68.61; H, 4.89; N, 3.34.
5.14. Methyl 7-(2-(2-(4-tert-butylphenyl)-
5-methyloxazol-4-yl)ethoxy)-2-oxochroman-
3-carboxylate (8d)
The title compound was prepared in 81.5% yield from
compound 7d as a white solid according to the procedure de-
5.18. Methyl 7-(2-(5-methyl-2-m-tolyloxazol-
4-yl)ethoxy)-2-oxochroman-3-carboxylate (8f)
1
scribed for 8a. Mp 101e102 ꢀC. H NMR (CDCl3): d 1.33 (s,
9H), 2.17 (s, 3H), 2.97 (t, J ¼ 6.74 Hz, 2H), 3.11 (dd,
J ¼ 15.60 Hz, J ¼ 6.70 Hz, 1H), 3.32 (dd, J ¼ 15.60 Hz,
J ¼ 8.59 Hz, 1H), 3.74 (m, 4H), 4.21 (t, J ¼ 6.74 Hz, 2H), 6.62
(d, J ¼ J ¼ 2.34 Hz, 1H), 6.66 (dd, J ¼ 8.38 Hz, J ¼ 2.48 Hz,
1H), 7.07 (d, J ¼ 8.25 Hz, 1H), 7.44 (dd, J ¼ 6.74 Hz,
J ¼ 2.06 Hz, 2H), 7.89 (dd, J ¼ 6.73 Hz, J ¼ 1.92 Hz, 2H). MS
(EI) m/z 463 [M]þ. Anal. Calcd for C27H29NO6: C, 69.96; H,
6.31; N, 3.02. Found: C, 70.00; H, 6.26; N, 3.10.
The title compound was prepared in 94.5% yield from com-
pound 2f as a white solid according to the procedure described
for 8a. Mp 129e130 ꢀC. 1H NMR (CDCl3): d 2.37 (s, 3H), 2.40
(s, 3H), 2.97 (t, J ¼ 6.60 Hz, 2H), 3.09 (dd, J ¼ 15.80 Hz,
J ¼ 6.05 Hz, 1H), 3.34 (dd, J ¼ 15.80 Hz, J ¼ 8.66 Hz, 1H),
3.74 (m, 4H), 4.21 (t, J ¼ 6.60 Hz, 2H), 6.23 (d, J ¼ 2.34 Hz,
1H), 6.67 (dd, J ¼ 8.24 Hz, J ¼ 2.47 Hz, 1H), 7.08 (d,
J ¼ 8.24 Hz, 1H), 7.22 (d, J ¼ 7.55 Hz, 1H), 7.32 (m, 1H),
7.77 (d, J ¼ 7.69 Hz, 1H), 7.82 (s, 1H). MS (EI) m/z 421
[M]þ. Anal. Calcd for C24H23NO6: C, 68.40; H, 5.50; N,
3.32. Found: C, 68.48; H, 5.42; N, 3.52.
5.15. Methyl 7-(2-(5-methyl-2-p-tolyloxazol-4-yl)ethoxy)-
2-oxo-2H-chromene-3-carboxylate (7e)
The title compound was prepared in 38.0% yield from
2-(5-methyl-2-p-tolyloxazol-4-yl)ethanol (6e) and methyl 7-
hydroxy-2-oxo-2H-chromene-3-carboxylate as a white solid
according to the procedure described for 7a. Mp 166e
5.19. Methyl 7-(2-(5-methyl-2-(3-
(trifluoromethyl)phenyl)oxazol-4-yl)ethoxy)-2-oxo-2H-
chromene-3-carboxylate (7g)
1
167 ꢀC. H NMR (CDCl3): d 2.38 (s, 3H), 2.39 (s, 3H), 3.02
(t, J ¼ 6.55 Hz, 2H), 3.93 (s, 3H), 4.34 (t, J ¼ 6.55 Hz, 2H),
6.83 (d, J ¼ 2.35 Hz, 1H), 6.88 (dd, J ¼ 8.73 Hz, J ¼ 2.35 Hz,
1H), 7.24 (d, J ¼ 8.39 Hz, 2H), 7.48 (d, J ¼ 9.06 Hz, 1H),
7.86 (d, J ¼ 8.39 Hz, 2H), 8.53 (s, 1H). MS (EI) m/z 419
[M]þ. Anal. Calcd for C24H21NO6: C, 68.73; H, 5.05; N,
3.34. Found: C, 68.42; H, 4.92; N, 3.30.
The title compound was prepared in 63.8% yield from 2-(5-
methyl-2-(3-(trifluoromethyl)phenyl)-oxazol-4-yl)ethanol (6g)
and methyl 7-hydroxy-2-oxo-2H-chromene-3-carboxylate as
a white solid according to the procedure described for 7a. Mp
187e188 ꢀC. 1H NMR (CDCl3): d 2.41 (s, 3H), 3.04 (t,
J ¼ 6.19 Hz, 2H), 3.93 (s, 3H), 4.34 (t, J ¼ 6.19 Hz, 2H), 6.83
(d, J ¼ 2.06 Hz, 1H), 6.89 (dd, J ¼ 8.80 Hz, J ¼ 2.62 Hz, 1H),
7.50 (d, J ¼ 8.80 Hz, 1H), 7.57 (t, J ¼ 7.98 Hz, 1H), 7.66 (d,
J ¼ 7.15 Hz, 1H), 8.16 (d, J ¼ 8.12 Hz, 1H), 8.24 (s, 1H), 8.54
(s, 1H). MS (EI) m/z 473 [M]þ. Anal. Calcd for C24H18F3NO6:
C, 60.89; H, 3.83; N, 2.96. Found: C, 60.67; H, 3.85; N, 2.74.
5.16. Methyl 7-(2-(5-methyl-2-p-tolyloxazol-4-yl)ethoxy)-
2-oxochroman-3-carboxylate (8e)
The title compound was prepared in 87.1% yield from com-
pound 7e as a white solid according to the procedure described
for 8a. Mp 136e137 ꢀC. 1H NMR (CDCl3): d 2.36 (s, 3H), 2.39
(s, 3H), 2.97 (t, J ¼ 6.59 Hz, 2H), 3.09 (dd, J ¼ 15.90 Hz,
J ¼ 6.04 Hz, 1H), 3.34 (dd, J ¼ 15.90 Hz, J ¼ 8.65 Hz, 1H),
3.73 (m, 4H), 4.21 (t, J ¼ 6.59 Hz, 2H), 6.63 (d, J ¼ 2.33 Hz,
1H), 6.67 (dd, J ¼ 8.24 Hz, J ¼ 2.47 Hz, 1H), 7.07 (d,
J ¼ 8.38 Hz, 1H), 7.23 (d, J ¼ 7.97 Hz, 2H), 7.86 (d,
5.20. Methyl 7-(2-(5-methyl-2-(3-
(trifluoromethyl)phenyl)oxazol-4-yl)ethoxy)-2-
oxochroman-3-carboxylate (8g)
The title compound was prepared in 85.0% yield from
compound 7g as a white solid according to the procedure

2434
J. Yu et al. / European Journal of Medicinal Chemistry 43 (2008) 2428e2435
1
described for 8a. Mp 118e119 ꢀC. H NMR (CDCl3): d 2.40
(s, 3H), 2.98 (t, J ¼ 6.74 Hz, 2H), 3.10 (dd, J ¼ 15.81 Hz,
J ¼ 5.91 Hz, 1H), 3.34 (dd, J ¼ 15.81 Hz, J ¼ 8.66 Hz, 1H),
3.75 (m, 4H), 4.22 (t, J ¼ 6.74 Hz, 2H), 6.63 (d,
J ¼ 2.47 Hz, 1H), 6.67 (dd, J ¼ 8.24 Hz, J ¼ 2.33 Hz, 1H),
7.08 (d, J ¼ 8.52 Hz, 1H), 7.57 (d, J ¼ 7.69 Hz, 1H), 7.66
(d, J ¼ 7.84 Hz, 1H), 8.16 (d, J ¼ 7.84 Hz, 1H), 8.24 (s,
1H). MS (EI) m/z 437 [M]þ. Anal. Calcd for
C24H20F3NO6: C, 60.63; H, 4.24; N, 2.95. Found: C, 60.36;
H, 4.35; N, 2.68.
5.24. Methyl 7-(2-(2-(3-fluorophenyl)-5-methyloxazol-
4-yl)ethoxy)-2-oxochroman-3-carboxylate (8i)
The title compound was prepared in 90.2% yield from com-
pound 7i as a white solid according to the procedure described
1
for 8a. Mp 124e125 ꢀC. H NMR (CDCl3): d 2.38 (s, 3H),
2.97 (t, J ¼ 5.87 Hz, 2H), 3.10 (dd, J ¼ 15.65 Hz,
J ¼ 8.41 Hz, 1H), 3.34 (dd, J ¼ 15.65 Hz, J ¼ 8.41 Hz, 1H),
3.74 (m, 4H), 4.22 (t, J ¼ 5.87 Hz, 2H), 6.63 (d,
J ¼ 2.15 Hz, 1H), 7.10 (m, 2H), 7.40 (dd, J ¼ 13.89 Hz,
J ¼ 7.83 Hz, 1H), 7.67 (d, J ¼ 9.59 Hz, 1H), 7.77 (d,
J ¼ 7.63 Hz, 1H). MS (EI) m/z 425 [M]þ. Anal. Calcd for
C23H20FNO6: C, 64.94; H, 4.74; N, 3.29. Found: C, 64.77;
H, 4.74; N, 3.17.
5.21. Methyl 7-(2-(2-(4-fluorophenyl)-5-methyloxazol-
4-yl)ethoxy)-2-oxo-2H-chromene-3-carboxylate (7h)
The title compound was prepared in 74.7% yield from
2-(2-(4-fluorophenyl)-5-methyloxazol-4-yl)ethanol (6h) and
5.25. Methyl 7-(2-(5-methyl-2-(3-nitrophenyl)oxazol-
4-yl)ethoxy)-2-oxo-2H-chromene-3-carboxylate (7j)
methyl
a white solid according to the procedure described for 7a.
7-hydroxy-2-oxo-2H-chromene-3-carboxylate as
The title compound was prepared in 57.1% yield from 2-(5-
methyl-2-(3-nitrophenyl)oxazol-4-yl)ethanol (6j) and methyl
7-hydroxy-2-oxo-2H-chromene-3-carboxylate as a white solid
according to the procedure described for 2a. Mp 189e190 ꢀC.
1H NMR (CDCl3): d 2.43 (s, 3H), 3.04 (t, J ¼ 6.45 Hz, 2H),
3.93 (s, 3H), 4.36 (t, J ¼ 6.45 Hz, 2H), 6.83 (d, J ¼ 2.19 Hz,
1H), 6.88 (dd, J ¼ 8.66 Hz, J ¼ 2.48 Hz, 1H), 7.49 (d,
J ¼ 8.65 Hz, 1H), 7.63 (t, J ¼ 8.10 Hz, 1H), 8.28 (m, 2H),
8.53 (s, 1H), 8.80 (t, J ¼ 1.93 Hz, 1H). MS (EI) m/z 450
[M]þ. Anal. Calcd for C23H18N2O8: C, 61.33; H, 4.03; N,
6.22. Found: C, 61.51; H, 4.03; N, 6.11.
1
Mp 168e169 ꢀC. H NMR (CDCl3): d 2.38 (s, 3H), 3.02 (t,
J ¼ 6.74 Hz, 2H), 3.93 (s, 3H), 4.34 (t, J ¼ 6.74 Hz, 2H),
6.83 (d, J ¼ 2.33 Hz, 1H), 6.88 (dd, J ¼ 8.66 Hz,
J ¼ 2.48 Hz, 1H), 7.11 (m, 2H), 7.49 (d, J ¼ 8.67 Hz, 1H),
7.96 (m, 2H), 8.53 (s, 1H). MS (EI) m/z 423 [M]þ. Anal.
Calcd for C23H18FNO6: C, 65.25; H, 4.29; N, 3.31. Found:
C, 65.27; H, 4.17; N, 3.09.
5.22. Methyl 7-(2-(2-(4-fluorophenyl)-5-methyloxazol-
4-yl)ethoxy)-2-oxochroman-3-carboxylate (8h)
The title compound was prepared in 89.9% yield from
compound 7h as a white solid according to the procedure de-
scribed for 8a. Mp 149e150 ꢀC. 1H NMR (CDCl3): d 2.36 (s,
3H), 2.96 (t, J ¼ 6.59 Hz, 2H), 3.09 (dd, J ¼ 15.93 Hz,
J ¼ 6.05 Hz, 1H), 2.34 (dd, J ¼ 15.93 Hz, J ¼ 8.52 Hz, 1H),
3.74 (m, 4H), 4.21 (t, J ¼ 6.59 Hz, 2H), 6.62 (d,
J ¼ 2.48 Hz, 1H), 6.67 (dd, J ¼ 8.52 Hz, J ¼ 2.61 Hz, 1H),
7.10 (m, 3H), 7.96 (m, 2H). MS (EI) m/z 425 [M]þ. Anal.
Calcd for C23H20FNO6: C, 64.94; H, 4.74; N, 3.29. Found:
C, 65.08; H, 4.71; N, 3.10.
Acknowledgements
The authors acknowledge Shenzhen Chipscreen Biosci-
ences Ltd. for the in vitro assays.
References
[1] U. Kintscher, R.E. Law, Am. J. Physiol. Endocrinol. Metab. 288 (2005)
E287eE291.
[2] D.H.V. Raalte, M. Li, P.H. Pritchard, K.M. Wasan, Pharm. Res. 21 (2004)
1531e1538.
[3] J. Fruchart, P. Duriez, B. Staels, Curr. Opin. Lipidol. 10 (1999) 245e257.
[4] K. Murakami, K. Tobe, T. Ide, T. Mochizuki, M. Ohashi, Y. Akanuma,
Y. Yazaki, T. Kadowaki, Diabetes 47 (1998) 1841e1847.
[5] B.R. Henke, S.G. Blanchard, M.F. Brackeen, K.K. Brown, J.E. Cobb,
J.L. Collins, W.W. Harrington Jr., M.A. Hashim, E.A. Hull-Ryde,
I. Kaldor, S.A. Kliewer, D.H. Lake, L.M. Leesnitzer, J.M. Lehmann,
J.M. Lenhard, L.A. Orband-Miller, J.F. Miller, R.A. Mook, S.A. Noble,
W. Oliver, D.J. Parks, K.D. Plunket, J.R. Szewczyk, T.M. Willson, J.
Med. Chem. 41 (1998) 5020e5036.
5.23. Methyl 7-(2-(2-(3-fluorophenyl)-5-methyloxazol-4-
yl)ethoxy)-2-oxo-2H-chromene-3-carboxylate (7i)
The title compound was prepared in 78.4% yield from
2-(2-(3-fluorophenyl)-5-methyloxazol-4-yl)ethanol (6i) and
methyl
7-hydroxy-2-oxo-2H-chromene-3-carboxylate
as
a white solid according to the procedure described for 7a.
Mp 179e180 ꢀC. 1H NMR (CDCl3): d 2.47 (s, 3H), 3.02
(t, J ¼ 6.33 Hz, 2H), 3.93 (s, 3H), 4.34 (t, J ¼ 6.33 Hz,
2H), 6.83 (d, J ¼ 2.20 Hz, 1H), 6.88 (dd, J ¼ 8.66 Hz,
J ¼ 2.34 Hz, 1H), 7.11 (m, 1H), 7.39 (m, 1H), 7.49 (d,
J ¼ 8.66 Hz, 1H), 7.67 (m, 1H), 7.77 (d, J ¼ 7.70 Hz, 1H),
8.53 (s, 1H). MS (EI) m/z 423 [M]þ. Anal. Calcd for
C23H18FNO6: C, 65.25; H, 4.29; N, 3.31. Found: C, 65.28;
H, 4.28; N, 3.20.
[6] B.B. Lohray, V.B. Lohray, A.C. Bajji, S. Kalchar, R.R. Poondra,
S. Padakanti, R. Chakrabarti, R.K. Vikramadithyan, P. Misra, S. Juluri,
N.V.S.R. Mamidi, R. Rajagopalan, J. Med. Chem. 44 (2001) 2675e2678.
[7] G.J. Etgen, B.A. Oldham, W.T. Johnson, C.L. Broderick, C.R. Montrose,
J.T. Brozinick, E.A. Misener, J.S. Bean, W.R. Bensch, D.A. Brooks,
A.J. Shuker, C.J. Rito, J.R. McCarthy, R.J. Ardecky, J.S. Tyhonas,
S.L. Dana, J.M. Bilakovics, J.R. Paterniti Jr., K.M. Ogilvie, S. Liu,
R.F. Kauffman, Diabetes 51 (2002) 1083e1087.
[8] P. Sauerberg, I. Pettersson, L. Jeppesen, P.S. Bury, J.P. Mogensen,
K. Wassermann, C.L. Brand, J. Sturis, H.F. Woldike, J. Fleckner,

J. Yu et al. / European Journal of Medicinal Chemistry 43 (2008) 2428e2435
2435
A.S. Andersen, S.B. Mortensen, L.A. Svensson, H.B. Rasmussen,
S.V. Lehmann, Z. Polivka, K. Sindelar, V. Panajotova, L. Ynddal,
E.M. Wulff, J. Med. Chem. 45 (2002) 789e804.
[13] G.R. Madhavan, R. Chakrabarti, K.A. Reddy, B.M. Rajesh, V. Balraju,
P.B. Rao, R. Rajagopalanb, J. Iqbala, Bioorg. Med. Chem. 14 (2006)
584e591.
[9] S. Ebdrup, I. Pettersson, H.B. Rasmussen, H.J. Deussen, A. Frost Jensen,
S.B. Mortensen, J. Fleckner, L. Pridal, L. Nygaard, P. Sauerberg, J. Med.
Chem. 46 (2003) 1306e1317.
[14] N. Mahindroo, Y. Peng, C. Lin, U. Tan, E. Prakash, T. Lien, I. Lu, H. Lee,
J. Hsu, X. Chen, C. Liao, P. Lyu, Y. Chao, S. Wu, H. Hsieh, J. Med.
Chem. 49 (2006) 6421e6424.
[10] P.V. Devasthale, S. Chen, Y. Jeon, F. Qu, C. Shao, W. Wang, H. Zhang,
M. Cap, D. Farrelly, R. Golla, G. Grover, T. Harrity, Z. Ma, L. Moore,
J. Ren, R. Seethala, L. Cheng, P. Sleph, W. Sun, A. Tieman,
J.R. Wetterau, A. Doweyko, G. Chandrasena, S.Y. Chang,
W.G. Humphreys, V.G. Sasseville, S.A. Biller, D.E. Ryono, F. Selan,
N. Hariharan, P.T.W. Cheng, J. Med. Chem. 48 (2004) 2248e2250.
[11] Y. Xu, C.J. Rito, G.J. Etgen, R.J. Ardecky, J.S. Bean, W.R. Bensch,
J.R. Bosley, C.L. Broderick, D.A. Brooks, S.J. Dominianni, P.J. Hahn,
S. Liu, D.E. Mais, C. Montrose-Rafizadeh, K.M. Ogilvie,
B.A. Oldham, M. Peters, D.K. Rungta, A.J. Shuker, G.A. Stephenson,
A.E. Tripp, S.B. Wilson, L.L. Winneroski, R. Zink, R.F. Kauffman,
J.R. McCarthy, J. Med. Chem. 47 (2004) 2422e2425.
[15] P.V. Devasthale, S. Chen, Y. Jeon, F. Qu, D.E. Ryono, W. Wang, H. Zhang,
L. Cheng, D. Farrelly, R. Golla, G. Grover, Z. Ma, L. Moore, R. Seethala,
W. Sun, A.M. Doweyko, G. Chandrasena, P. Sleph, N. Hariharanb,
P.T.W. Cheng, Bioorg. Med. Chem. Lett. 17 (2007) 2312e2316.
[16] H. Han, S.H. Kim, K. Kim, G. Hur, H.J. Yim, H. Chung, S.H. Woo,
K.D. Koo, C. Lee, J.S. Koh, G.T. Kim, Bioorg. Med. Chem. Lett. 17
(2007) 937e941.
[17] L. Tang, J. Yu, Y. Leng, Y. Feng, Y. Yang, R. Ji, Bioorg. Med. Chem.
Lett. 13 (2003) 3437e3440.
[18] T. Sohda, K. Mizuno, Y. Momose, H. Ikeda, T. Fujita, K. Meguro, J.
Med. Chem. 35 (1992) 2617e2626.
[19] A.G. Godfrey, D.A. Brooks, L.A. Hay, M. Peters, J.R. McCarthy,
D. Mitchell, J. Org. Chem. 68 (2003) 2623e2632.
[20] Z. Cai, J. Feng, Y. Guo, P. Li, Z. Shen, F. Chu, Z. Guo, Bioorg. Med.
Chem. 14 (2006) 866e874.
[12] A. Pinelli, C. Godio, A. Laghezza, N. Mitro, G. Fracchiolla,
V. Tortorella, A. Lavecchia, E. Novellino, J. Fruchart, B. Staels,
M. Crestani, F. Loiodice, J. Med. Chem. 48 (2005) 5509e5519.