Discovery of novel heteroaryl-substituted chalcones as inhibitors of TNF-α-induced VCAM-1 expression

Article abstract of DOI:10.1016/j.bmcl.2004.01.021

Novel chalcone derivatives have been discovered as potent inhibitors of TNF-α-induced VCAM-1 expression. Thienyl or benzothienyl substitution at the meta-position of ring B helps boost potency while large substitution at the para-position on ring B is detrimental. Various substitutions are tolerated on ring A. A lipophilicity-potency relationship has been observed in several sub-series of compounds.

Full text of DOI:10.1016/j.bmcl.2004.01.021

Bioorganic & Medicinal Chemistry Letters 14 (2004) 1513–1517
Discovery of novel heteroaryl-substituted chalcones as inhibitors of
TNF-ꢀ-induced VCAM-1 expression
Charles Q. Meng,* X. Sharon Zheng, Liming Ni, Zhihong Ye, Jacob E. Simpson,
Kimberly J. Worsencroft, Martha R. Hotema, M. David Weingarten,
Jason W. Skudlarek, Joshua M. Gilmore, Lee K. Hoong, Russell R. Hill,
Elaine M. Marino, Ki-Ling Suen, Charles Kunsch, Martin A. Wasserman
and James A. Sikorski
AtheroGenics, Inc., 8995 Westside Parkway, Alpharetta, GA 30004, USA
Received 25 September 2003; accepted 2 January 2004
Abstract—Novel chalcone derivatives have been discovered as potent inhibitors ofTNF- a-induced VCAM-1 expression. Thienyl or
benzothienyl substitution at the meta-position ofring B helps boost potency while large substitution at the para-position on ring B
is detrimental. Various substitutions are tolerated on ring A. A lipophilicity–potency relationship has been observed in several
sub-series ofcompounds.
# 2004 Elsevier Ltd. All rights reserved.
At sites ofinflammation, the recruitment ofleukocytes
is mediated, at least in part, by the expression ofvas-
cular cell adhesion molecule-1 (VCAM-1) in response to
various cytokines such as tumor necrosis factor-a
(TNF-a).1 Evidence from patients and animal models
has indicated that upregulation ofVCAM-1 occurs in
plasma and tissues ofnumerous chronic inflammatory
diseases such as asthma, rheumatoid arthritis and
atherosclerosis.2ꢀ6 A variety ofagents have been reported
as potent inhibitors ofVCAM-1 expression. 7 Some have
shown therapeutic efficacy in various animal models,
establishing pharmacological proof-of-concept for
VCAM-1 modulation as a therapeutic target.8ꢀ10 Simi-
larly, we have disclosed a multifunctional antioxidant
with inhibiting effects on inducible VCAM-1 expression,
which has shown efficacy in animal models ofathero-
sclerosis and is currently in phase III clinical trials for
these compounds, we set out to screen simple compounds
containing this moiety. This led to the discovery ofa
series ofchalcone derivatives as potent inhibitors of
VCAM-1 expression. Naturally occurring and synthetic
chalcones are known to have a wide range ofpotential
pharmacologic activities16 on cancer,17 malaria,18 leish-
maniasis,19 etc. Some chalcones have also been reported
as anti-inflammatory agents.20ꢀ23 Herein we report a novel
series ofheteroaryl-substituted chalcones exhibiting low
micromolar IC50 values for inhibiting TNF-a-induced
VCAM-1 expression.
11ꢀ13
the treatment ofcoronary artery disease.
Some natural products, such as 114 and 2,15 are known
to inhibit the expression ofVCAM-1. Since an a,b-
unsaturated carbonyl is a common structural feature of
As shown in Table 1, the two phenyl rings ofthe
chalcone skeleton are designated ‘ring A’ and ‘ring B’,
respectively, for convenience of discussion herein. While
the parent chalcone, 3, exhibits weak inhibition on
inducible VCAM-1 expression (IC50=23 mM), when a
* Corresponding author. Tel.: +1-678-336-2540; fax: +1-678-336-2501;
e-mail: cmeng@atherogenics.com
0960-894X/$ - see front matter # 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.01.021

1514
C. Q. Meng et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1513–1517
Table 1. Inhibiting profile ofchalcones on inducible VCAM-1 expression 24
Compd
R
R0
VCAM-1
IC50 (mM)
ClogP
3
4
5
6
7
8
9
Hydrogen
4-Methoxy
3,4-Dimethoxy
3,4,5-Trimethoxy
3,4-Dimethoxy
4-Methoxy
2,4-Dimethoxy
4-Methoxy
Hydrogen
Hydrogen
Hydrogen
Hydrogen
4-Methoxy
3,4-Dimethoxy
4-Methoxy
2,4-Dimethoxy
Hydrogen
Hydrogen
4-Methoxy
4-Methoxy
4-Fluoro
23
14
8
6
6
15
7
29
47
9
>50
17
25
4
6
12
5
3
3
2
2
3
3
3
3
2
2
2
2
2
2
3
11
5
2
8
3.58
3.59
3.60
3.61
3.61
3.61
3.61
3.61
5.67
6.19
5.68
6.19
3.86
5.59
5.34
5.33
5.30
5.35
5.33
5.34
5.34
5.34
5.34
5.35
6.48
6.50
6.49
5.65
5.65
5.65
5.65
5.56
6.50
6.51
5.35
6.51
4.39
5.96
4.39
5.56
7.29
5.05
5.36
5.36
5.23
4.84
3.63
5.27
5.21
4.84
4.80
5.22
4.93
5.21
6.30
6.30
6.30
7.08
8.25
6.49
5.31
5.60
5.49
5.86
6.61
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
3,5-Di-tert-butyl-4-hydroxy
3,5-Di-tert-butyl-4-methoxy
3,5-Di-tert-butyl-4-hydroxy
3,5-Di-tert-butyl-4-Methoxy
4-Fluoro
4-Fluoro
3,4,5-Trimethoxy
3,4-Dimethoxy
Hydrogen
3,4,5-Trimethoxy
4-Methoxy
2,5-Dimethoxy
3,5-Dimethoxy
3,4-Dimethoxy
2,6-Dimethoxy
2,4,6-Trimethoxy
4-Methoxy
3,4,5-Trimethoxy
3,4-Dimethoxy
3,4-Dimethoxy
3,4-Dimethoxy
3,4,5-Trimethoxy
3,4,5-Trimethoxy
3,4,5-Trimethoxy
3,4-Dimethoxy
3,4,5-Trimethoxy
2,3,4-Trimethoxy
2,3,4-Trimethoxy
3,4,5-Trimethoxy
3-(Thien-2-yl)-4-fluoro
4-(Thien-2-yl)
4-(Thien-2-yl)
2-Methoxy-5-(thien-2-yl)
2-Methoxy-5-(thien-2-yl)
2-Methoxy-5-(thien-2-yl)
2-Methoxy-5-(thien-2-yl)
2-Methoxy-5-(thien-2-yl)
2-Methoxy-5-(thien-2-yl)
2-Methoxy-5-(thien-2-yl)
2-Methoxy-5-(thien-2-yl)
2-Methoxy-5-(benzo[b]thien-2-yl)
2-Methoxy-5-(benzo[b]thien-2-yl)
2-Methoxy-5-(benzo[b]thien-2-yl)
2-Methoxy-5-(5-methylthien-2-yl)
2-Methoxy-5-(4-methylthien-2-yl)
2-Methoxy-5-(5-methylthien-2-yl)
2-Methoxy-5-(4-methylthien-2-yl)
3,4-Dimethoxy-5-(5-acetylthien-2-yl)
2,4-Dimethoxy-5-(benzo[b]thien-2-yl)
2,4-Dimethoxy-5-(benzo[b]thien-2-yl)ꢀ
2,4-Dimethoxy-5-(thien-2-yl)
2,4-Dimethoxy-5-(benzo[b]thien-2-yl)
3-Bromo-4,5-dimethoxy
3-Bromo-4,5-dimethoxy
3-Bromo-4,5-dimethoxy
3-Bromo-4,5-dimethoxy
2,4-Dimethoxy-5-(benzo[b]thien-2-yl)ꢀ
2-Methoxy-5-(thien-2-yl)
2-Methoxy-5-(5-methylthien-2-yl)
2-Methoxy-5-(4-methylthien-2-yl)
3,4,5-Trimethoxy
4
3,5-Dimethoxy-4-benzyloxy
2,4,5-Trimethoxy
2,4,5-Triethoxy
>50
2
15
>50
4
3,5-Dimethoxy-4-cyclopropylmethoxy
3,4-Methylenedioxy
3,4-Methylenedioxy
3
4
3
4
5
3
1
2
3
2
3
2
3
3
4
4
3,4-Methylenedioxy
3,5-Dimethoxy-4-(3,4,5-trimethoxybenzyloxy)
3-Methoxy-4-(1,4-benzodioxan-3-methoxy)
3,5-Dimethoxy-4-(2-methoxyethoxy)
3,5-Dimethoxy-4-(thien-2-ylmethoxy)
3,5-Dimethoxy-4-(4-methoxybenzyloxy)
3,5-Dimethoxy-4-(1,4-benzodioxan-3-methoxy)
3,5-Dimethoxy-4-furfuryloxy
3,5-Dimethoxy-4-(3,4-dimethoxybenzyloxy)
3,5-Dimethoxy-4-(3,4-methylenedioxybenzyloxy)
3-Methoxy-4-(3,4-dimethoxybenzyloxy)
3-Methoxy-4-(pyrid-2-ylmethoxy)
3-Methoxy-4-(pyrid-3-ylmethoxy)
3-Methoxy-4-(pyrid-4-ylmethoxy)
3-Methoxy-4-(4-ethoxycarbonylbenzyloxy)
3-Methoxy-4-(4-tert-butyloxycarbonylaminobenzyloxy)
3-Methoxy-4-(4-aminobenzyloxy)
2,4-Dimethoxy-5-(2,4-dimethoxyphenyl)
2-Methoxy-4-(thien-2-yl)
2-Methoxy-4-(3-acetylphenyl)
2-Methoxy-5-(thien-2-yl)
3-Methoxy-4-(4-carboxybenzyloxy)
3,4,5-Trimethoxy
3,4,5-Trimethoxy
3,4,5-Trimethoxy
3,4,5-Trimethoxy
3,4,5-Trimethoxy
3,4,5-Trimethoxy
3,4,5-Trimethoxy
3,4,5-Trimethoxy
3,4,5-Trimethoxy
2-Methoxy-5-(thien-2-yl)
2-Methoxy-5-(thien-2-yl)
2-Methoxy-5-(thien-2-yl)
2-Methoxy-5-(thien-2-yl)
2-Methoxy-5-(thien-2-yl)
2-Methoxy-5-(thien-2-yl)
3,4,5-Trimethoxy
3,4-Difluoro
3,4,5-Trimethoxy
3-Fluoro-4-ethoxy
2-Methoxy-5-(thien-2-yl)
>50
7
3
2
4
4
5
(continued on next page)

C. Q. Meng et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1513–1517
1515
Table 1 (continued)
Compd
R
R0
VCAM-1
IC50 (mM)
ClogP
68
69
70
71
72
73
74
75
76
77
78
79
3,5-Dimethoxy-4-carboxymethoxy
3,5-Dimethoxy-4-carboxymethoxy
4-(2-Carboxyisopropoxy)
4-Carboxymethylthio
2-Methoxy-5-(thien-2-yl)
3,4-Dimethoxy-5-(thien-2-yl)
1
1
6
1
1
4
1
7
1
5.96
4.81
6.72
6.66
5.94
6.58
6.20
5.03
3.78
3.69
4.38
4.39
2,4-Dimethoxy-5-(benzo[b]thien-2-yl)
2,4-Dimethoxy-5-(benzo[b]thien-2-yl)
2-Carboxymethoxy-4-methoxy-5-(benzo[b]thien-2-yl)
2-(Carboxyisopropoxy)-4-methoxy-5-(thien-2-yl)
2,4-Dimethoxy-5-(benzo[b]thien-2-yl)
2-Methoxy-5-(thien-2-yl)
Hydrogen
4-Trifluoromethyl
3,5-Dimethoxy-4-hydroxy
3-Methoxy-4-hydroxy
3,4-(Dihydroxymethylmethylenedioxy)
4-(d-Glucopyranosylamino)
3,4,5-Trimethoxy
3,4-Dimethoxy-5-(thien-2-yl)
2,4-Dimethoxy-5-(benzo[b]thien-2-yl)
2-Methoxy-5-bromo
2,4-Dimethoxy-5-bromo
17
1
2
3,4,5-Trimethoxy
80
81
>50
>50
4.31
4.30
methoxy group is introduced to ring A the potency
increases (compound 4, IC50=14 mM). A second meth-
oxy group on ring A brings the IC50 value to 8 mM
(compound 5) and a third one improves the potency
slightly further (compound 6, IC50=6 mM). This meth-
oxy effect was observed in the beginning ofour ofray
into the chalcone series.
this compound the potency is increased dramatically
(16, IC50=4 mM). On the other hand, however, com-
pound 6 has an IC50 value of6 mM; the introduction of
a thienyl group to the para-position ofring B does not
change the potency (17, IC50=6 mM). The introduction
ofa thienyl group to the para-position ofring B of 5
even brings the IC50 value from 8 to 12 mM (compound
18). As further discussed below, these findings directed
the design ofnovel, more potent compounds in this
project. We decided, from this point on to put a het-
eroaryl group on the meta-position and avoid large
substitution on the para-position ofring B.
Compounds 7 and 8 show different inhibitory effects on
VCAM-1 expression, although both have the same
number ofmethoxy groups in the molecule; compound
7, with two methoxy groups on ring A, is more potent
than 8, with one methoxy group on ring A (IC50=6 and
15 mM, respectively). Comparison ofanother pair,
9
Due to the dramatic meta-thienyl effect on ring B, com-
pound 19, without any substitution on ring A, is already
a relatively potent inhibitor ofVCAM-1 expression
(IC50=5 mM). Therefore, introduction of methoxy
group(s) to ring A of 19 does not increase the potency
by much (20 through 26, IC50=2-3 mM). This is also
true when the thienyl group is replaced by a benzothienyl
group (compare 27, IC50=3 mM, with 28, IC50=2 mM,
and 29, IC50=2 mM).
(IC50=7 mM) and 10 (IC50=29 mM), further shows that
methoxy substitution on ring A is more important than
on ring B for the inhibitory effect on VCAM-1 expres-
sion. As shown above, however, when there are already
two methoxy groups on ring A, the contribution ofa
third one on ring A in boosting potency ofthe com-
pound is limited (compare 5, IC50=8 mM, with 6,
IC50=6 mM). Therefore, it makes almost no difference
on potency whether an additional methoxy group is
introduced to ring A or B when there are already two
methoxy groups on ring A. For example, introduction
ofa methoxy group to ring A of 5 generates compound
6 and to ring B generates 7; compounds 6 and 7 are
equipotent (IC50=6 mM).
The substitution patterns on ring A of 7 and 9 are dif-
ferent, but yet the two compounds show similar poten-
cies on VCAM-1 expression. Compounds 22–25 are
regioisomers each with two methoxy groups on ring A
and all have roughly the same potency on inhibition
ofVCAM-1 expression. Compounds 20 and 26 are
regioisomers each with three methoxy groups on ring A
and show the same potency. These data suggest that,
in contrast to ring B, substitution patterns on ring A do
not affect the efficacy ofcompounds as dramatically.
Phenol 11 shows poor potency on the inhibition of
VCAM-1 expression (IC50=47 mM). However, when
the phenol group of 11 is methylated, the corresponding
methyl ether (12) exhibits better potency (IC50=9 mM).
This outcome is presumably due to an increase in lipo-
philicity in 12. Comparison ofanother pair, 13 (IC50
>50 mM) and 14 (IC50=17 mM), shows a similar trend.
Substitutions on the accompanying thienyl ring are also
accommodated. Comparison of 30 or 31 with 24 reveals
that the introduction ofa methyl group to the thienyl
group does not affect potency. This can also be con-
firmed by comparison of 32 or 33 with 20. An acetyl
group on the thienyl group is also tolerated (34).
Compound 15 exhibits weak inhibition for VCAM-1
expression with an IC50 value of25 mM. When a thienyl
group is introduced to the meta-position ofring B of

1516
C. Q. Meng et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1513–1517
Furthermore, when the thienyl group is replaced by a
benzothienyl group the potency remains or increases
slightly (compare 27 with 21, 29 with 24, or 28 with 20).
These results further suggest that there might be a large
pocket for the meta-position ofring B at the binding site
ofa yet unknown biological target. And, as discussed
above (15 and 16), occupation ofthis pocket by the
ligand helps increase its potency.
directly attached or fused to ring A can also be tolerated
(63–66).
Having achieved satisfactory inhibitory potency on
VCAM-1 expression with some ofthe compounds dis-
cussed above, we turned our attention then to the
introduction ofsolubility to them. Since many ofthe
compounds contained methyl ether substitution(s), var-
ious carboxylic residues were attached to the chalcone
skeleton through an ether linkage. Compound 67 with a
benzoic acid-containing side chain on ring A shows
modest potency (IC50=5 mM). A glycolic acid residue
on ring A gives better potency (68, 69, IC50=1 mM,
respectively). Compound 70 (IC50=6 mM) with an iso-
butyric acid-containing side chain is less potent, likely
due to the para-methoxy on ring B, as discussed above.
Thioether linkage is also tolerated (71, IC50=1 mM). A
glycolic group can also be introduced to the ortho-posi-
tion ofring B ( 72 and 73, IC50=1, and 4 mM, respec-
tively). Hydroxy groups were also considered for
improving solubility (74–77).
Compound 29 has an IC50=2 mM. When a methoxy
group is introduced to the para-position ofring B
(compound 35), the potency is reduced 5-fold to
IC50=11 mM. Comparison of 28 with 36 also indicates
that a methoxy group at the para-position ofring B
lowers potency when there is a benzothienyl at the meta-
position. The same trend does not exist with the smaller
thienyl in the meta-position (compare 37 with 38). This
could mean that the binding site ofring B is sterically
constrained. When there is a (smaller) thienyl substitu-
tion at the meta-position, a methoxy group at the para-
position can be tolerated; however, when there is
already a (larger) benzothienyl at the meta-position
occupying the site, there is no room for a methoxy
group at the para-position.
Although it has been observed with many compounds
reported herein and elsewhere,11 dependence ofpotency
on lipophilicity is secondary to structural requirements.
For example, 7 and 8 are regioisomers and have the
same calculated log P value, but have different effects on
VCAM-1 expression (Table 1). In other words, the
lipophilicity-potency relationship is only meaningful
within structurally similar sub-series ofcompounds.
Any further extrapolation would only generate confu-
sion. When the methyl group ofthe para-methoxy on
ring A of 36 (IC50=5 mM) is removed, the potency
increases (74, IC50=1 mM) presumably due to the
decrease in lipophilicity. However, the same exercise on
24 (IC50=3 mM) results in a decrease in potency (75,
IC50=7 mM). Here, 24 already has the right lipophilicity
and the removal ofthe methyl group moves the lipo-
philicity ofthe compound out ofthe optimal range.
Diol 76 (IC50=1 mM) is more potent than tetraol 77
(IC50=17 mM). Although both have similar ClogP
values (Table 1), the former is in the optimal range and
the latter is not in their respective series.
When a methoxy group on ring A of 39 is replaced by a
benzyloxy group (40) the potency is completely lost.
Replacement ofthe methoxy groups on ring A of 41
with ethoxy groups (42) also dramatically decreases the
potency. Even when the para-methoxy on ring A of 36 is
replaced with a small cyclopropylmethoxy group (43)
the potency is completely lost. On the other hand, when
the two methoxy groups on ring A of 24, 30, or 31 are
replaced with a methylene dioxy group, respectively, the
potency is not affected by much (44, 45, or 46). Taken
together, it would seem that only small substitutions can
be tolerated on ring A. However, further investigation
revealed that many other compounds with an ether
linkage longer than a methoxy group (47–56) are potent
inhibitors ofVCAM-1 expression. From 41 to 42, there
is significant increase in calculated logP value (from 5.96
to 4.39), while there is not much change from, e.g., 24
(IC50=3 mM) to 44 (IC50=4 mM). In fact, all the cal-
culated logP values ofcompounds 47–56 are lower than
that ofcompound 40 (Table 1). These data suggest that
large substituents can be tolerated on ring A, but the
lipophilicity needs to be in the right range for the com-
pounds to be potent for the inhibition of VCAM-1
expression.
When the C–C double bond of 78 (IC50=1 mM) or 79
(IC50=2 mM) is reduced, the potency is completely lost
(80, 81, IC50>50 mM, respectively). This indicates that
the a,b-unsaturated carbonyl in the compounds repor-
ted herein is probably (part of) the pharmacophore.
Compounds 57, 58, and 59 all have a pyridylmethoxy
substitution on ring A. Although they all have higher
ClogP values than compound 40 (Table 1), these are
potent inhibitors ofVCAM-1 expression. Thereofre,
different sub-series ofcompounds have different lipo-
philicity requirements for the compounds to be potent.
Similarly, when a carbonyl is introduced to the mole-
cule, the requirement for ClogP is changed. Compound
60 has a high ClogP value (7.08) but still is relatively
potent. However, compound 61, with a ClogP of8.25, is
too lipophilic to be potent. When the Boc group is
removed from 61, the ClogP drops to 6.49 and the
compound (62) shows moderate potency. An aryl group
Except for a few commercially available ones, all the
compounds reported herein have been prepared through
an aldol condensation ofa ring A-containing ketone
and a ring B-containing aldehyde. Heteroaryl substitu-
tions on either ring are introduced through a cross-
coupling reaction such as the Suzuki reaction. As shown
in Scheme 1, 5-bromo-2,4-dimethoxybenzaldehyde (82)
was coupled with benzo[b]thiophene-2-boronic acid (83) in
the presence oftetrakis(triphenylphosphine)palladium(0)
to give 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde
(84) in 93% yield, which was in turn condensed with
30,40,50-trimethoxyacetophenone (85) under
condition to give compound 36 in 88% yield.
a basic

C. Q. Meng et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1513–1517
1517
Scheme 1. Reagents and conditions: (1) Tetrakis(triphenylphosphine)palladium(0), sodium carbonate solution (2 M), ethylene glycol dimethyl ether
(DME), reflux; (2) Sodium hydroxide solution (50%), ethanol.
In summary, a series ofnovel, heteroaryl-substituted
chalcone derivatives has been discovered as potent
inhibitors ofinducible VCAM-1 expression. Thienyl or
benzothienyl substitution at the meta-position ofring B
helps boost potency while large substitution at the para-
position on ring B is detrimental. Various substitutions
are tolerated on ring A. A lipophilicity–potency rela-
tionship has been observed in several sub-series of
compounds. Current SAR efforts are focused on bring-
ing favorable pharmacologic and pharmacokinetic
properties to some ofthe lead compounds reported
herein for asthma and rheumatoid arthritis drug
discovery, and the results will be reported in due course.
S.; Saxena, U.; Sikorski, J. A.; Wasserman, M. A. Bioorg.
Med. Chem. Lett. 2002, 12, 2545.
12. Sundell, C. L.; Somers, P. K.; Meng, C. Q.; Hoong, L. K.;
Suen, K. L.; Hill, R. R.; Landers, L. K.; Chapman, A.;
Butteiger, D.; Jones, M.; Edwards, D.; Daugherty, A.;
Wasserman, M. A.; Alexander, R. W.; Medford, R. M.;
Saxena, U. J. Pharmacol. Exp. Ther. 2003, 305, 1116.
13. Tardif, J. C.; Gregoire, J.; Schwartz, L.; Title, L.;
Laramee, L.; Reeves, F.; Lesperance, J.; Bourassa, M. G.;
L’Allier, P. L.; Glass, M.; Lambert, J.; Guertin, M. C.
Effects of AGI- and Probucol after Percutaneous Coronary
Interventions. Circulation 2003, 1067, 107 552.
14. JP7-304667 (1995).
15. JP9-208588 (1977).
16. Dimmock, J. R.; Elias, D. W.; Beazely, M. A.; Kandepu,
N. M. Curr. Med. Chem. 1999, 6, 1125.
17. De Vincenzo, R.; Ferlini, C.; Distefano, M.; Gaggini, C.;
Riva, A.; Bombardelli, E.; Morazzoni, P.; Valenti, P.;
Belluti, F.; Ranelletti, F. O.; Mancuso, S.; Scambia, G.
Cancer Chemother. Pharmacol. 2000, 46, 305.
18. Liu, M.; Wilairat, P.; Go, M. L. J. Med. Chem. 2001, 44,
4443.
References and notes
1. Springer, T. A. Cell 1994, 76, 301.
2. Bevilacqua, M. P.; Nelson, R. M.; Mannori, G.; Cecconi,
O. Annu. Rev. Med. 1994, 45, 361.
3. McMurray, R. W. Semin. Arthritis Rheum. 1996, 25, 215.
4. Pilewski, J. M.; Albelda, S. M. Am. J. Respir. Cell Mol.
Biol. 1995, 12, 1.
5. Wagner, O. F.; Jilma, B. Horm. Metab. Res. 1997, 29,
627.
6. Foster, C. A. J. Allergy Clin. Immunol. 1996, 98, S270.
7. Schreiner, E. P.; Oberhauser, B.; Foster, C. A. Expert
Opin. Ther. Patents 2003, 13, 149.
8. Foster, C. A.; Besemer, J.; Meingassner, J. G.; Naegeli,
H. U.; Schon, G.; Bevec, D.; Brend, T. Skin Pharmacol.
1996, 9, 149.
9. Oguchi, S.; Dimayuga, P.; Zhu, J.; Chyu, K.-Y.; Yano, J.;
Shah, P. K.; Nilsson, J.; Cercek, B. Arterioscler. Thromb.
Vasc. Biol. 2000, 20, 1729.
10. Nakao, H.; Doi, T.; Suda, M.; Umetani, M.; Ohtaka, M.;
Shiratsuchi, M.; Kodama, T. J. Atheroscler. Thromb.
1998, 4, 149.
19. Nielsen, S. F.; Christensen, S. B.; Cruciani, G.; Kharazmi,
A.; Liljefors, T. J. Med. Chem. 1998, 41, 4819.
20. Hsieh, H. K.; Lee, T. H.; Wang, J. P.; Wang, J. J.; Lin,
C. N. Pharm. Res. 1998, 15, 39.
21. Herencia, F.; Ferrandiz, M. L.; Ubeda, A.; Guillen, I.;
Dominguez, J. N.; Charris, J. E.; Lobo, G. M.; Alcaraz,
M. J. FEBS Lett. 1999, 453, 129.
22. Nakamura, C.; Kawasaki, N.; Miyataka, H.; Jayachan-
dran, E.; Kim, I. H.; Kirk, K. L.; Taguchi, T.; Takeuchi,
Y.; Hori, H.; Satoh, T. Bioorg. Med. Chem. 2002, 10, 699.
23. Ko, H. H.; Tsao, L. T.; Yu, K. L.; Liu, C. T.; Wang, J. P.;
Lin, C. N. Bioorg. Med. Chem. 2003, 11, 105.
24. A detailed protocol ofthe VCAM-1 assay has been
reported25; IC50 numbers reflect an average ofat least
three determinations; ClogP values were calculated and
were obtained by using LeadScope PC Professional
2.0.11.
11. Meng, C. Q.; Somers, P. K.; Rachita, C. L.; Holt, L. A.;
Hoong, L. K.; Zheng, X. S.; Simpson, J. E.; Hill, R. R.;
Olliff, L. K.; Kunsch, C.; Sundell, C. L.; Parthasarathy,
25. Meng, C. Q.; Zheng, X. S.; Holt, L. A.; Hoong, L. K.;
Somers, P. K.; Hill, R. R.; Saxena, U. Bioorg. Med.
Chem. Lett. 2001, 11, 1823.