F. Gaudette et al. / Bioorg. Med. Chem. Lett. 20 (2010) 848–852
851
Table 2
VEGFR2 and c-Met IC50 enzymatic assay and cell-based assay for compounds 7–10 of general structure
H
H
N
1
R
N
2
R
CF
O
3
O
N
S
N
N
Me
#
R1 R2
VEGFR2 IC50
(lM) c-Met IC50
(lM) Phospho-TPR-Met Elisa IC50
(
lM) A549 wound healing inh. IC50
(
lM) DU145 scattering inh. IC50 (lM)
7
8
9
F
F
F
H
H
0.01
0.02
0.02
0.02
0.12
0.84
0.09
0.18
0.60
1.80
0.37
0.88
2
2
0.4
2
2
o-OMe
p-F
p-F
10
0.4
2
10
Table 3
Table 5
Effect of compound 15 on VEGF-mediated cellular endpoints
VEGFR2 and c-Met IC50 enzymatic assay for compounds 11–13 of general structure
H
N
H
N
#
VEGF-dept
HUVEC
Angiokit,
tubule
Angiokit,
tubule
Angiokit,
tubule
Angiokit,
tubule
F
R1
R2
proliferation
length IC50 length
branching
IC50 (lM)
branching
with VEGF
(% inh.)
IC50
(
lM)
(
lM)
with VEGF
(% inh.)
O
MeO
MeO
X
15 0.04
0.01
97
0.006
95
N
#
X
R1
R2
VEGFR2 IC50
(
lM)
c-Met IC50 (lM)
tion within the quinoline series (compound 13) has even more pro-
nounced effect in favor of VEGFR2 enzyme while pyrimidine-based
compounds become VEGFR2-selective (compound 15). Hence,
appropriately positioned substituted trifluoroethylamine moiety
can be successfully used in the design and the synthesis of novel
VEGFR inhibitors.
11
12
13
N
CH
CH
@O
@O
CF3
CF3
CF3
@O
0.86
0.36
0.03
>5
0.68
0.91
Table 4
VEGFR2 and c-Met IC50 enzymatic assay for compounds 14 and 15 of general
structure
References and notes
H
N
H
N
1. Blume-Jensen, P.; Hunter, T. Nature 2001, 411, 355.
F
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R1
R2
O
R3
O
N
N
N
H
N
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#
R1
R2
R3
VEGFR2 IC50
(l
M)
c-Met IC50 (lM)
14
15
@O
CF3
CF3
@O
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H
1.2
0.04
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>5
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angiogenesis assay, which measures the formation of tubules gen-
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growth and branch formation and was also able to almost com-
pletely inhibit tubule growth and junction formation at 100 nM
dose where cells were supplemented with VEGF ligand (Table 5).
Thus, these results demonstrate that compound 15 has a signifi-
cant effect on VEGF-dependent angiogenic activity in endothelial
cells.
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amide isostere (as in compound 7 but not in compound 6) can af-
ford potent and selective VEGFR2 inhibitors with reduced activity
against the c-Met enzyme—compounds 7–10. The same modifica-
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