2694
V. Gracias et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2691–2695
Table 3. Kinase inhibitory activity of meta-urea analogs
R3
O
R4
N
H
N
NH2
H
N
N
N
N
H
a
a
a
Compound
R3
R4
KDR IC50 (lM)
KDR (cell)b IC50 (lM)
Flt3 IC50 (lM)
c-Kit IC50 (lM)
1o
1p
14
H
Ph
3-CF3-Ph
3-CF3-Ph
0.888
0.126
0.006
NDc
2.696
0.145
0.135
3.022
0.091
0.012
H
Me
0.790
0.052
a IC50 values are based on an eleven point curve at 1 mM ATP concentration.
b Activity against VEGF-induced KDR phosphorylation in 3T3-murine fibroblast cells.
c ND stands for not determined.
tion (1h) resulted in losses in KDR potency. Di-substi-
tuted analogs containing the meta-trifluoromethyl group
and a fluoro group in various positions resulted in com-
pounds with similar in vitro KDR potency, (1k and 1l)
however, their cellular potency was inferior to that of
compound 1g.
and 14 is potentially due to the different gatekeeper res-
idues for the two enzymes, Val 916 for KDR and Phe
691 for Flt3, which is in the direct vicinity of the aryl
Me group of 14.
In conclusion, we have identified pyrimido-diazepines as
novel kinase hinge binders and were able to rapidly
transform them to potent VEGFR and PDGFR inhibi-
tors using modeling and our expertise in kinase inhibi-
tion. We are in the process of finding other
applications for this unique core and our findings will
be reported in due course.
The meta-substituted phenyl urea 1o (Table 3) exhibited
a similar drop in potency when compared to 1a. How-
ever, the meta-trifluoromethyl phenyl analog of the
meta-urea 1p was not as potent as 1g. Modeling of 1p
in the active site of KDR (Fig. 3) suggested the presence
of a small pocket that could be filled with additional
functionality. Thus compound 14 was prepared follow-
ing procedures similar to those in Scheme 1. To our de-
light compound 14 exhibited improved in vitro and
cellular KDR potency and an apparent selectivity for
KDR versus Flt3 (Table 3). This is in stark contrast to
the para-urea series (Table 2) where most of the com-
pounds were equipotent for Flt3 and to meta-urea ana-
logs such as 1p lacking the methyl group. The altered
KDR/Flt3 enzyme potency ratio for compounds 1p
Acknowledgments
The authors thank the Abbott High Throughput Purifi-
cation and Structural Chemistry groups for their sup-
port with purification and analytical data, respectively.
References and notes
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Figure 3. Model of compound 1p, green carbons, bound to KDR with
the urea of 1p hydrogen-bonded to Glu 885. The arrow shows a vector
that projects into a small hydrophobic volume comprising the
sidechains of Val 848, Val 916, and the methylenes of Lys 868.