1374
A. S. Kiselyov et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1369–1375
Table 2. Passive diffusion potential across Caco-2 cell monolayer for
selected compounds
References and notes
1. (a) Risau, W. Nature 1997, 386, 671; (b) Hanahan, D.;
Folkman, J. Cell 1996, 86, 353; (c) Folkman, J.; Klags-
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2003, 9, 669; (b) Carmeliet, P.; Jain, R. Nat. Med. 2003, 9,
653; (c) Veikkola, T.; Karkkainen, M.; Claesson-Welsh,
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3. (a) Klagsbrun, M.; D’Amore, P. Annual Rev. Physiol.
1991, 53, 217; (b) Neufeld, G.; Cohen, T.; Gengrinovitch,
S.; Poltorak, Z. FASEB J. 1999, 13, 9; (c) Zachary, I.
Biochem. Soc. Trans. 2003, 31, 1171; (d) Klagsbrun, M.;
Moses, M. A. Chem. Biol. 1999, 6, R217; The anti-
angiogenic antibody AvastinTM (Bevacizumab) has recently
been approved to treat colorectal cancer, see: (e) Culy, C.
Drugs Today 2005, 41, 23; The anti-angiogenic aptamer
MacugenTM (Pegaptanib sodium) has recently been
approved to treat neovascular age-related macular degen-
eration, see: (f) Fine, S. L.; Martin, D. F.; Kirkpatrick, P.
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Compound
Intrinsic permeability,
Pm value · 10À5 cm/min
38.6 (lit. 45.2)6
17.3 (lit. 21.7)6
32.4
5.7
Absorption
potential
C
High
med
D
5
High
Low
17
19
20
27
28
29
30
33
34
43
47
55
60
45.3
37.2
High
High
High
36.9
21.6
Med/high
High
High
42.2
49.3
35.6
42.6
High
High
32.5
37.5
Med/high
High
High
40.4
33.1
Med/high
4. Bold, G.; Altmann, K.-H.; Jorg, F.; Lang, M.; Manley, P.
W.; Traxler, P.; Wietfeld, B.; Bruggen, J.; Buchdunger, E.;
Cozens, R.; Ferrari, S.; Pascal, F.; Hofmann, F.; Martiny-
Baron, G.; Mestan, J.; Rosel, J.; Sills, M.; Stover, D.;
Acemoglu, F.; Boss, E.; Emmenegger, R.; Lasser, L.;
Masso, E.; Roth, R.; Schlachter, C.; Vetterli, W.; Wyss,
D.; Wood, J. M. J. Med. Chem. 2000, 43, 2310.
Table 3. Compounds (19), (34), and (43) are ATP-competitive inhib-
itors of VEGFR-2
Compound
Ki at IC50 (lM)
Ki at IC90 (lM)
19
34
43
0.20
0.16
0.17
0.17
0.15
0.18
5. (a) Hennequin, L. F.; Stokes, E. S. E.; Thomas, A. P.;
Johnstone, C.; Ple, P. A.; Ogilvie, D. J.; Dukes, M.;
Wedge, S. R.; Kendrew, J.; Curwen, J. O. J. Med. Chem.
2002, 45, 1300; (b) Wedge, S. R.; Kendrew, J.; Hennequin,
L. F.; Valentine, P. J.; Barry, S. T.; Brave, S. R.; Smith, N.
R.; James, N. H.; Dukes, M.; Curwen, J. O.; Chester, R.;
Jackson, J. A.; Boffey, S. J.; Kilburn, L. L.; Barnett, S.;
Richmond, G. H. P.; Wadsworth, P. F.; Walker, M.;
Bigley, A. L.; Taylor, S. T.; Cooper, L.; Beck, S.;
Juergensmeier, J. M.; Ogilvie, D. J. Cancer Res. 2005,
65, 4389.
VEGFR-2 in the absence, IC50 or IC90 concentrations,
of the inhibitors for 45 min at RT. A double reciprocal
graph of the degree of phosphorylation (1/cpm) against
ATP-concentration (1/[ATP]) was plotted. The data
were analyzed by a non-linear least-squares program
to determine kinetic parameters using GraphPad soft-
ware. Selected Ki values for the three selected com-
pounds are listed in Table 3. Determined Ki values for
IC50 or IC90 concentration were compared and found
to be identical within experimental error.
6. (a) Manley, P. W.; Furet, P.; Bold, G.; Bruggen, J.;
¨
Mestan, J.; Meyer, T.; Schnell, C.; Wood, J. J. Med.
Chem. 2002, 45, 5697; (b) Manley, P. W.; Bold, G.;
Fendrich, G.; Furet, P.; Mestan, J.; Meyer, T.; Meyhack,
B.; Strauss, A.; Wood, J. Cell. Mol. Biol. Lett. 2003, 8,
532; (c) Altmann, K.-H.; Bold, G.; Furet, P.; Manley,
P.W.; Wood, J.M.; Ferrari, S.; Hofmann, F.; Mestan, J.;
Huth, A.; Kruger, M.; Seidelmann, D.; Menrad, A.;
¨
Haberey, M.; Thierauch, K.-H., US Patent 6,878,720 B2,
2005.
In summary, we have developed a series of novel potent
ortho-substituted azole derivatives active against kinases
VEGFR-1 and -2. Both specific and dual ATP-compet-
itive inhibitors of VEGFR-2 were identified. Kinase
selectivity could be controlled by varying the arylamido
substituent at the azole ring. Compound activities in
both enzymatic and cell-based assays (IC50 < 100 nM)
were in the range of that for the reported clinical and
development candidates, including PTK787 (Vatala-
nib)TM. The analogs presented in this report are potential-
ly useful in the treatment of conditions such as cancer.
Further details on their biological properties, such as
functional activity, together with murine oral exposure
data will be presented in due course.
7. (a) Piatnitski, E. L.; Duncton, M.; Katoch-Rouse, R.;
Sherman, D.; Kiselyov, A. S.; Milligan, D.; Balagtas, C.;
Wong, W.; Kawakami, J.; Doody, J. Bioorg. Med. Chem.
Lett. 2005, 15, 4696; (b) Kiselyov, A. S.; Piatnitski, E. L.;
Semenova, M.; Semenov, V. V. Bioorg. Med. Chem. Lett.
2006, 16, 602; (c) Kiselyov, A. S.; Semenova, M.;
Semenov, V. V.; Piatnitski, E. L.; Ouyang, S. Bioorg.
Med. Chem. Lett. 2006, 16, 2559; (d) Kiselyov, A. S.;
Semenova, M.; Semenov, V. V.; Piatnitski, E. L. Bioorg.
Med. Chem. Lett. 2006, 16, 1726; (e) Kiselyov, A. S.;
Semenova, M.; Semenov, V. V.; Milligan, D. Bioorg. Med.
Chem. Lett. 2006, 16, 1913.
8. Sobenina, L. N.; Drichkov, V. N.; Mikhaleva, A. I.;
Petrova, O. V.; Ushakov, I. A.; Trofimov, B. A. Tetrahe-
dron 2005, 61, 4841.
9. Analytical data for selected active compounds:
Compound 19: N-(4-tert-butylphenyl)-1-methyl-4-(pyri-
din-4-ylmethylamino)-1H- imidazole-5-carboxamide; mp
Acknowledgments
We thank Dr. J. Doody and Dr. Y. Hadari of ImClone
Systems Inc. for developing enzymatic and cellular assay
conditions published in our earlier studies.