2322 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 12
Bold et al.
Endothelial Growth Factor Receptor-2 Tyrosine Kinase (VEG-
FR2 TK), a Key Enzyme in Angiogenesis. Biochemistry 1998,
37, 16788-16801.
and crystallization from acetonitrile yielded 116 mg (29%) of
66: mp 253-255 °C; H NMR (DMSO-d6) δ 9.7 (s, HN), 8.62
(d, 1H), 8.46 (d, 2H), 8.37 (d, 1H), 8.26 (s, 1H), 8.17 (d, 1H),
8.01 (m, 2H), 7.33 (d, 2H), 7.25 (d, 1H), 4.63 (s, 2H); FAB MS
(M + H)+ ) 399. Anal. (C21H14N4F4) C, H, N.
1
(6) Kerbel, R. S. A cancer therapy resistant to resistance. Nature
1997, 390, 335-336.
(7) Cursiefen, C.; Scho¨nherr, U. Angiogenese und Angiogenesehem-
mung im Auge. Klin. Monatsbl. Augenheilkd. 1997, 210, 341-
351.
Ack n ow led gm en t. The authors like to thank Mr.
E. Batt, Mr. B. Bohler, Mr. G. Goutte, Mr. P. Hauser,
Mrs. D. Kempf, Mrs. C. Kowalik, and Mrs. B. Schacher
for their capable technical assistance in biological test-
ing and Dr. J . Schneider and Mr. W. Salamin for
spectral measurements.
(8) (a) Sun, L.; Tran, N.; Tang, F.; App, H.; Hirth, P.; McMahon,
G.; Tang, C. Synthesis and Biological Evaluations of 3-Substi-
tuted Indolin-2-ones: A Novel Class of Tyrosine Kinase Inhibi-
tors That Exhibit Selectivity toward Particular Receptor Ty-
rosine Kinases. J . Med. Chem. 1998, 41, 2588-2603. (b) Fong,
T. A. T.; Shawver, L. K.; Sun, L.; Tang, C.; App, H.; Powell, T.
J .; Kim, Y. H.; Schreck, R.; Wang, X.; Risau, W.; Ullrich, A.;
Hirth, K. P.; McMahon, G. SU5416 Is a Potent and Selective
Inhibitor of the Vascular Endothelial Growth Factor Receptor
(Flk-1/KDR) That Inhibits Tyrosine Kinase Catalysis, Tumor
Vascularization, and Growth of Multiple Tumor Types. Cancer
Res. 1999, 59, 99-106.
(9) Bold, G.; Frei, J .; Traxler, P.; Altmann, K.-H.; Mett, H.; Stover,
D. R.; Wood, J . Phthalazines with angiogenesis inhibiting
activity. WO-98/35958-A1, priority date, February 13, 1997;
publication date, August 20, 1998.
(10) (a) Manly, D. G.; Richardson, A.; Stock, A. M.; Tilford, C. H.;
Amstutz, E. D. A Study of the Chemistry of Pyrophthalone and
Related Compounds. J . Org. Chem. 1958, 23, 373-380. (b)
Ploquin, J .; Sparfel, L.; Le Baut, G.; Floc′h, R.; Letourneux, Y.
â-Dice´to e´namines he´te´rocyclique: 1. Indanediones-1,3 substitu-
e´es en 2 par un he´te´rocycle azote´. J . Heterocyc. Chem. 1980, 17,
961-973.
(11) Druey, J .; Marxer, A. German Auslegeschrift no. 1 061 788,
publication date: J uly 23, 1959.
(12) Andersen, L.; Pedersen, E. B. Synthesis of 4-Arylamino-1H-
pyrazolo[3, 4-d]pyrimidines. Acta Chem. Scand., Ser. B. 1988,
B42, 492-493.
(13) Van der Geer, P.; Hunter, T.; Lindberg, R. A. Receptor Protein-
Tyrosine Kinases and Their Signal Transduction Pathways.
Annu. Rev. Cell Biol. 1994, 10, 251-337.
(14) Wood, J . M.; Bold, G.; Buchdunger, E.; Cozens, R.; Ferrari, S.;
Frei, J .; Hofmann, F.; Mestan, J .; Mett, H.; O′Reilly, T.; Persohn,
E.; Ro¨sel, J .; Schnell, C.; Stover, D.; Theuer, A.; Towbin, H.;
Wenger, F.; Woods-Cook, K.; Menrad, A.; Siemeister, G.; Schirn-
er, M.; Thierauch, K.-H.; Schneider, M. R.; Drevs, J .; Martiny-
Baron, G.; Totzke, F.; Marme´, D. PTK787/ZK 222584, a Novel
and Potent Inhibitor of Vascular Endothelial Growth Factor
Receptor Tyrosine Kinases, Impairs Vascular Endothelial Growth
Factor-induced Responses and Tumor Growth after Oral Ad-
ministration. Cancer Res. 2000, 60, 2178-2189.
Refer en ces
(1) (a) Folkman, J . Anti-Angiogenesis: New Concept for Therapy
of Solid Tumors. Ann. Surg. 1972, 175, 409-416. (b) Folkman,
J . What Is the Evidence That Tumors Are Angiogenesis De-
pendent? J . Natl. Cancer Inst. 1990, 82, 4-6. (c) Folkman, J .;
Shing, Y. Angiogenesis. J . Biol. Chem. 1992, 267, 10931-10934.
(2) (a) Liotta, L. A.; Kleinerman, J .; Saidel, G. M. Quantitative
Relationships of Intravascular Tumor Cells, Tumor Vessels, and
Pulmonary Metastases following Tumor Implantation. Cancer
Res. 1974, 34, 997-1004. (b) Liotta, L. A.; Steeg, P. S.; Stetler-
Stevenson, W. G. Cancer Metastasis and Angiogenesis: An
Imbalance of Positive and Negative Regulation. Cell 1991, 64,
327-336.
(3) (a) Klagsbrun, M.; Moses, M. A. Molecular angiogenesis. Chem.
Biol. 1999, 6, R217-R224. (b) van Hinsbergh, V. W. M.; Collen,
A.; Koolwijk, P. Angiogenesis and anti-angiogenesis: Perspec-
tives for the treatment of solid tumors. Ann. Oncol. 1999, 10,
60-63. (c) Chaplin, D. J .; Dougherty, G. J . Tumour vasculature
as a target for cancer therapy. Br. J . Cancer. 1999, 80, 57-64.
(d) Eckhardt, S. G. Angiogenesis Inhibitors as Cancer Therapy.
Hospital Practice 1999, 63-84. (e) Bergers, G.; J avaherian, K.;
Lo, K.-M.; Folkman, J .; Hanahan, D. Effects of Angiogenesis
Inhibitors on Multistage Carcinogenesis in Mice. Science 1999,
284, 808-812. (f) Mousa, S. A. Mechanisms of angiogenesis in
vascular disorders: potential therapeutic targets. Drugs Future
1998, 23, 51-60. (g) O′Reilly, M. S. The preclinical evaluation
of angiogenesis inhibitors. Invest. New Drugs 1997, 15, 5-13.
(h) Gastl, G.; Hermann, T.; Steurer, M.; Zmija, J .; Gunsilius,
E.; Unger, C.; Kraft, A. Angiogenesis as a Target for Tumor
Treatment. Oncology 1997, 54, 177-184. (i) Folkman, J . Fighting
Cancer by Attacking Its Blood Supply. Sci. Am. 1996, 2-5. (j)
Folkman, J . The influence of angiogenesis research on manage-
ment of patients with breast cancer. Breast Cancer Res. Treat.
1995, 36, 109-118. (k) Fan, T.-P. D.; J aggar, R.; Bicknell, R.
Controlling the vasculature: angiogenesis, anti-angiogenesis and
vascular targeting of gene therapy. Trends Pharmacol. Sci. 1995,
16, 57-66. (l) Seed, M. P. Angiogenesis inhibition as a drug
target for disease: an update. Exp. Opin. Invest. Drugs 1996, 5,
1617-1637. (m) Augustin, H. G. Antiangiogenic tumour
therapy: Will it work? Trends Pharmacol. Sci. 1998, 19, 216-
222. (n) Kim, K. J .; Li, B.; Winer, J .; Armanini, M.; Gillett, N.;
Phillips, H. S.; Ferrara, N. Inhibition of vascular endothelial
growth factor-induced angiogenesis suppresses tomour growth
in vivo. Nature 1993, 362, 841-844.
(4) (a) Senger, D. R.; Van De Water, L.; Brown, L. F.; Nagy, J . A.;
Yeo, K.-T.; Yeo, T.-K.; Berse, B.; J ackman, R. W.; Dvorak, A.
M.; Dvorak, H. F. Vascular permeability factor (VPF, VEGF) in
tumor biology. Cancer Metastat. Rev. 1993, 12, 303-324. (b)
Ko¨lch, W.; Martiny-Baron, G.; Kieser, A.; Marme´, D. Regulation
of the expression of VEGF/VPS and its receptors: role in
tumorangiogenesis. Breast Cancer Res. Treat. 1995, 36, 139-
155. (c) Breier, G.; Risau, W. The role of vascular endothelial
growth factor in blood vessel formation. Trends Cell Biol. 1996,
6, 454-456. (d) Leenders, W. P. J . Targetting VEGF in anti-
angiogenic and anti-tumour therapy: Where are we now? Int.
J . Exp. Pathol. 1998, 79, 339-346.
(5) (a) Strawn, L. M.; McMahon, G.; App, H.; Schreck, R.; Kuchler,
W. R.; Longhi, M. P.; Hui, T. H.; Tang, C.; Levitzki, A.; Gazit,
A.; Chen, I.; Keri, G.; Orfi, L.; Risau, W.; Flamme, I.; Ullrich,
A.; Hirth, K. P.; Shawver, L. K. Flk-1 as a Target for Tumor
Growth Inhibition. Cancer Res. 1996, 56, 3540-3545. (b) Fer-
rara, N. The role of vascular endothelial growth factor in
pathological angiogenesis. Breast Cancer Res. Treat. 1995, 36,
127-137. (c) Shawver, L. K.; Lipson, K. E.; Fong, T. A. T.;
McMahon, G.; Plowman, G. D.; Strawn, L. M. Receptor tyrosine
kinases as targets for inhibition of angiogenesis. Drug Discovery
Today 1997, 2, 50-63. (d) Parast, C. V.; Mroczkowski, B.; Pinko,
C.; Misialek, S.; Khambatta, G.; Appelt, K. Characterization and
Kinetic Mechanism of Catalytic Domain of Human Vascular
(15) (a) Mohammadi, M.; Schlessinger, J .; Hubbard, S. R. Structure
of the FGF Receptor Tyrosine Kinase Domain Reveals A Novel
Autoinhibitory Mechanism. Cell. 1996, 86, 577-587. (b) Mo-
hammadi, M.; McMahon, G.; Sun, L.; Tang, C.; Hirth, P.; Yeh,
B. K.; Hubbard, S. R.; Schlessinger, J . Structures of the Tyrosine
Kinase Domain of Fibroblast Growth Factor Receptor in Com-
plex with Inhibitors. Science 1997, 276, 955-960.
(16) Will be published separately (Furet, P.; et al.).
(17) Although the coordinates of X-ray crystal structure reported by
Agouron scientists are not yet available, the information given
in the article clearly supports the use of the FGFR1 structure
to model the ATP binding site of KDR. McTigue, M. A.;
Wickersham, J . A.; Pinko, C.; Showalter, R. E.; Parast, C. V.;
Tempczyk-Russel, A.; Gehring, M. R.; Mroczkowski, B.; Kan, C.-
C.; Villafranca, J . E.; Appelt, K. Crystal structure of the kinase
domain of human vascular endothelial growth factor receptor
2: A key enzyme in angiogenesis. Structure 1999, 7, 319-330.
(18) See for example ref 15b or Furet, P.; Caravatti, G.; Lydon, N.;
Priestle, J . P.; Sowadski, J . M.; Trinks, U.; Traxler, P. Modeling
study of protein kinase inhibitors: Binding mode of staurospo-
rine and origin of the selectivity of CGP 52411. J . Comput. Aid.
Mol. Design 1995, 9, 465-472.
(19) A recent paper reports the X-ray crystal structure of the kinase
domain of FGFR1 complexed with an inhibitor possessing a 3,5-
dimethoxy phenyl group filling the equivalent hydrophobic
pocket of this enzyme. Mohammadi, M.; Froum, S.; Hamby, J .
M.; Schroeder, M. C.; Panek, R. L.; Lu, G. H.; Eliseenkova, A.
V.; Green, D.; Schlessinger, J .; Hubbard, S. R. Crystal structure
of an angiogenesis inhibitor bound to the FGF receptor tyrosine
kinase domain. EMBO J . 1998, 17, 5896-5904.
(20) Trinks, U.; Buchdunger, E.; Furet, P.; Kump, W.; Mett, H.;
Meyer, T.; Mu¨ller, M.; Regenass, U.; Rihs, G.; Lydon, N.; Traxler,
P. Dianilinophthalimides: Potent and Selective, ATP-Competi-
tive Inhibitors of the EGF-Receptor Protein Tyrosine Kinase.
J . Med. Chem. 1994, 37, 1015-1027.
(21) Druker, B. J .; Mamon, H. J .; Roberts, T. M. Oncogenes, Growth
Factors, and Signal Transduction. New Engl. J . Med. 1989, 321,
1383-1391.