Discovery of 5-[5-fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2, 4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase

Journal of Medicinal Chemistry

Volumn 46, Issue 7, 2003, Pages 1116-1119

  Sun, Li ^a   Liang, Chris ^a   Shirazian, Sheri ^a   Zhou, Yong ^a   Miller, Todd ^a   Cui, Jean ^a   Fukuda, Juri Y ^a   Chu, Ji Yu ^a   Nematalla, Asaad ^a   Wang, Xueyan ^a   Chen, Hui ^a   Sistla, Anand ^a   Luu, Tony C ^a   Tang, Flora ^a   Wei, James ^a   Tang, Cho ^a  

^a SUGEN INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

5 (5 FLUORO 2 OXO 1,2 DIHYDROINDOLYLIDENEMETHYL) 2,4 DIMETHYL 1H PYRROLE 3 CARBOXYLIC ACID (2 DIETHYLAMINOETHYL)AMIDE; EPIDERMAL GROWTH FACTOR RECEPTOR; FIBROBLAST GROWTH FACTOR RECEPTOR 1; PLATELET DERIVED GROWTH FACTOR RECEPTOR; PROTEIN TYROSINE KINASE; PROTEIN TYROSINE KINASE INHIBITOR; SUNITINIB; UNCLASSIFIED DRUG; VASCULOTROPIN RECEPTOR 2;

ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER; CLINICAL TRIAL; CYTOTOXICITY; DRUG BIOAVAILABILITY; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG SOLUBILITY; DRUG SYNTHESIS; HUMAN; NONHUMAN;

3T3 CELLS; ANIMALS; ANTINEOPLASTIC AGENTS; BIOLOGICAL AVAILABILITY; ENZYME INHIBITORS; INDOLES; MICE; PYRROLES; RECEPTOR, PLATELET-DERIVED GROWTH FACTOR BETA; SOLUBILITY; STRUCTURE-ACTIVITY RELATIONSHIP; VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-2;

EID: 0037468875     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm0204183     Document Type: Article

References (13)

1. Cherrington, J. M.; Strawn, L. M.; Shawver, L. K. New paradigms for the treatment of cancer; the role of anti-angiogenesis agents. In Advances in Cancer Research, 1st ed.; Klein, G., Van de Woude, G. F., Eds.; Academic Press: San Diego, CA, 2000; Vol. 70, pp 1-38.
2. Gale, N. W.; Yancopoulos, G. D. Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, angiopoietins, and ephrins in vascular development. Genes Dev. 1999, 13, 1055-1066.
3. Ferrara, N. VEGF: an update on biological and therapeutic aspects. Curr. Opin. Biotechnol. 2000, 11, 617-624.
4. Rosenkranz, S.; Kazlauskas, A. Evidence for distinct signaling properties and biological responses induced by the PDGF receptor alpha and beta subtypes. Growth Factors 1999, 16, 201-216.
5. Sun, L.; Tran, N.; Tang, T.; App, H.; Hirth, P.; McMahon, G.; Tang, C. Synthesis and biological evaluations of 3-substituted indolin-2-ones: a novel class of tyrosine kinase inhibitors that exhibit selectivity towards particular receptor tyrosine kinases. J. Med. Chem. 1998, 41 (14), 2588-2603.
6. Laird, A. D.; Vajkoczy, P.; Shawver, L. K.; Thurnher, A.; Liang, C.; Mohammadi, M.; Schlessinger, J.; Ullrich, A.; Hubbard, S. R.; Blake, R. A.; Fong, A. T.; Strawn, L. M.; Sun, L.; Tang, C.; Hawtin, R.; Tang, F.; Shenoy, N.; Hirth, K. P.; McMahon, G.; Cherrington, J. M. SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors. Cancer Res. 2000, 60, 4152-4160.
7. Sun, L.; Tran, N.; Liang, C.; Tang, F.; Rice, A.; Schreck, R.; Waltz, K.; Shawver, L. K.; McMahon, G.; Tang, C. Design, synthesis, and evaluations of substituted 3-[(3- or 4-carboxyethylpyrrol-2-ylmethylidenyl]indolin-2-ones as inhibitors of VEGF, FGF, and PDGF receptor tyrosine kinases. J. Med. Chem. 1999, 42, 5120-5130.
8. Mendel, D. B.; Laird, A. D.; Xin, X.; Louie, S. G.: Christensen, J. G.; Li, G.; Schreck, R. E.; Abrams, T. J.; Ngai, T. J.; Lee, L. B.; Murray, L. J.; Carver, J.; Chan, E.; Moss, K. G.; Haznedar, J. O.; Sukbuntherng, J.; Blake, R. A.; Sun, L.; Tang, C.; Miller, T.; Shirazian, S.; McMahon, G.; Cherrington, J. M. In vivo anti-tumor activity of SU11248, a novel tyrosine kinase inhibitor targeting VEGF and PDGF receptors: Determination of a pharmacokinetic/pharmacodynamic relationship. Clin. Cancer Res. 2003, 9, 327-337.
9. Fong, A. T. T.; Shawver, L. K.; Sun, L.; Tang, C.; App, H.; Powell, T. J.; Kim, Y. H.; Schreck, R.; Wang, X. Y.; 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.
10. 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. Novel 4-anilinoquinazolines with C-7 basic side chains: Design and structure activity relationship of a series of potent, orally active, VEGF receptor tyrosine kinase inhibitors. J. Med. Chem. 2002, 45, 1300-1312.
11. Liao, A. T.; Chien, M. B.; Shenoy, N.; Mendel, D. B.; McMahon, G.; Cherrington, J. M.; London, C. A. Inhibition of constitutively active forms of mutant kit by multitargeted indolinone tyrosine kinase inhibitors. Blood 2002, 100, 585-593.
12. 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 (1), 99-106.
13. Mendel, D. B.; Laird, A. D.; Xin, X.; Abrams, T. J.; Li, G.; Schreck, R. E.; Carver, J.; Louie, S. G.; Ngai, T. J.; Lee, L. B.; Nannini, M. A.; Murray, L. J.; Tang, C.; McMahon, G.; Cherrington, J. M. In vivo antitumor and mechanism of action studies of SU11248, a potent and selective inhibitor of the VEGF and PDGF receptors. Presented at the American Association for Cancer Reserch, 2002; Poster 5349.