Novel 2,3-dihydro-1,4-benzoxazines as potent and orally bioavailable inhibitors of tumor-driven angiogenesis

Journal of Medicinal Chemistry

Volumn 51, Issue 6, 2008, Pages 1695-1705

  La, Daniel S ^a   Belzile, Julie ^a   Bready, James V ^a   Coxon, Angela ^a   DeMelfi, Thomas ^a   Doerr, Nicholas ^a   Estrada, Juan ^a   Flynn, Julie C ^a   Flynn, Shaun R ^a   Graceffa, Russell F ^a   Harriman, Shawn P ^a   Larrow, Jay F ^a   Long, Alexander M ^a   Martin, Matthew W ^a   Morrison, Michael J ^a   Patel, Vinod F ^a   Roveto, Philip M ^a   Wang, Ling ^a   Weiss, Matthew M ^a   Whittington, Douglas A ^a   Teffera, Yohannes ^a   Zhao, Zhiyang ^a   Polverino, Anthony J ^a   Harmange, Jean Christophe ^a   more..

^a Department of Chemistry Research and Discovery ^*

Author keywords

[No Author keywords available]

Indexed keywords

2,3 DIHYDRO 1,4 BENZOXAZINE DERIVATIVE; 7 [[6 (AMINOCARBONYL) 7 (METHOXY) 4 QUINOLINYL]OXY] N (4 METHYLPHENYL) 2,3 DIHYDRO 4H 1,4 BENZOXAZINE 4 CARBOXAMIDE; 7 [[6,7 BIS(METHLOXY) 4 QUINOLINYL]OXY] N (4 METHYLPHENYL) 2,3 DIHYDRO 4H 1,4 BENZOXAZINE 4 CARBOXAMIDE; 7 [[6,7 BIS(METHLOXY) 4 QUINOLINYL]OXY] N (4FLUOROPHENYL) 2,3 DIHYDRO 4H 1,4 BENZOXAZINE 4 CARBOXAMIDE; 7 [[6,7 BIS(METHLOXY) 4 QUINOLINYL]OXY] N PHENYL 2,3 DIHYDRO 4H 1,4 BENZOXAZINE 4 CARBOXAMIDE; BENZOXAZINE DERIVATIVE; N (4 CHLOROPHENYL) 7 (6,7 DIMETHOXYNAPHTHALEN 1 YLOXY) 2,3 DIHYDROBENZO[B][1,4]OXAZINE 4 CARBOXAMIDE; UNCLASSIFIED DRUG; VASCULOTROPIN RECEPTOR 2;

ANGIOGENESIS; AREA UNDER THE CURVE; ARTICLE; CELL PROLIFERATION; CONTROLLED STUDY; DRUG EFFICACY; DRUG INHIBITION; DRUG SELECTIVITY; DRUG STRUCTURE; ENDOTHELIUM CELL; HUMAN; HUMAN CELL; IN VIVO STUDY; TUMOR;

ADMINISTRATION, ORAL; ANGIOGENESIS INHIBITORS; ANIMALS; BENZOXAZINES; BIOLOGICAL AVAILABILITY; CELL LINE; CELL PROLIFERATION; CORNEAL NEOVASCULARIZATION; CRYSTALLOGRAPHY, X-RAY; DOSE-RESPONSE RELATIONSHIP, DRUG; ENDOTHELIAL CELLS; FEMALE; HUMANS; INJECTIONS, SUBCUTANEOUS; LIGANDS; MALE; MICE; MICE, INBRED BALB C; MICE, NUDE; MODELS, ANIMAL; MODELS, MOLECULAR; MOLECULAR STRUCTURE; NEOPLASMS; NEOVASCULARIZATION, PATHOLOGIC; RATS; RATS, SPRAGUE-DAWLEY; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; VASCULAR ENDOTHELIAL GROWTH FACTOR A; VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-2;

EID: 41149155425     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm701129j     Document Type: Article

References (31)

1. Carmeliet, P. Angiogenesis in Health and Disease. Nat. Med. 2003, 9, 653-660.
2. Folkman, J. Tumor Angiogenesis: Therapeutic Implications. N. Engl. J. Med. 1971, 285, 1182-1186.
3. Ferrara, N.; Gerber, H.; LeCouter, J. The Biology of VEGF and Its Receptor. Nat. Med. 2003, 9, 669-676.
4. Breier, G.; Risau, W. The Role of Vascular Endothelial Growth Factor in Blood Vessel Formation. Trends Cell Biol. 1996, 6, 454-456.
5. Boehm, T.; Folkman, J.; Browder, T.; O'Reilly, M. Antiangiogenic Therapy of Experimental Cancer Does Not Induce Acquired Drug Resistance. Nature 1997, 390, 404-407.
6. Zakarija, A.; Soff, G. Update on Angiogenesis Inhibitors. Curr. Opin. Oncol. 2005, 17, 578-583.
7. D'Adamo, D.; Anderson, S.; Albritton, K.; Yamada, J.; Riedel, E.; Scheu, K.; Schwartz, G.; Chen, H.; Maki, R. Phase II Study of Doxorubicin and Bevacizumab for Patients with Metastatic Soft-Tissue Sarcomas. J. Clin. Oncol. 2005, 23, 7135-7142.
8. Yang, J.; Haworth, L.; Sherry, R.; Hwu, P.; Schwartzentruber, D.; Topalian, S.; Steinberg, S.; Chen, H.; Rosenberg, S. A Randomized Trial of Bevacizumab, an Anti-Vascular Endothelial Growth Factor Antibody, for Metastatic Renal Cancer. N. Engl. J. Med. 2003, 349, 427-434.
9. Drevs, J.; Müller-Driver, R.; Wittig, C.; Fuxius, S.; Esser, N.; Hugenschmidt, H.; Konerding, M.; Allegrini, P.; Wood, J.; Hennig, J.; Unger, C.; Marmé, D. PTK787/ZK 222584, a Specific Vascular Endothelial Growth Factor-Receptor Tyrosine Kinase Inhibitor. Affects the Anatomy of the Tumor Vascular Bed and the Functional Vascular Properties As Detected by Dynamic Enhanced Magnetic Resonance Imaging. Cancer Res. 2002, 62, 4015-4022.
10. Bold, G.; Altman, K.; Frei, J.; Lang, M.; Manley, P.; Traxler, P.; Wietfeld, B.; Brüggen, J.; Buchdunger, E.; Cozens, R.; Ferrari, S.; Furet, P.; Hofmann, F.; Martiny-Baron, G.; Mestan, J.; Rösel, J.; Sills, M.; Stover, D.; Acemoglu, F.; Boss, E.; Emmenegger, R.; Lässer, L.; Masso, E.; Roth, R.; Schlachter, C.; Vetterli, W.; Wyss, D.; Wood, J. New Anilinophthalazines as Potent and Orally Well Absorbed Inhibitors of the VEGF Receptor Tyrosine Kinases Useful as Antagonists of Tumor-Driven Angiogenesis. J. Med. Chem. 2000, 43, 2310-2323.
11. Ciardiello, F.; Caputo, R.; Damiano, V.; Caputo, R.; Troiani, T.; Vitagliano, D.; Carlomangno, F.; Veneziani, B.; Fontanini, G.; Bianco, R.; Tortora, G. Antitumor Effects of ZD6474, a Small Molecule Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, with Additional Activity Against Epidermal Growth Factor Receptor Tyrosine Kinase. Clin. Cancer Res. 2003, 9, 1546-1556.
12. Hennequin, L.; Stokes, E.; Thomas, A.; Johnstone, C.; Plé, P.; Ogilvie, D.; Dukes, M.; Wedge, S.; Kendrew, J.; Curwen, J. 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.
13. Beebe, J.; Jani, J.; Knauth, E.; Goodwin, P.; Higdon, C.; Rossi, A.; Emerson, E.; Finkelstein, M.; Floyd, E.; Harriman, S.; Atherton, J.; Hillerman, S.; Soderstrom, C.; Kou, K.; Gant, T.; Noe, M.; Foster, B.; Rastinejad, F.; Marx, M.; Schaeffer, T.; Whalen, P.; Roberts, W. Pharmacological Characterization of CP-547,632, a Novel Vascular Endothelial Growth Factor Receptor-2 Tyrosine Kinase Inhibitor for Cancer Therapy. Cancer Res. 2003, 63, 7301-7309.
14. Pietras, K.; Hanahan, D. A Multitargeted, Metronomic, and Maximum-Tolerated Dose "Chemo-Switch" Regimen Is Antiangiogenic, Producing Objective Responses and Survival Benefit in a Mouse Model of Cancer. J. Clin. Oncol. 2005, 23, 939-952.
15. Mendel, D.; Laird, D.; Xin, X.; Louie, S.; Christensen, J.; Li, G.; Schreck, R.; Abrams, T.; Ngai, T.; Lee, L.; Murray, L.; Carver, J.; Chan, E.; Moss, K.; Haznedar, J.; Sukbuntherng, J.; Blake, R.; Sun, L.; Tang, C.; Miller, T.; Shirazian, S.; McMahon, G.; Cherrington, J. In Vivo Antitumor Activity of SU11248, a Novel Tyrosine Kinase Inhibitor Targeting Vascular Endothelial Growth Factor and Platelet-Derived Growth Factor Receptors: Determination of a Pharmacokinetic/Pharmacodynamic Relationship. Clin. Cancer Res. 2003, 9, 327-337.
16. Atkins, M.; Jones, C. A.; Kirkpatrick, P. Sunitinib Maleate. Nat. Rev. Drug Discovery 2006, 5 (4), 279-280.
17. Ng, R.; Chen, E. X. Sorafinib (BAY 43-9006): Review of Clinical Developement. Curr. Clin. Pharmacol. 2006, 1, 223-228.
18. Polverino, A.; Coxon, A.; Starnes, C.; Diaz, Z.; Demelfi, T.; Wang, L.; Bready, J.; Estrada, J.; Cattley, R.; Kaufman, S.; Chen, D.; Gan, Y.; Kumar, G.; Meyer, J.; Neervannan, S.; Alva, G.; Talvenheimo, J.; Montestruque, S.; Tasker, A.; Patel, V.; Radinsky, R.; Kendall, R. AMG 706, an Oral, Multikinase Inhibitor That Selectively Targets Vascular Endothelial Growth Factor, Platelet-Derived Growth Factor, and Kit Receptors, Potently Inhibits Angiogenesis and Induces Regression in Tumor Xenografts. Cancer Res. 2006, 66 (17), 8715-8721.
19. Rosen, L. S.; Kurzrock, R.; Mulay, M.; Van Vugt, A.; Purdom, M.; Ng, C.; Silverman, J.; Koutsoukos, A.; Sun, Y.-N.; Bass, M. B.; Xu, R. Y.; Polverino, A.; Wiezorek, J. S.; Chang, D. D.; Benjamin, R.; Herbst, R. S. Safety, Pharmacokinetics, and Efficacy of AMG 706, an Oral Multikinase Inhibitor, in Patients with Advanced Solid Tumors. J. Clin. Oncol. 2007, 25 (17), 2369-2376.
20. (a) Harmange, J.; Weiss, M.; Germain, J.; Polverino, A. J.; Borg, G.; Bready, J.; Buckner, W.; Chen, D.; Choquette, D.; Coxon, A.; DeMelfi, T. DiPietro, L.; Doerr, N.; Estrada, J.; Fellows, I.; Flynn, J.; Graceffa, R. F.; Harriman, S. P.; Kaufman, S.; La, D. S.; Long, A.; Martin, M. W.; Neervannan, S.; Patel, V. F.; Potashman, M.; Regal, K.; Roveto, P. M.; Schrag, M. L.; Starnes, C.; Tasker, A.; Teffera, Y.; Wang, L.; White, R. D.; Whittington, D.; Zanon, R. Naphthamides as Novel and Potent VEGF Receptor Tyrosine Kinase Inhibitors: Design, Synthesis, and Evaluation. J. Med. Chem. 2008, 51, 1649-1667.
21. (b) Weiss, M. M.; Harmange, J.; Polverino, A. J.; Bauer, D.; Berry, L.; Berry, V.; Borg, G.; Bready, J.; Bretz, A.; Chen, D.; Chi, V.; Choquette, D.; Coxon, A.; DeMelfi, T.; Doerr, N.; Estrada, J.; Fellows, I.; Flynn, J.; Graceffa, R. F.; Harriman, S. P.; Kaufman, S.; La, D. S.; Long, A.; Neervannan, S.; Patel, V. F.; Potashman, M.; Regal, K.; Roveto, P. M.; Schrag, M. L.; Starnes, C.; Tasker, A.; Teffera, Y.; Whittington, D.; Zanon, R. Evaluation of a Series of Naphthamides as Potent, Orally Active VEGFR-2 Tyrosine Kinase Inhibitors. J. Med. Chem. 2008, 51, 1668-1680.
22. Liu, Y.; Gray, N. Rational Design of Inhibitors That Bind to Inactive Kinase Conformations. Nat. Chem. Biol. 2006, 2, 358-364.
23. cLogP values were calculated employing software from ACD Labs (Advanced Chemistry Development Inc.).
24. (a) Mazzone, M.; Comoglio, P. M. The Met Pathway: Master Switch and Drug Target in Cancer Progression. FASEB J. 2006, 20, 1611-1621.
25. (b) Yu, Q. The Dynamic Roles of Angiopoietins in Tumor Angiogenesis. Future Med. 2005, 1, 475-484.
26. (a) Parson, S. J.; Parsons, J. T. Src Family Kinases, Key Regulators of Signal Transduction. Oncogene 2004, 23, 7906-7909.
27. (b) Palacios, E. H.; Weiss, A. Function of the Src-Family Kinases, Lck and Fyn, in T-Cell Development and Activation. Oncogene 2004, 23, 7990-8000.
28. Pierce, A. C.; Sandretto, K. L.; Bemis, G. W. Kinase Inhibitors and the Case for CH-O Hydrogen Bonds in Protein-Ligand Binding. Proteins: Struct., Funct., Genet. 2002, 49 (4), 567-576.
29. Tan, H.; Semin, D.; Wacker, M.; Cheetham, J. An Automated Screening Assay for Determination of Aqueous Equilibrium Solubility Enabling SPR Study during Drug Lead Optimization. J. Assoc. Lab. Autom. 2005, 10, 364-373.
30. Vascular permeability was induced using a modified Miles assay: Miles, A.; Miles, E. Vascular Reactions to Histamine, Histamine-Liberator and Leukotaxine in the Skin of Guinea-Pigs. J. Physiol. 1952, 118, 228-257.
31. Coxon, A.; Bolon, B.; Estrada, J.; Kaufman, S.; Scully, S.; Rattan, A.; Duryea, D.; Hu, Y.; Rex, K.; Pacheco, E.; Van, G.; Zack, D.; Feige, U. Inhibition of Interleukin-1 but Not Tumor Necrosis Factor Suppresses Neovascularization in Rat Models of Corneal Angiogenesis and Adjuvant Arthritis. Arthritis Rheum. 2002, 46, 2604-2612.