Discovery of brivanib alaninate ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol- 5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl) 2-aminopropanoate), a novel prodrug of dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 kinase inhibitor (BMS-540215)

Journal of Medicinal Chemistry

Volumn 51, Issue 6, 2008, Pages 1976-1980

  Cai, Zhen Wei ^a   Zhang, Yongzheng ^a   Borzilleri, Robert M ^a   Qian, Ligang ^a   Barbosa, Stephanie ^a   Wei, Donna ^a   Zheng, Xiaoping ^a   Wu, Lawrence ^a   Fan, Junying ^a   Shi, Zhongping ^a   Wautlet, Barri S ^a   Mortillo, Steve ^a   Jeyaseelan Sr , Robert ^a   Kukral, Daniel W ^a   Kamath, Amrita ^a   Marathe, Punit ^a   D'Arienzo, Celia ^a   Derbin, George ^a   Barrish, Joel C ^a   Robl, Jeffrey A ^a   Hunt, John T ^a   Lombardo, Louis J ^a   Fargnoli, Joseph ^a   Bhide, Rajeev S ^a   more..

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 [4 (4 FLUORO 2 METHYL 1H INDOL 5 YLOXY) 5 METHYLPYRROLO[2,1 F][1,2,4]TRIAZIN 6 YLOXY]PROPAN 2 OL; BMS 540215; BMS 582664; BRIVANIB ALANINATE; ENZYME INHIBITOR; ESTER DERIVATIVE; FIBROBLAST GROWTH FACTOR RECEPTOR 1; PRODRUG; UNCLASSIFIED DRUG; VASCULOTROPIN RECEPTOR 2;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; DRUG BLOOD LEVEL; DRUG METABOLISM; DRUG STRUCTURE; ENZYME SUBSTRATE; HUMAN; HUMAN TISSUE; MOUSE; NONHUMAN;

ADMINISTRATION, ORAL; ANIMALS; BIOLOGICAL AVAILABILITY; CARCINOMA; CELL PROLIFERATION; CLINICAL TRIALS, PHASE II AS TOPIC; DRUG DESIGN; DRUG EVALUATION, PRECLINICAL; HUMANS; INTESTINES; LIVER; LUNG NEOPLASMS; MICE; MICROSOMES; MOLECULAR STRUCTURE; PRODRUGS; PROTEIN KINASE INHIBITORS; PYRROLES; RECEPTOR, FIBROBLAST GROWTH FACTOR, TYPE 1; SOLUBILITY; STEREOISOMERISM; TRIAZINES; VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-2; WATER; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 41149122199     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm7013309     Document Type: Article

References (26)

1. (a) Klagsbrun, M.; Moses, M. A. Molecular angiogenesis. Chem. Biol. 1999, 6, R217-224.
2. (b) Folkman, J.; Shing, Y. Angiogenesis. J. Biol. Chem. 1992, 267, 10931-10934.
3. (c) Folkman, J.; Klagsbrun, M. Angiogenic factors. Science 1987, 235, 442-447.
4. Carmeliet, P.; Jain, R. K. Angiogenesis in cancer and other diseases. Nature 2000, 407, 249-257.
5. (a) Ellis, L. M.; Fidler, I. J. Angiogenesis and metastasis. Eur. J. Cancer 1996, 32A, 2451-2460.
6. (b) Folkman, J. Angiogenesis-dependent diseases. Semin. Oncol. 2001, 28, 536-542.
7. (a) Ferrara, N. VEGF and the quest for tumor angiogenesis factors. Nat. Rev. Cancer 2002, 2, 795-803.
8. (b) Risau, W. Mechanism of angiogenesis. Nature 2000, 407, 249-257.
9. (a) Baka, S.; Clamp, A. R.; Jayson, G. C. A review of the latest clinical compounds to inhibit VEGF in pathological angiogenesis. Expert Opin. Ther. Targets 2006, 10, 867-876.
10. (b) Sepp-Lorenzino, L.; Thomas, K. A. Antiangiogenic agents targeting vascular endothethial growth factor and its receptors in clinical development. Expert Opin. Invest. Drugs 2002, 11, 1447-1465.
11. (c) Klebl, B. M.; Muller, G. Second-generation kinase inhibitors. Expert Opin. Ther. Targets 2005, 9, 975-993.
12. (d) Supuran, C. T.; Scozzafava, A. Protein tyrosine kinase inhibitors as anticancer agents. Expert Opin. Ther. Pat. 2004, 14, 35-53.
13. (a) Kiselyov, A.; Balakin, K. V.; Tkachenko, S. E. VEGF/VEGFR signaling as a target for inhibiting angiogenesis. Expert Opin. Invest. Drugs 2007, 16, 83-107.
14. (b) Herbst, R. S. Therapeutic options to target angiogenesis in human malignancies. Expert Opin. Emerging Drugs 2006, 11, 635-650.
15. Presta, M.; Dell'Era, P.; Mitola, S.; Moroni, E.; Ronca, R.; Rusnati, M. Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev. 2005, 16, 159-178.
16. Ozen, M. A. C.; Medrano, E. E. B.; Ittmann, M. A. C. Inhibition of proliferation and survival of melanoma cells by adenoviral-mediated expression of dominant negative fibroblast growth factor receptor. Melanoma Res. 2004, 14 (1), 13-21.
17. Auguste, P.; Gürsel, D. B.; Lemière, S.; Reimers, D.; Cuevas, P.; Carceller, F.; Di Santo, J. P.; and Bikfalvi, A. Inhibition of fibroblast growth factor/fibroblast growth factor receptor activity in glioma cells impedes tumor growth by both angiogenesis-dependent and -independent mechanisms. Cancer Res. 2001, 61, 1717-1726.
18. Kornmann, M.; Beger, H. G.; Korc, M. Role of fibroblast growth factors and their receptors in pancreatic cancer and chronic pancreatitis. Pancreas 1998, 17, 169-175.
19. Lamy, A.; Gobet, F.; Laurent, M.; Blanchard, F.; Varin, C.; Moulin, C.; Andreou, A.; Frebourg, T.; Pfister, C. Molecular profiling of bladder tumors based on the detection of FGFR3 and TP53 mutations. J. Urol. 2006, 176, 2686-9.
20. Bhide, R. S.; Cai, Z.-W.; Zhang, Y.-Z.; Qian, L.; Wei, D.; Barbosa, S.; Lombardo, L. J.; Borzilleri, R. M.; Zheng, X.; Wu, L. I.; Barrish, J. C.; Kim, S.-H.; Leavitt, K.; Mathur, A.; Leith, L.; Chao, S.; Wautlet, B.; Mortillo, S.; Jayaseelan Sr., R.; Kukral, D.; Hunt, J.; Kamath, A.; Fura, A.; Vyas, V.; Marathe, P.; D'Arienzo, C.; Derbin, G.; Fargnoli, J. Discovery and preclinical studies of (R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5- methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propanol (BMS-540215), an in vivo active potent VEGFR-2 inhibitor. J. Med. Chem. 2006, 49, 2143-2146.
21. Hu, L. Prodrug approaches to drug delivery. In Drug Delivery Principles and Applications. Wang, B., Siahaan, T., Soltero, R. A., Eds.; John Wiley & Son, Inc.: New Jersey, 2005; pp 125#x2013;165.
22. Borzilleri, R. M.; Cai, Z.-W.; Ellis, C.; Fargnoli, J.; Fura, A.; Gerhardt, T.; Goyal, B.; Hunt, J. T.; Mortillo, S.; Qian, L.; Tokarski, J.; Vyas, V.; Wautlet, B.; Zheng, X.; Bhide, R. S. Synthesis and SAR of 4-(3-hydroxyphenylamino)pyrrolo[2,1-f][1,2,4]triazine based VEGFR-2 kinase inhibitors. Bioorg. Med. Chem. Lett. 2005, 15, 1429-1433.
23. Kabalka, G. W.; Reddy, N. K.; Narayana, C. Sodium perborate: A convenient reagent for benzylic hydroperoxide rearrangement. Tetrahedron Lett. 1993, 34, 7667-7668.
24. Borzilleri, R. M.; Zheng, X.; Qian, L.; Ellis, C.; Cai, Z.-W.; Wautlet, B.; Mortillo, S.; Jeyaseelan, R.; Kukral, D.; Fura, A.; Kamath, A.; Vyas, V.; Tokarski, J.; Barrish, J. C.; Hunt, J. T.; Lombardo, L. J.; Fargnoli, J.; Bhide, R. Design, synthesis, and evaluation of orally active 4-(2,4-difluoro-5- (methoxycarbamoyl)phenylamino)-pyrrolo[2,1-f][1,2,4]triazines as dual vascular endothelial growth factor receptor-2 (VEGFR-2) and fibroblast growth factor receptor-1 (FGFR-1) inhibitors. J. Med. Chem. 2005, 48, 3991-4008.
25. For detailed in vivo assay condition, see Experimental Section in ref 16.
26. Chen, B.-C.; Zhao, R.; Sundeen, J. E.; Leftheris, K.; Hynes, J.; Wrobleski, S. T. Process for preparing pyrrolotriazine kinase inhibitors. U.S. patent application, US 2004157846, 2004.