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

被引:76
作者
La, Daniel S. [1 ,6 ]
Belzile, Julie [1 ,6 ]
Bready, James V. [2 ,7 ]
Coxon, Angela [2 ,7 ]
DeMelfi, Thomas [2 ,7 ]
Doerr, Nicholas [2 ,7 ]
Estrada, Juan [2 ,7 ]
Flynn, Julie C. [3 ,8 ]
Flynn, Shaun R. [4 ,9 ]
Graceffa, Russell F. [1 ,6 ]
Harriman, Shawn P. [3 ,8 ]
Larrow, Jay F. [1 ,6 ]
Long, Alexander. M. [5 ,10 ]
Martin, Matthew W. [1 ,6 ]
Morrison, Michael J. [4 ,7 ,9 ]
Patel, Vinod F. [1 ,6 ]
Roveto, Philip M. [1 ,6 ]
Wang, Ling [2 ]
Weiss, Matthew M. [1 ,6 ]
Whittington, Douglas A. [5 ,10 ]
Teffera, Yohannes [3 ,8 ]
Zhao, Zhiyang [3 ,8 ]
Polverino, Anthony J. [2 ]
Harmanget, Jean-Christophe [1 ,6 ]
机构
[1] Amgen Inc, Dept Chem Res Discovery, Cambridge, MA 02139 USA
[2] Amgen Inc, Dept Oncol, Cambridge, MA 02139 USA
[3] Amgen Inc, Dept Pharmacokinet & Drug Metab, Cambridge, MA 02139 USA
[4] Amgen Inc, Dept HTS & Mol Pharmacol, Cambridge, MA 02139 USA
[5] Amgen Inc, Dept Mol Sturct, Cambridge, MA 02139 USA
[6] Amgen Inc, Dept Chem Res & Discovery, Thousand Oaks, CA 91320 USA
[7] Amgen Inc, Dept Oncol, Thousand Oaks, CA 91320 USA
[8] Amgen Inc, Dept Pharmacokinet & Drug Metab, Thousand Oaks, CA 91320 USA
[9] Amgen Inc, Dept HTS & Mol Pharmacol, Thousand Oaks, CA 91320 USA
[10] Amgen Inc, Dept Mol Struct, Thousand Oaks, CA 91320 USA
关键词
D O I
10.1021/jm701129j
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Angiogenesis is vital for solid tumor growth, and its prevention is a proven strategy for the treatment of disease states such as cancer. The vascular endothelial growth factor (VEGF) pathway provides several opportunities by which small molecules can act as inhibitors of endothelial proliferation and migration. Critical to these processes is signaling through VEGFR-2 or the kinase insert domain receptor (KDR) upon stimulation by its ligand VEGF. Herein, we report the discovery of 2,3-dihydro-1,4-benzoxazines as inhibitors of intrinsic KDR activity (IC50 < 0.1 mu M) and human umbilical vein endothelial cell (HUVEC) proliferation with IC50 < 0.1 mu M. More specifically, compound 16 was identified as a potent (KDR: < 1 nM and HUVEC: 4 nM) and selective inhibitor that exhibited efficacy in angiogenic in vivo models. In addition, this series of molecules is typically well-absorbed orally, further demonstrating the 2,3-dihydro-1,4-benzoxazine moiety. as a promising platform for generating kinase-based antiangiogenic therapeutic agents.
引用
收藏
页码:1695 / 1705
页数:11
相关论文
共 31 条
[1]  
*ADV CHEM DEV INC, CLOGP VAL CALC EMPL
[2]   Sunitinib maleate [J].
Atkins, M ;
Jones, CA ;
Kirkpatrick, P .
NATURE REVIEWS DRUG DISCOVERY, 2006, 5 (04) :279-280
[3]  
Beebe JS, 2003, CANCER RES, V63, P7301
[4]   Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance [J].
Boehm, T ;
Folkman, J ;
Browder, T ;
OReilly, MS .
NATURE, 1997, 390 (6658) :404-407
[5]   New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis [J].
Bold, G ;
Altmann, KH ;
Frei, J ;
Lang, M ;
Manley, PW ;
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, JM .
JOURNAL OF MEDICINAL CHEMISTRY, 2000, 43 (12) :2310-2323
[6]   The role of vascular endothelial growth factor in blood vessel formation [J].
Breier, G ;
Risau, W .
TRENDS IN CELL BIOLOGY, 1996, 6 (12) :454-456
[7]   Angiogenesis in health and disease [J].
Carmeliet, P .
NATURE MEDICINE, 2003, 9 (06) :653-660
[8]  
Ciardiello F, 2003, CLIN CANCER RES, V9, P1546
[9]   Inhibition of interleukin-1 but not tumor necrosis factor suppresses neovascularization in rat models of corneal angiogenesis and adjuvant arthritis [J].
Coxon, A ;
Bolon, B ;
Estrada, J ;
Kaufman, S ;
Scully, S ;
Rattan, A ;
Duryea, D ;
Hu, YL ;
Rex, K ;
Pacheco, E ;
Van, G ;
Zack, D ;
Feige, U .
ARTHRITIS AND RHEUMATISM, 2002, 46 (10) :2604-2612
[10]   Phase II study of doxorubicin and bevacizumab for patients with metastatic soft-tissue sarcomas [J].
D'Adamo, DR ;
Anderson, SE ;
Albritton, K ;
Yamada, J ;
Riedel, E ;
Scheu, K ;
Schwartz, GK ;
Chen, H ;
Maki, RG .
JOURNAL OF CLINICAL ONCOLOGY, 2005, 23 (28) :7135-7142