Novel 2,3-dihydro-1,4-benzoxazines as potent and orally bioavailable inhibitors of tumor-driven angiogenesis.
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 (IC 50 < 0.1 microM) and human umbilical vein endothelial cell (HUVEC) proliferation with IC 50 < 0.1 microM. 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.
La
Daniel S
DS
Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Cambridge, MA 02139, USA. daniel.la@amgen.com
Belzile
Julie
J
Bready
James V
JV
Coxon
Angela
A
DeMelfi
Thomas
T
Doerr
Nicholas
N
Estrada
Juan
J
Flynn
Julie C
JC
Flynn
Shaun R
SR
Graceffa
Russell F
RF
Harriman
Shawn P
SP
Larrow
Jay F
JF
Long
Alexander M
AM
Martin
Matthew W
MW
Morrison
Michael J
MJ
Patel
Vinod F
VF
Roveto
Philip M
PM
Wang
Ling
L
Weiss
Matthew M
MM
Whittington
Douglas A
DA
Teffera
Yohannes
Y
Zhao
Zhiyang
Z
Polverino
Anthony J
AJ
Harmange
Jean-Christophe
JC
D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D000818:Animals; D048588:Benzoxazines / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D001682:Biological Availability; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D016510:Corneal Neovascularization / Q000097:blood; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D008024:Ligands; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D023421:Models, Animal; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D048588:Benzoxazines; D008024:Ligands; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2