title: Novel 2,3-dihydro-1,4-benzoxazines as potent and orally bioavailable inhibitors of tumor-driven angiogenesis.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Cambridge, MA 02139, USA. daniel.la@amgen.com
authors.forename: Daniel S
authors.initials: DS
authors.lastname: La
authors.forename: Julie
authors.initials: J
authors.lastname: Belzile
authors.forename: James V
authors.initials: JV
authors.lastname: Bready
authors.forename: Angela
authors.initials: A
authors.lastname: Coxon
authors.forename: Thomas
authors.initials: T
authors.lastname: DeMelfi
authors.forename: Nicholas
authors.initials: N
authors.lastname: Doerr
authors.forename: Juan
authors.initials: J
authors.lastname: Estrada
authors.forename: Julie C
authors.initials: JC
authors.lastname: Flynn
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Flynn
authors.forename: Russell F
authors.initials: RF
authors.lastname: Graceffa
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Harriman
authors.forename: Jay F
authors.initials: JF
authors.lastname: Larrow
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Long
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Martin
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Morrison
authors.forename: Vinod F
authors.initials: VF
authors.lastname: Patel
authors.forename: Philip M
authors.initials: PM
authors.lastname: Roveto
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Weiss
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Whittington
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Teffera
authors.forename: Zhiyang
authors.initials: Z
authors.lastname: Zhao
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Polverino
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Harmange
mesh_terms: 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
chemical_list: D020533:Angiogenesis Inhibitors; D048588:Benzoxazines; D008024:Ligands; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2