title: Design, synthesis, and evaluation of orally active benzimidazoles and benzoxazoles as vascular endothelial growth factor-2 receptor tyrosine kinase inhibitors.
abstract: Inhibition of the VEGF signaling pathway has become a valuable approach in the treatment of cancers. Guided by X-ray crystallography and molecular modeling, a series of 2-aminobenzimidazoles and 2-aminobenzoxazoles were identified as potent inhibitors of VEGFR-2 (KDR) in both enzymatic and HUVEC cellular proliferation assays. In this report we describe the synthesis and structure-activity relationship of a series of 2-aminobenzimidazoles and benzoxazoles, culminating in the identification of benzoxazole 22 as a potent and selective VEGFR-2 inhibitor displaying a good pharmacokinetic profile. Compound 22 demonstrated efficacy in both the murine matrigel model for vascular permeability (79% inhibition observed at 100 mg/kg) and the rat corneal angiogenesis model (ED(50) = 16.3 mg/kg).
authors: Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139, USA. michelep@amgen.com
authors: Michele H
authors: MH
authors: Potashman
authors: James
authors: J
authors: Bready
authors: Angela
authors: A
authors: Coxon
authors: Thomas M
authors: TM
authors: DeMelfi
authors: Lucian
authors: L
authors: DiPietro
authors: Nicholas
authors: N
authors: Doerr
authors: Daniel
authors: D
authors: Elbaum
authors: Juan
authors: J
authors: Estrada
authors: Paul
authors: P
authors: Gallant
authors: Julie
authors: J
authors: Germain
authors: Yan
authors: Y
authors: Gu
authors: Jean-Christophe
authors: JC
authors: Harmange
authors: Stephen A
authors: SA
authors: Kaufman
authors: Rick
authors: R
authors: Kendall
authors: Joseph L
authors: JL
authors: Kim
authors: Gondi N
authors: GN
authors: Kumar
authors: Alexander M
authors: AM
authors: Long
authors: Seshadri
authors: S
authors: Neervannan
authors: Vinod F
authors: VF
authors: Patel
authors: Anthony
authors: A
authors: Polverino
authors: Paul
authors: P
authors: Rose
authors: Simon van der
authors: Sv
authors: Plas
authors: Douglas
authors: D
authors: Whittington
authors: Roger
authors: R
authors: Zanon
authors: Huilin
authors: H
authors: Zhao
mesh_terms: D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001583:Benzoxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D002199:Capillary Permeability / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003315:Cornea / Q000098:blood supply / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014471:Umbilical Veins / Q000166:cytology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: C523906:4-((2-((4-chloro-3-(((1-methyl-2-pyrrolidinyl)methyl)oxy)phenyl)amino)-1,3-benzoxazol-5-yl)oxy)-N-methyl-2-pyridinecarboxamide; D020533:Angiogenesis Inhibitors; D001562:Benzimidazoles; D001583:Benzoxazoles; D011725:Pyridines; D040301:Vascular Endothelial Growth Factor Receptor-2