Design, synthesis, and evaluation of orally active benzimidazoles and benzoxazoles as vascular endothelial growth factor-2 receptor tyrosine kinase inhibitors.
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).
Potashman
Michele H
MH
Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139, USA. michelep@amgen.com
Bready
James
J
Coxon
Angela
A
DeMelfi
Thomas M
TM
DiPietro
Lucian
L
Doerr
Nicholas
N
Elbaum
Daniel
D
Estrada
Juan
J
Gallant
Paul
P
Germain
Julie
J
Gu
Yan
Y
Harmange
Jean-Christophe
JC
Kaufman
Stephen A
SA
Kendall
Rick
R
Kim
Joseph L
JL
Kumar
Gondi N
GN
Long
Alexander M
AM
Neervannan
Seshadri
S
Patel
Vinod F
VF
Polverino
Anthony
A
Rose
Paul
P
Plas
Simon van der
Sv
Whittington
Douglas
D
Zanon
Roger
R
Zhao
Huilin
H
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
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