Evaluation of a series of naphthamides as potent, orally active vascular endothelial growth factor receptor-2 tyrosine kinase inhibitors.
We have previously shown N-arylnaphthamides can be potent inhibitors of vascular endothelial growth factor receptors (VEGFRs). N-Alkyl and N-unsubstituted naphthamides were prepared and found to yield nanomolar inhibitors of VEGFR-2 (KDR) with an improved selectivity profile against a panel of tyrosine and serine/threonine kinases. The inhibitory activity of this series was retained at the cellular level. Naphthamides 3, 20, and 22 exhibited good pharmacokinetics following oral dosing and showed potent inhibition of VEGF-induced angiogenesis in the rat corneal model. Once-daily oral administration of 22 for 14 days led to 85% inhibition of established HT29 colon cancer and Calu-6 lung cancer xenografts at doses of 10 and 20 mg/kg, respectively.
Weiss
Matthew M
MM
Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Cambridge, MA 02139, USA. mmweiss@amgen.com
Harmange
Jean-Christophe
JC
Polverino
Anthony J
AJ
Bauer
David
D
Berry
Loren
L
Berry
Virginia
V
Borg
George
G
Bready
James
J
Chen
Danlin
D
Choquette
Deborah
D
Coxon
Angela
A
DeMelfi
Tom
T
Doerr
Nicholas
N
Estrada
Juan
J
Flynn
Julie
J
Graceffa
Russell F
RF
Harriman
Shawn P
SP
Kaufman
Stephen
S
La
Daniel S
DS
Long
Alexander
A
Neervannan
Sesha
S
Patel
Vinod F
VF
Potashman
Michele
M
Regal
Kelly
K
Roveto
Phillip M
PM
Schrag
Michael L
ML
Starnes
Charlie
C
Tasker
Andrew
A
Teffera
Yohannes
Y
Whittington
Douglas A
DA
Zanon
Roger
R
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016510:Corneal Neovascularization / Q000097:blood; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000187:drug effects*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D009281:Naphthalenes; D047428:Protein Kinase Inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2