Arylphthalazines as potent, and orally bioavailable inhibitors of VEGFR-2.
A series of arylphthalazine derivatives were synthesized and evaluated as antagonists of VEGF receptor II (VEGFR-2). IM-094482 57, which was prepared in two steps from commercially available starting materials, was found to be a potent inhibitor of VEGFR-2 in enzymatic, cellular and mitogenic assays (comparable activity to ZD-6474). Additionally, 57 inhibited the related receptor, VEGF receptor I (VEGFR-1), and showed excellent exposure when dosed orally to female CD-1 mice.
Duncton
Matthew A J
MA
ImClone Systems, Inc., 180 Varick Street, New York, NY 10014, USA. mattduncton@yahoo.com
Piatnitski Chekler
Eugene L
EL
Katoch-Rouse
Reeti
R
Sherman
Dan
D
Wong
Wai C
WC
Smith
Leon M
LM
Kawakami
Joel K
JK
Kiselyov
Alexander S
AS
Milligan
Daniel L
DL
Balagtas
Chris
C
Hadari
Yaron R
YR
Wang
Ying
Y
Patel
Sheetal N
SN
Rolster
Robin L
RL
Tonra
James R
JR
Surguladze
David
D
Mitelman
Stan
S
Kussie
Paul
P
Bohlen
Peter
P
Doody
Jacqueline F
JF
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D005260:Female; D007546:Isoquinolines / Q000138:chemical synthesis / Q000493:pharmacokinetics; D051379:Mice; D008815:Mice, Inbred Strains; D010793:Phthalazines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D010880:Piperidines; D011799:Quinazolines; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
C539299:IM-094482 57; D007546:Isoquinolines; D010793:Phthalazines; D010880:Piperidines; D011799:Quinazolines; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; C452423:vandetanib