title: Arylphthalazines as potent, and orally bioavailable inhibitors of VEGFR-2.
abstract: 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.
authors.affiliation: ImClone Systems, Inc., 180 Varick Street, New York, NY 10014, USA. mattduncton@yahoo.com
authors.forename: Matthew A J
authors.initials: MA
authors.lastname: Duncton
authors.forename: Eugene L
authors.initials: EL
authors.lastname: Piatnitski Chekler
authors.forename: Reeti
authors.initials: R
authors.lastname: Katoch-Rouse
authors.forename: Dan
authors.initials: D
authors.lastname: Sherman
authors.forename: Wai C
authors.initials: WC
authors.lastname: Wong
authors.forename: Leon M
authors.initials: LM
authors.lastname: Smith
authors.forename: Joel K
authors.initials: JK
authors.lastname: Kawakami
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Kiselyov
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Milligan
authors.forename: Chris
authors.initials: C
authors.lastname: Balagtas
authors.forename: Yaron R
authors.initials: YR
authors.lastname: Hadari
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Sheetal N
authors.initials: SN
authors.lastname: Patel
authors.forename: Robin L
authors.initials: RL
authors.lastname: Rolster
authors.forename: James R
authors.initials: JR
authors.lastname: Tonra
authors.forename: David
authors.initials: D
authors.lastname: Surguladze
authors.forename: Stan
authors.initials: S
authors.lastname: Mitelman
authors.forename: Paul
authors.initials: P
authors.lastname: Kussie
authors.forename: Peter
authors.initials: P
authors.lastname: Bohlen
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: Doody
mesh_terms: 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*
chemical_list: 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