Arylphthalazines as potent, and orally bioavailable inhibitors of VEGFR-2

  • Bioorg Med Chem. 2009 Jan 15;17(2):731-40. doi: 10.1016/j.bmc.2008.11.049.
Matthew A J Duncton  1 ,  Eugene L Piatnitski Chekler ,  Reeti Katoch-Rouse ,  Dan Sherman ,  Wai C Wong ,  Leon M Smith 2nd ,  Joel K Kawakami ,  Alexander S Kiselyov ,  Daniel L Milligan ,  Chris Balagtas ,  Yaron R Hadari ,  Ying Wang ,  Sheetal N Patel ,  Robin L Rolster ,  James R Tonra ,  David Surguladze ,  Stan Mitelman ,  Paul Kussie ,  Peter Bohlen ,  Jacqueline F Doody
Affiliations
  • 1. ImClone Systems, Inc., 180 Varick Street, New York, NY 10014, USA. [email protected]
PMID: 19101155 DOI: 10.1016/j.bmc.2008.11.049
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.