A Novel Potent Oral Series of VEGFR2 Inhibitors Abrogate Tumor Growth by Inhibiting Angiogenesis

  • J Med Chem. 2016 Jan 14;59(1):132-46. doi: 10.1021/acs.jmedchem.5b01582.
Guido Bold  1 ,  Christian Schnell  1 ,  Pascal Furet  1 ,  Paul McSheehy  1 ,  Josef Brüggen  1 ,  Jürgen Mestan  1 ,  Paul W Manley  1 ,  Peter Drückes  1 ,  Marion Burglin  1 ,  Ursula Dürler  1 ,  Jacqueline Loretan  1 ,  Robert Reuter  1 ,  Markus Wartmann  1 ,  Andreas Theuer  1 ,  Beatrice Bauer-Probst  1 ,  Georg Martiny-Baron  1 ,  Peter Allegrini  1 ,  Arnaud Goepfert  1 ,  Jeanette Wood  1 ,  Amanda Littlewood-Evans  1
Affiliations
  • 1. Oncology Research, Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
PMID: 26629594 DOI: 10.1021/acs.jmedchem.5b01582
Abstract

This paper describes the identification of 6-(pyrimidin-4-yloxy)-naphthalene-1-carboxamides as a new class of potent and selective human vascular endothelial growth factor receptor 2 (VEGFR2) tyrosine kinase inhibitors. In biochemical and cellular assays, the compounds exhibit single-digit nanomolar potency toward VEGFR2. Compounds of this series show good exposure in rodents when dosed orally. They potently inhibit VEGF-driven angiogenesis in a chamber model and rodent tumor models at daily doses of less than 3 mg/kg by targeting the tumor vasculature as demonstrated by ELISA for TIE-2 in lysates or by immunohistochemical analysis. This novel series of compounds shows a potential for the treatment of solid Tumors and Other Diseases where angiogenesis plays an important role.

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