1. Academic Validation
  2. A Novel Potent Oral Series of VEGFR2 Inhibitors Abrogate Tumor Growth by Inhibiting Angiogenesis

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

Affiliation

  • 1 Oncology Research, Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
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/KDR/Flk-1) tyrosine kinase inhibitors. In biochemical and cellular assays, the compounds exhibit single-digit nanomolar potency toward VEGFR2/KDR/Flk-1. 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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