Journal of Medicinal Chemistry p. 132 - 146 (2016)
Update date:2022-08-03
Topics:
Bold, Guido
Schnell, Christian
Furet, Pascal
McSheehy, Paul
Brüggen, Josef
Mestan, Jürgen
Manley, Paul W.
Drückes, Peter
Burglin, Marion
Dürler, Ursula
Loretan, Jacqueline
Reuter, Robert
Wartmann, Markus
Theuer, Andreas
Bauer-Probst, Beatrice
Martiny-Baron, Georg
Allegrini, Peter
Goepfert, Arnaud
Wood, Jeanette
Littlewood-Evans, Amanda
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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