Abstract
Here we report on novel quinoxalines as highly potent and selective inhibitors of the type III receptor tyrosine kinases PDGFR, FLT3, and KIT. These compounds, tricyclic quinoxalines, were generated in order to improve bioavailability over the highly hydrophobic bicyclic quinoxalines. Four of the highly active compounds were characterized in detail and are shown to inhibit PDGFR kinase activity of the isolated receptor as well as in intact cells in the sub-micromolar concentration range. We show that the most active inhibitor (compound
13, AGL 2043) is ∼15–20 times more potent than its isomer (compound
14, AGL 2044). We therefore compared the three dimensional structures of the two compounds by X-ray crystallography. These compounds are also highly effective in blocking the kinase activity of FLT3, KIT, and the oncogenic protein Tel-PDGFR in intact cells. These compounds are potent inhibitors of the proliferation of pig heart smooth muscle cells. They fully arrest the growth of these cells and the effect is fully reversible. The chemical, biochemical and cellular properties of these compounds as well as the solubility properties make them suitable for development as anti-restenosis and anti-cancer agents.
The imidazolo quinoxalines
13 and
14 are potent and selective PDGFR kinase inhibitors where
13 is 20-fold more potent than
14. Compound
13 is highly potent inhibitor of PDGFR signaling, non-toxic and with balanced solubility properties, making it a good drug candidate.