Daniel L. Milligan

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

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.

4 -(azolylphenyl ) -phthalazin-1 -amines : Novel inhibitors of vegf receptors I and II

Novel potent derivatives of phthalazine are described as ATP‐competitive inhibitors of vascular endothelial growth factor receptors I and II (VEGFR‐1/2). A number of compounds display VEGFR‐2 inhibitory activity reaching that of VatalanibTM3 (IC50 < 100 nm) in an HTRF enzymatic assay. Several derivatives also show good potential for the development as VEGFR‐2 specific inhibitors showing 15–20‐fold selectivity over VEGFR‐1.

1H-1,2,4-triazol-3-yl-anilines: novel potent inhibitors of vascular endothelial growth factor receptors 1 and 2.

Novel derivatives of 1,2,4‐triazoles are described as potent ATP‐competitive inhibitors of vascular endothelial growth factor receptors I and II (VEGFR‐1/2). A number of compounds display VEGFR‐2 inhibitory activity comparable to that of VatalanibTM and VandetanibTM in both homogenous time‐resolved fluorescence enzymatic and cellular assays. Several active molecules feature high intrinsic permeability (>30 × 10−5 cm/min) across Caco‐2 cell monolayer.