Discovery of novel tricyclic pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine derivatives as VEGFR-2 inhibitors

• We report novel tricyclic-based ATP-competitive VEGFR-2 inhibitors.
• Compound (9d) inhibits VEGFR-2/KDR selectively with IC50 value 2.6 μM.
• Docking studies indicate an important H-bond with Cys917.

In an effort to develop ATP-competitive VEGFR-2 selective inhibitors, a novel series of tricyclic pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine derivatives were designed and synthesized. These compounds were characterized by IR, 1H NMR, 13C NMR, elemental and mass spectral analyses. Docking studies have given a partial insight into the molecular determinants of the activity of this novel series in VEGFR-2 kinase active site. Moreover, these compounds were assessed at 10 μM for their selective inhibitory activities over a panel of 6 human kinases, namely VEGFR-1/Flt-1, VEGFR-2/KDR, EGFR, CDK5/p25, GSK3α and GSK3β. Compound N-(4,6-dimethylthieno[2,3-b]pyridine)-7,9-dimethylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine (9d) exhibited the most potent and selective inhibitory activity against VEGFR-2/KDR over the six human kinases, with an IC50 value 2.6 μM. The identification of this hit candidate could aid the design of new tricyclic-based VEGFR-2 kinase modulators.

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