Potential oral VEGFR2 inhibitors: Treatment of wet age-related macular degeneration.

[Display omitted] • New VEGFR2 inhibitors for the treatment of w-AMD were designed and synthesized. • Compounds 9 , 11 , 12 , 13 , and 16 exhibited stronger activity than Vorolanib in VEGFR2 enzyme inhibition and anti-cell proliferation experiments. • Compound 16 showed minimal cardiotoxicity and hepatotoxicity similar to Vorolanib. • Compound 16 was found to inhibit VEGFR2 phosphorylation in HUVECs in a dose-dependent manner by WB assay. • Compound 16 exhibited remarkable stability in plasma, moderate stability in liver microsomes, and demonstrated acceptable oral bioavailability with an F value of 20.2%. Wet age-related macular degeneration (w-AMD) is one of the leading causes of vision loss in industrialized countries. A large body of evidence suggests that inhibitors targeting VEGFR2 may be effective in the treatment of w-AMD. The identification of an oral VEGFR2 inhibitor for the treatment of w-AMD provides an opportunity for a route of administration other than intravitreal injection. While screening potent VEGFR2 inhibitors at the enzyme and cellular levels, ensuring the safety of the compounds was our primary strategy for screening optimal compounds. Finally, compound 16 was identified, exhibiting enhanced inhibition of VEGFR2 enzyme and proliferation of BaF3-TEL-VEGFR2 cells compared to Vorolanib. Compound 16 had a weak inhibitory effect on human Ether-a-go-go-related gene (hERG) channel currents, showing a cardiac safety profile similar to Vorolanib. Compound 16 showed no significant toxicity to human liver cell LX-2, indicating a liver safety profile similar to Vorolanib. The water solubility of compound 16 was found to be higher than that of Vorolanib when tested at pH = 7.4. In addition, compound 16 was found to inhibit VEGFR2 phosphorylation in human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner by WB assay. Furthermore, the in vitro preliminary evaluation of the drug-like properties of compound 16 showed remarkable plasma stability and moderate liver microsomal stability. Based on in vivo pharmacokinetic studies in ICR mice, compound 16 exhibited acceptable oral bioavailability (F = 20.2 %). Overall, these findings provide evidence that compound 16 is a leading potential oral drug candidate for w-AMD. [ABSTRACT FROM AUTHOR]