Discovery of highly potent and selective VEGFR2 kinase inhibitors for the treatment of rheumatoid arthritis.

Abstract

Synovial angiogenesis is essential for the development of rheumatoid arthritis (RA). Human vascular endothelial growth factor receptor 2 tyrosine kinase (VEGFR2) is a direct target gene that is notably elevated in RA synovium. Herein, we report the identification of indazole derivatives as a novel class of potent VEGFR2 inhibitors. The most potent compound, compound 25, displayed single-digit nanomolar potency against VEGFR2 in biochemical assays and achieved good selectivity for other protein kinases in the kinome. In addition, compound 25 dose-dependently inhibited the phosphorylation of VEGFR2 in Human Umbilical Vein Endothelial Cells (HUVECs) and showed an anti-angiogenic effect, as evidenced by the inhibition of capillary-like tube formation in vitro. Moreover, compound 25 reduced the severity and development of adjuvant-induced arthritis in rats by inhibiting synovial VEGFR2 phosphorylation and angiogenesis. Overall, these findings provide evidence that compound 25 is a leading potential drug candidate for anti-arthritic and anti-angiogenic therapy.

• Authors: Qingling Chen, Zhuoying Chen, Feilong Li, Haoyu Zha, Wei He, Fei Jiang, Jiamu Wei, Jiajia Xu, Rong Li, Li Cai, Xuesong Liu
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 257 Pg. 115456 (Sep 05 2023) ISSN: 1768-3254 [Electronic] France
• PMID: 37216810 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 Elsevier Masson SAS. All rights reserved.

Chemical References

• Vascular Endothelial Growth Factor A

Topics

• Rats
• Humans
• Animals
• Signal Transduction
• Vascular Endothelial Growth Factor A (metabolism)
• Cell Proliferation
• Neovascularization, Pathologic (drug therapy)
• Human Umbilical Vein Endothelial Cells
• Arthritis, Rheumatoid (drug therapy)