First Discovery of the Dual-Functional Inhibitor Targeting VEGFR/PDGFR/CA II for the Treatment of Neovascular Glaucoma

  • J Med Chem. 2026 Jul 9;69(13):15731-15765. doi: 10.1021/acs.jmedchem.6c00831.
Xiaomeng Xiu  1 ,  Yulong Cheng  1 ,  Jiarao Wang  1 ,  Jiachong Chi  2 ,  Xudong Wang  1 ,  Fangbo Deng  1 ,  Zhenli Li  1 ,  Jingkai Gu  2 ,  Yang Liu  1 ,  Maosheng Cheng  1 ,  Huali Yang  1
Affiliations
  • 1. Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Liaoning, Shenyang 110016, China.
  • 2. Research Center for Drug Metabolism, School of Life Science, Jilin University, Changchun 130012, China.
PMID: 42308467 DOI: 10.1021/acs.jmedchem.6c00831
Abstract

Neovascular glaucoma (NVG) seriously threatens visual, through elevated intraocular pressure (IOP) and intraocular neovascularization. At present, no clinical drug simultaneously lowers IOP and inhibits vascular growth. Moreover, to address the high invasiveness of intravitreal injection and the high systemic toxicity of oral administration, we ultimately discovered the first VEGFR/PDGFR/CA II dual-functional inhibitor H24 for treating NVG that can be administered through the subconjunctival injection. Compared with positive drugs Vorolanib and Acetazolamide, H24 exhibited better inhibitory activity against VEGFR2, PDGFRα/β and CA II Enzymes. Moreover, H24 exhibited potent antiproliferative activity in VEGFR2-BAF3 cells and robust inhibition of angiogenesis in HUVECs. Furthermore, H24 also inhibited the formation of corneal neovascularization in rabbits through multiple signaling pathways. In acute and chronic glaucoma model, H24 significantly reduced the IOP of rabbits. Overall, these findings provided compelling evidence that H24 offers new perspectives in the treatment of NVG.

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