Discovery of Novel Small-Molecule Antiangiogenesis Agents to Treat Diabetic Retinopathy

  • J Med Chem. 2021 May 13;64(9):5535-5550. doi: 10.1021/acs.jmedchem.0c01965.
Donghwa Kim  1 ,  Sang Won Choi  1 ,  Jihee Cho  1 ,  Jae-Hui Been  1 ,  Kyoungsun Choi  1 ,  Wenzhe Jiang  1 ,  Jaeho Han  1 ,  Jedo Oh  2 ,  Changmin Park  2 ,  Soongyu Choi  2 ,  Songyi Seo  3 ,  Koung Li Kim  3 ,  Wonhee Suh  3 ,  Sang Kook Lee  1 ,  Sanghee Kim  1
Affiliations
  • 1. College of Pharmacy, Seoul National University, Seoul 08826, Korea.
  • 2. Hana Pharmaceutical Co., Pangyo 13486, Korea.
  • 3. Department of Global Innovative Drug, Graduate School of Chung-Ang University, College of Pharmacy, Chung-Ang University, Seoul 06974, Korea.
PMID: 33902285 DOI: 10.1021/acs.jmedchem.0c01965
Abstract

Diabetic retinopathy is the leading cause of blindness which is associated with excessive angiogenesis. Using the structure of wondonin Marine natural products, we previously created a scaffold to develop a novel type of antiangiogenesis agent that possesses minimized cytotoxicity. To overcome its poor pharmaceutical properties, we further modified the structure. A new scaffold was derived in which the stereogenic carbon was changed to nitrogen and the 1,2,3-triazole ring was replaced by an alkyl chain. By comparing the bioactivity versus cytotoxicity, compound 31 was selected, which has improved aqueous solubility and an enhanced selectivity index. Mechanistically, 31 suppressed angiopoietin-2 (ANGPT2) expression induced by high glucose in retinal cells and exhibited in vivo antiangiogenic activity in choroidal neovascularization and oxygen-induced retinopathy mouse models. These results suggest the potential of 31 as a lead to develop antiangiogenic small-molecule drugs to treat diabetic retinopathy and as a chemical tool to elucidate new mechanisms of angiogenesis.