Structurally Minimalized and Druglike TGase2 Inhibitors Based on 7-Aminoquinoline-5,8-dione Scaffolds for the Treatment of Diabetic Retinopathy

  • J Med Chem. 2024 Nov 14;67(21):19716-19735. doi: 10.1021/acs.jmedchem.4c02081.
Jihee Kang  1 ,  Hye-Yoon Jeon  2  3 ,  Jieon Lee  1 ,  Seri Bae  1 ,  Ga Young Park  1 ,  Kyoung-Jin Min  1 ,  Jeongmin Joo  1 ,  Ah-Jun Lee  2 ,  Hyo-Ji Kim  1 ,  Chun Young Im  1 ,  Eun-Bin Kim  2 ,  Ji Hun Lee  1 ,  Ji Sun Hwang  1 ,  Seungju Lee  1 ,  Jee-Young Lee  1 ,  Pauline Navals  4 ,  Jeffrey W Keillor  4 ,  Kwon-Soo Ha  2 ,  Minsoo Song  1
Affiliations
  • 1. New Drug Discovery Center (NDDC), Daegu Gyeongbuk Medical Innovation Foundation (K-MEDI hub), 80 Cheombok-ro Dong-gu, Daegu 41061, Korea.
  • 2. Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Kangwon-do 24341, Korea.
  • 3. Scripps Korea Antibody Institute, Kangwon National University Chuncheon Campus, Chuncheon, Kangwon-do 24341, Korea.
  • 4. Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Ontario K1N 6N5, Canada.
PMID: 39445793 DOI: 10.1021/acs.jmedchem.4c02081
Abstract

Diabetic retinopathy is a disease that can cause vision loss leading to blindness in people with diabetes. Improved methods to treat and prevent vision loss in diabetic patients are in high demand owing to limited current treatment procedures. Herein, we report a new class of Transglutaminase 2 (TGase2) inhibitors for the treatment of diabetic retinopathy based on 7-aminoquinoline-5,8-dione derivatives. 7-Amino-2-phenylquinoline-5,8-dione 11 and 7-amino-2-{4-[(1-methylpiperidin-4-yl)oxy]phenyl}quinoline-5,8-dione 23 exhibited potent inhibitory activities against TGase2 in a fibrinogen array-based on-chip TGase2 activity assay and in an in situ assay in human retinal microvascular endothelial cells, with IC50 values of 5.88 and 1.12 μM in vitro, and 0.09 and 0.07 μM in situ, respectively. Pharmacokinetically favorable 7-amino-2-{4-[(1-isopropylpiperidin-4-yl)oxy] phenyl}quinoline-5,8-dione 22 inhibited vascular leakage in the retinas of streptozotocin-induced diabetic mice via oral administration. Results from the AL5 kinetic assay and a molecular docking study suggest that the inhibitors may bind to TGase2 remote from the active site.

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