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  3. Discovery of novel diaryl substituted isoquinolin-1(2H)-one derivatives as hypoxia-inducible factor-1 signaling inhibitors for the treatment of rheumatoid arthritis

Discovery of novel diaryl substituted isoquinolin-1(2H)-one derivatives as hypoxia-inducible factor-1 signaling inhibitors for the treatment of rheumatoid arthritis

  • Eur J Med Chem. 2024 May 5:271:116417. doi: 10.1016/j.ejmech.2024.116417.
Li Cai 1,  Peng-Fei Xiong 2,  Tao Li 2,  Chong Li 2,  Zheng-Xing Wu 2,  Ya-Ling Hong 2,  Jin-Ting Wang 3,  Meng-Yue Zhang 4,  Xi-Qin Yang 4,  Qian-Qian Xu 2,  Huan Shi 2,  Qi-Chao Luo 5,  Rong Li 6,  Ming-Ming Liu 7
Affiliations

Affiliations

  • 1 School of Basic Medicine, Anhui Medical University, Hefei, 230032, Anhui Province, PR China; Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui Province, PR China.
  • 2 Anhui Province Key Laboratory of Inflammation and Immune Diseases, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China.
  • 3 The First Clinical Medical College, Anhui Medical University, Hefei, 230032, Anhui Province, PR China.
  • 4 The Second Clinical Medical College, Anhui Medical University, Hefei, 230032, Anhui Province, PR China.
  • 5 School of Basic Medicine, Anhui Medical University, Hefei, 230032, Anhui Province, PR China. Electronic address: luoqichao@ahmu.edu.cn.
  • 6 Anhui Province Key Laboratory of Inflammation and Immune Diseases, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China; Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, 230026, Anhui Province, PR China. Electronic address: aydlirong@163.com.
  • 7 Anhui Province Key Laboratory of Inflammation and Immune Diseases, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China. Electronic address: lmm@ahmu.edu.cn.
PMID: 38688063 DOI: 10.1016/j.ejmech.2024.116417
Abstract

Since synovial hypoxic microenvironment significantly promotes the pathological progress of rheumatoid arthritis (RA), hypoxia-inducible factor 1 (HIF-1) has been emerged as a promising target for the development of novel therapeutic agents for RA treatment. In this study, we designed and synthesized a series of diaryl substituted isoquinolin-1(2H)-one derivatives as HIF-1 signaling inhibitors using scaffold-hopping strategy. By modifying the substituents on N-atom and 6-position of isoquinolin-1-one, we discovered compound 17q with the most potent activities against HIF-1 (IC50 = 0.55 μM) in a hypoxia-reactive element (HRE) luciferase reporter assay. Further pharmacological studies revealed that 17q concentration-dependently blocked hypoxia-induced HIF-1α protein accumulation, reduced inflammation response, inhibited cellular invasiveness and promoted VHL-dependent HIF-1α degradation in human RA synovial cell line. Moreover, 17q improved the pathological injury of ankle joints, decreased angiogenesis and attenuated inflammation response in the adjuvant-induced arthritis (AIA) rat model, indicating the promising therapeutic potential of compound 17q as an effective HIF-1 inhibitor for RA therapy.

Keywords

Anti-angiogenesis; Anti-inflammation; Hypoxia-inducible factor 1; Isoquinolin-1(2H)-One; Rheumatoid arthritis.

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