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

• Published in: European journal of medicinal chemistry 2024-05, Vol.271, p.116417-116417, Article 116417
• Main Authors: Cai, Li, Xiong, Peng-Fei, Li, Tao, Li, Chong, Wu, Zheng-Xing, Hong, Ya-Ling, Wang, Jin-Ting, Zhang, Meng-Yue, Yang, Xi-Qin, Xu, Qian-Qian, Shi, Huan, Luo, Qi-Chao, Li, Rong, Liu, Ming-Ming
• Format: Article
• Language: English
• Subjects: Animals; Anti-angiogenesis; Anti-inflammation; Antirheumatic Agents - chemical synthesis; Antirheumatic Agents - chemistry; Antirheumatic Agents - pharmacology; Arthritis, Experimental - drug therapy; Arthritis, Experimental - metabolism; Arthritis, Experimental - pathology; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - metabolism; Arthritis, Rheumatoid - pathology; Dose-Response Relationship, Drug; Drug Discovery; Humans; Hypoxia-inducible factor 1; Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Isoquinolin-1(2H)-One; Isoquinolines - chemical synthesis; Isoquinolines - chemistry; Isoquinolines - pharmacology; Male; Molecular Structure; Rats; Rheumatoid arthritis; Signal Transduction - drug effects; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116417

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. [Display omitted] •A series of isoquinolinone derivatives were designed, synthesized and evaluated for their inhibition on HIF-1 signaling.•17q showed enhanced inhibition on HIF-1 signaling than its parent compound in inflammatory synovial cell line.•17q improved the pathological injury of ankle joints, decreased angiogenesis and attenuated the inflammation in vivo.