2. Academic Validation
  3. Exploration and structure-activity relationship research of benzenesulfonamide derivatives as potent TRPV4 inhibitors for treating acute lung injury

Exploration and structure-activity relationship research of benzenesulfonamide derivatives as potent TRPV4 inhibitors for treating acute lung injury

  • Bioorg Chem. 2024 Jun:147:107396. doi: 10.1016/j.bioorg.2024.107396.
Mengyuan Wang 1,  Yuehao Zhang 2,  Xu Cai 3,  Shangze Yang 1,  Shiyang Sun 3,  Sheng Zhou 2,  Weizhen Lv 1,  Na Du 4,  Yan Li 1,  Chao Ma 5,  Kexin Ren 4,  Mingliang Liu 4,  Bowen Tang 5,  Apeng Wang 4,  Xingjuan Chen 6,  Pengyun Li 7,  Kai Lv 8,  Zhibing Zheng 3
Affiliations

Affiliations

  • 1 Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710072, China.
  • 2 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Department of Pharmaceutical Chemistry, School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China.
  • 3 National Engineering Research Center for Strategic Drugs, Beijing Institute of Pharmacology and Toxicology Institution, Beijing 100850, China.
  • 4 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 5 MindRank AI Ltd., Hangzhou 310000, China.
  • 6 Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710072, China. Electronic address: xjchen@nwpu.edu.
  • 7 National Engineering Research Center for Strategic Drugs, Beijing Institute of Pharmacology and Toxicology Institution, Beijing 100850, China. Electronic address: bnuhuaxuelpy@163.com.
  • 8 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: lvkai@imb.pumc.edu.cn.
PMID: 38705108 DOI: 10.1016/j.bioorg.2024.107396
Abstract

RN-9893, a TRPV4 antagonist identified by Renovis Inc., showcased notable inhibition of TRPV4 channels. This research involved synthesizing and evaluating three series of RN-9893 analogues for their TRPV4 inhibitory efficacy. Notably, compounds 1b and 1f displayed a 2.9 to 4.5-fold increase in inhibitory potency against TRPV4 (IC50 = 0.71 ± 0.21 μM and 0.46 ± 0.08 μM, respectively) in vitro, in comparison to RN-9893 (IC50 = 2.07 ± 0.90 μM). Both compounds also significantly outperformed RN-9893 in TRPV4 current inhibition rates (87.6 % and 83.2 % at 10 μM, against RN-9893's 49.4 %). For the first time, these RN-9893 analogues were profiled in an in vivo mouse model, where intraperitoneal injections of 1b or 1f at 10 mg/kg notably mitigated symptoms of acute lung injury induced by lipopolysaccharide (LPS). These outcomes indicate that compounds 1b and 1f are promising candidates for acute lung injury treatment.

Keywords

Acute lung injury; Antagonist; Calcium influx; Endothelial barrier; TRPV4.

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