2. Academic Validation
  3. Discovery and pharmacological characterization of a novel benzimidazole TRPV4 antagonist with cyanocyclobutyl moiety

Discovery and pharmacological characterization of a novel benzimidazole TRPV4 antagonist with cyanocyclobutyl moiety

  • Eur J Med Chem. 2023 Mar 5;249:115137. doi: 10.1016/j.ejmech.2023.115137.
Chongyi Ai 1,  Zhuang Wang 2,  Pengyun Li 3,  Mengyuan Wang 2,  Wenjuan Zhang 3,  Huijuan Song 4,  Xu Cai 3,  Kai Lv 5,  Xingjuan Chen 6,  Zhibing Zheng 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China; Tianjin Institute of Environmental and Operational Medicine, Tianjin, 300050, China.
  • 2 Institute of Medical Research, Northwestern Polytechnical University, Xi'an, 710072, China.
  • 3 State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China.
  • 4 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • 5 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: lvkai@imb.pumc.edu.cn.
  • 6 Institute of Medical Research, Northwestern Polytechnical University, Xi'an, 710072, China. Electronic address: xjchen@nwpu.edu.cn.
  • 7 State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China. Electronic address: zzbcaptain@aliyun.com.
PMID: 36696767 DOI: 10.1016/j.ejmech.2023.115137
Abstract

GSK-Bz, a TPRV4 antagonist discovered by GSK, displayed potent in vitro TRPV4 inhibition activity, and demonstrated ability to inhibit TRPV4-mediated pulmonary edema in an in vivo rat model. In this study, a series of GSK-Bz derivatives were designed and synthesized based on our previous findings. Compound 2b with cyanocyclobutyl moiety (IC50 = 22.65 nM) was found to be 5.3-fold more potent than GSK-Bz (IC50 = 121.6 nM) in the calcium imaging experiment. Patch-clamp experiments confirmed that compound 2b (IR = 77.1%) also gave significantly improved potency on TRPV4 currents measured at -60 mV. Furthermore, 2b effectively suppressed the permeability response to LPS in HUVEC with negligible cytotoxicity (CC50 > 100 μM). The in vivo protective effects of compounds 2b on acute lung injury were finally assessed in an LPS-induced ALI mice model. Notably, 2b gave better results than HC-067047 against all of the tested indexes (lung W/D ratios, the concentrations of BALF protein and pathological scores), indicating that 2b is a novel and highly potent TRPV4 antagonist which is worth for further development. Currently, evaluation for the drug-like properties of 2b is underway.

Keywords

Acute lung injury; Antagonist; Endothelial permeability; TRPV4.

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