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

Chongyi Ai; Zhuang Wang; Pengyun Li; Mengyuan Wang; Wenjuan Zhang; Huijuan Song; Xu Cai; Kai Lv; Xingjuan Chen; Zhibing Zheng

doi:10.1016/j.ejmech.2023.115137

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. Epub 2023 Jan 20.

Authors

Chongyi Ai¹, Zhuang Wang², Pengyun Li³, Mengyuan Wang², Wenjuan Zhang³, Huijuan Song⁴, Xu Cai³, Kai Lv⁵, Xingjuan Chen⁶, Zhibing Zheng⁷

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.

MeSH terms

Animals
Benzimidazoles / pharmacology
Lipopolysaccharides / metabolism
Lipopolysaccharides / pharmacology
Lung / metabolism
Mice
Pulmonary Edema* / metabolism
Pulmonary Edema* / pathology
Rats
TRPV Cation Channels* / metabolism

Substances

TRPV Cation Channels
Lipopolysaccharides
Benzimidazoles
Trpv4 protein, mouse
Trpv4 protein, rat