Design, synthesis, and biological evaluations of 5-aryl-pyrazole-3-carboxamide derivatives as selective CB2 receptor agonists for the treatment of colitis

Bei-Er Jiang; Ying He; Jie Chen; Xing-Wu Jiang; Zi-Liang Qiu; Qiu-Wen Liang; Xin-Long Gao; Han-Kun Zhang; Hai-Gang Tian; Ming-Yao Liu; Wei-Qiang Lu; Li-Fang Yu

doi:10.1016/j.ejmech.2024.117117

Design, synthesis, and biological evaluations of 5-aryl-pyrazole-3-carboxamide derivatives as selective CB2 receptor agonists for the treatment of colitis

Eur J Med Chem. 2025 Feb 5:283:117117. doi: 10.1016/j.ejmech.2024.117117. Epub 2024 Dec 2.

Authors

Bei-Er Jiang¹, Ying He², Jie Chen³, Xing-Wu Jiang⁴, Zi-Liang Qiu⁴, Qiu-Wen Liang⁴, Xin-Long Gao², Han-Kun Zhang⁴, Hai-Gang Tian³, Ming-Yao Liu⁴, Wei-Qiang Lu⁵, Li-Fang Yu⁶

Affiliations

¹ Naval Medical Center, Naval Medical University, 800 Xiangyin Road, Shanghai, 200433, PR China; Drug Discovery Unit, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, PR China.
² Naval Medical Center, Naval Medical University, 800 Xiangyin Road, Shanghai, 200433, PR China.
³ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, PR China.
⁴ Drug Discovery Unit, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, PR China.
⁵ Drug Discovery Unit, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, PR China. Electronic address: wqlu@bio.ecnu.edu.cn.
⁶ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, PR China. Electronic address: lfyu@sat.ecnu.edu.cn.

PMID: 39653620
DOI: 10.1016/j.ejmech.2024.117117

Abstract

Synthetic CB2 receptor agonists exhibit great potential in the treatment of neurodegenerative diseases, chronic and neuropathic pain, cancer, and inflammation-associated pathologies while avoiding adverse psychoactive effects caused by interactions with CB1 receptors. Herein, a class of 5-aryl-pyrazole-3-carboxamide derivatives was thus designed, synthesized, and biologically evaluated. Among the compounds tested, compound 33, one of the most potent leads, showed a remarkably high potency and selectivity at the CB2 receptor (EC_{50, CB2} = 16.2 nM, EC_{50, CB1} > 10⁵ nM). Furthermore, 33 treatment significantly attenuate colon inflammation in a dextran sodium sulfate (DSS)-induced mouse model of colitis, supporting that CB2 receptor agonists might serve as potential therapeutics for treating colitis.

Keywords: 5-aryl-pyrazole-3-carboxamide derivatives; CB2 receptor; Colitis.

MeSH terms

Animals
Colitis* / chemically induced
Colitis* / drug therapy
Dextran Sulfate*
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Design*
Humans
Male
Mice
Mice, Inbred C57BL
Molecular Structure
Pyrazoles* / chemical synthesis
Pyrazoles* / chemistry
Pyrazoles* / pharmacology
Receptor, Cannabinoid, CB2* / agonists
Receptor, Cannabinoid, CB2* / metabolism
Structure-Activity Relationship

Substances

Receptor, Cannabinoid, CB2
Pyrazoles
Dextran Sulfate