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

• Published in: European journal of medicinal chemistry 2025-02, Vol.283, Article 117117
• Main Authors: Jiang, Bei-Er, He, Ying, Chen, Jie, Jiang, Xing-Wu, Qiu, Zi-Liang, Liang, Qiu-Wen, Gao, Xin-Long, Zhang, Han-Kun, Tian, Hai-Gang, Liu, Ming-Yao, Lu, Wei-Qiang, Yu, Li-Fang
• Format: Article
• Language: English
• Subjects: 5-aryl-pyrazole-3-carboxamide derivatives; CB2 receptor; Colitis
• ISSN: 0223-5234
• DOI: 10.1016/j.ejmech.2024.117117

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 (EC50, CB2 = 16.2 nM, EC50, 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. [Display omitted] •A new series of 5-aryl-pyrazole-3-carboxamides as selective CB2 receptor agonists were designed and synthesized.•Structure-based optimization and structure-activity relationship study were comprehensively conducted.•33 showed high potency and selectivity at CB2 and exerted significant therapeutic effects on DSS-induced colitis in vivo.