The discovery of quinoline derivatives, as NF-κB inducing kinase (NIK) inhibitors with anti-inflammatory effects in vitro, low toxicities against T cell growth. (1st January 2021)

• Record Type: Journal Article
• Authors: Song, Jianing; Zhu, Yuqin; Zu, Weidong; Duan, Chunqi; Xu, Junyu; Jiang, Fei; Wang, Xinren; Li, Shuwen; Liu, Chenhe; Gao, Qianqian; Li, Hongmei; Zhang, Yanmin; Tang, Weifang; Lu, Tao; Chen, Yadong
• Is Part Of: Bioorganic & medicinal chemistry. Volume 29(2021)
• Publication Date: 2021-01-01
• Subjects: NIK Nuclear factor kappa-B inducing kinase -- NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells -- TNFSFR Tumor necrosis factor superfamily receptor -- CD40 Cluster of differentiation 40 -- CD40L Cluster of differentiation 40 ligand -- TRAF3 Tumor necrosis factor receptor-associated factor 3 -- BAFF B-cell activating factor -- BAFF-R B-cell activating factor receptor -- Fn14 (TWEAK-R or TNFRSF12A) Tumor necrosis factor receptor superfamily member 12A -- TRAF2-cIAPs Tumor necrosis factor receptor (TNFR)-associated factor 2-Cellular Inhibitor of apoptosis proteins -- IKKα IκB kinase α -- IMQ Imiquimod; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115856
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: NIK is a critical regulatory protein of the non-classical NF-kB pathway, and its dysregulated activation has been proved to be one of the pathogenic factors in a variety of autoimmune diseases and inflammatory diseases. Nevertheless, its corresponding development of inhibitors faces many obstacles, including the lack of structure types of known inhibitors, immature activity evaluation methods of compounds in vitro. In this study, a series of quinoline derivatives were obtained through rational design and chemical synthesis. Among them, the representative compounds 17c and 24c have excellent inhibitory activities on LPS-induced macrophage (J774) nitric oxide release and anti-Con A-stimulated primary T cell proliferation. This evaluation method has good universality and overcomes the obstacles mentioned above, which are faced by the current inhibitor research to a certain extent. Besides, the compound's toxicity against the growth of T cells under non-stress conditions was evaluated, for the first time, as an indicator for the investigation to avoid potential safety risks. Pharmacokinetic properties evaluation of the less toxic compound 24c confirmed its good metabolic behavior (especially oral properties, F% = 21.7%), and subsequent development value.