Synthesis and activity of N-(5-hydroxy-3,4,6-trimethylpyridin-2-yl)acetamide analogues as anticolitis agents via dual inhibition of TNF-α- and IL-6-induced cell adhesions

• Published in: Bioorganic & medicinal chemistry letters 2021-07, Vol.43, p.128059-128059, Article 128059
• Main Authors: Karmacharya, Ujjwala, Regmi, Sushil Chandra, Awasthi, Bhuwan Prasad, Chaudhary, Prakash, Kim, Ye Eun, Lee, Iyn-Hyang, Nam, Tae-gyu, Kim, Jung-Ae, Jeong, Byeong-Seon
• Format: Article
• Language: English
• Subjects: Amidopyridinol; IL-6; Inflammatory bowel disease; TNBS-induced colitis; TNF-α
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2021.128059

[Display omitted] Tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) are the critical pro-inflammatory cytokines involved in the pathogenesis of inflammatory bowel disease (IBD). Inhibition of these cytokines and related signaling pathways has been a target for the development of IBD therapeutics. In the current study, 6-acetamido-2,4,5-trimethylpyridin-3-ol (1) and various analogues with the amido scaffold were synthesized and examined for their inhibitory activities in in vitro and in vivo IBD models. The parent compound 1 (1 μM) showed an inhibitory activity against TNF-α- and IL-6-induced adhesion of monocytes to colon epithelial cells, which was similar to tofacitinib (1 μM), a JAK inhibitor, but much better than mesalazine (1,000 μM). All the analogues showed a positive relationship (R2 = 0.8943 in a linear regression model) between the inhibitory activities against TNF-α-induced and those against IL-6-induced adhesion. Compound 2–19 turned out to be the best analogue and showed much better inhibitory activity against TNF-α- and IL-6-induced adhesion of the cells than tofacitinib. In addition, oral administration of compound 1 and 2–19 resulted in a significant suppression of clinical signs of TNBS-induced rat colitis, including weight loss, colon tissue edema, and myeloperoxidase activity, a marker for inflammatory cell infiltration in colon tissues. More importantly, compound 2–19 (1 mg/kg) was more efficacious in ameliorating colitis than compound 1 and sulfasalazine (300 mg/kg), the commonly prescribed oral IBD drug. Taken together, the results suggest that compound 2–19 can be a novel platform for dual-acting IBD drug discovery targeting both TNF-α and IL-6 signaling.