Synthesis and evaluation of 6-heteroarylamino-2,4,5-trimethylpyridin-3-ols as inhibitors of TNF-α-induced cell adhesion and inflammatory bowel disease

• Published in: MedChemComm 2018-08, Vol.9 (8), p.1305-1310
• Main Authors: Park, Sang Won, Banskota, Suhrid, Gurung, Pallavi, Jin, You Jin, Kang, Han-Eol, Chaudhary, Chhabi Lal, Lee, Sang Yeul, Jeong, Byeong-Seon, Kim, Jung-Ae, Nam, Tae-Gyu
• Format: Article
• Language: English
• Subjects: Acids; Adhesion; Adhesion tests; Cell adhesion; Cell adhesion & migration; Chemistry; Colon; Cytokines; Epithelial cells; Gastrointestinal tract; Inflammatory bowel disease; Inflammatory bowel diseases; Intercellular adhesion molecule 1; Interleukin 10; Interleukin 6; Intestine; Monocyte chemoattractant protein; Monocyte chemoattractant protein 1; Monocytes; Oral administration; Pathogenesis; Peroxidase; Proteins; Tumor necrosis factor-α
• ISSN: 2040-2503; 2040-2511; 2040-2511
• DOI: 10.1039/c8md00156a

Inflammatory bowel disease (IBD) is an inflammatory disease of the gastrointestinal tract with complex pathogenesis. Here, we synthesized 6-heteroarylamino analogues to inhibit TNF-α-induced adhesion of monocytes to colon epithelial cells which are implicated in the initial inflammation process of IBD. The best analogue, , showed IC = 0.29 μM, which is about five orders of magnitude better than that of 5-aminosalicylic acid (5-ASA), a positive control. Oral administration of and dramatically ameliorated 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colon inflammation in rat. The ameliorating effects were accompanied by a high level of recovery in colon and body weights and in the myeloperoxidase (MPO) level. Consistently, the compounds suppressed the expression of intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein 1 (MCP-1). Moreover, they significantly suppressed the expression of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 while increasing the level of IL-10, an anti-inflammatory cytokine.